BACKGROUND OF THE INVENTION The cellular processes regulating modification and maintenance of protein molecules coordinate their function, conformation, stabilization, and degradation. Each of these processes is mediated by key enzymes or proteins such as kinases, phosphatases, proteases, protease inhibitors, isomerases, transferases, and molecular chaperones.

Kinases Kinases catalyze the transfer of high-energy phosphate groups from adenosine triphosphate (ATP) to target proteins on the hydroxyamino acid residues serine, threonine, or tyrosine. Addition of a phosphate group alters the local charge on the acceptor molecule, causing internal conformational changes and potentially influencing intermolecular contacts. Reversible protein phosphorylation is the ubiquitous strategy used to control many of the intracellular events in eukaryotic cells. It is estimated that more than ten percent of proteins active in a typical mammalian cell are phosphorylated.

Extracellular signals including hormones, neurotransmitters, and growth and differentiation factors can activate kinases, which can occur as cell surface receptors or as the activators of the final effector protein, as well as elsewhere along the signal transduction pathway. Kinases are involved in all aspects of a cell's function, from basic metabolic processes, such as glycolysis, to cell-cycle regulation, differentiation, and communication with the extracellular environment through signal transduction cascades. Inappropriate phosphorylation of proteins in cells has been linked to changes in cell cycle progression and cell differentiation. Changes in the cell cycle have been linked to induction of apoptosis or cancer. Changes in cell differentiation have been linked to diseases and disorders of the reproductive system, immune system, and skeletal muscle.

There are two classes of protein kinases. One class, protein tyrosine kinases (PTKs), phosphorylates tyrosine residues, and the other class, protein serine/threonine kinases (STKs), phosphorylates serine and threonine residues. Some PTKs and STKs possess structural

PROTEIN MODIFICATION AND MAINTENANCE MOLECULES TECHNICAL FIELD The invention relates to novel nucleic acids, protein modification and maintenance molecules encoded by these nucleic acids, and to the use of these nucleic acids and proteins in the diagnosis, treatment, and prevention of gastrointestinal, cardiovascular, autoimmune/inflammatory, cell proliferative, developmental, epithelial, neurological, and reproductive disorders. The invention also relates to the assessment of the effects of exogenous compounds on the expression of nucleic acids and protein modification and maintenance molecules.

BACKGROUND OF THE INVENTION The cellular processes regulating modification and maintenance of protein molecules coordinate their function, conformation, stabilization, and degradation. Each of these processes is mediated by key enzymes or proteins such as kinases, phosphatases, proteases, protease inhibitors, isomerases, transferases, and molecular chaperones.

Kinases Kinases catalyze the transfer of high-energy phosphate groups from adenosine triphosphate (ATP) to target proteins on the hydroxyamino acid residues serine, threonine, or tyrosine. Addition of a phosphate group alters the local charge on the acceptor molecule, causing internal conformational changes and potentially influencing intermolecular contacts. Reversible protein phosphorylation is the ubiquitous strategy used to control many of the intracellular events in eukaryotic cells. It is estimated that more than ten percent of proteins active in a typical mammalian cell are phosphorylated.

Extracellular signals including hormones, neurotransmitters, and growth and differentiation factors can activate kinases, which can occur as cell surface receptors or as the activators of the final effector protein, as well as elsewhere along the signal transduction pathway. Kinases are involved in all aspects of a cell's function, from basic metabolic processes, such as glycolysis, to cell-cycle regulation, differentiation, and communication with the extracellular environment through signal transduction cascades. Inappropriate phosphorylation of proteins in cells has been linked to changes in cell cycle progression and cell differentiation. Changes in the cell cycle have been linked to induction of apoptosis or cancer. Changes in cell differentiation have been linked to diseases and disorders of the reproductive system, immune system, and skeletal muscle.

There are two classes of protein kinases. One class, protein tyrosine kinases (PTKs), phosphorylates tyrosine residues, and the other class, protein serine/threonine kinases (STKs), phosphorylates serine and threonine residues. Some PTKs and STKs possess structural

characteristics of both families and have dual specificity for both tyrosine and serine/threonine residues. Almost all kinases contain a conserved 250-300 amino acid catalytic domain containing specific residues and sequence motifs characteristic of the kinase family. (Reviewed in Hardie, G. and S. Hanks (1995) The Protein Kinase Facts Book, Vol I, Academic Press, San Diego, CA, pp. 17- 20).

Phosphatases Phosphatases hydrolytically remove phosphate groups from proteins. Phosphatases are essential in determining the extent of phosphorylation in the cell and, together with kinases, regulate key cellular processes such as metabolic enzyme activity, proliferation, cell growth and differentiation, cell adhesion, and cell cycle progression. Protein phosphatases are characterized as either serine/threonine-or tyrosine-specific based on their preferred phospho-amino acid substrate. Some phosphatases (DSPs, for dual specificity phosphatases) can act on phosphorylated tyrosine, serine, or threonine residues. The protein serine/threonine phosphatases (PSPs) are important regulators of many cAMP-mediated hormone responses in cells. Protein tyrosine phosphatases (PTPs) play a significant role in cell cycle and cell signaling processes.

Proteases Proteases cleave proteins and peptides at the peptide bond that forms the backbone of the protein or peptide chain. Proteolysis is one of the most important and frequent enzymatic reactions that occurs both within and outside of cells. Proteolysis is responsible for the activation and maturation of nascent polypeptides, the degradation of misfolded and damaged proteins, and the controlled turnover of peptides within the cell. Proteases participate in digestion, endocrine function, tissue remodeling during embryonic development, wound healing, and normal growth. Proteases can play a role in regulatory processes by affecting the half life of regulatory proteins. Proteases are involved in the etiology or progression of disease states such as inflammation, angiogenesis, tumor dispersion and metastasis, cardiovascular disease, neurological disease, and bacterial, parasitic, and viral infections.

Proteases can be categorized on the basis of where they cleave their substrates.

Exopeptidases, which include aminopeptidases, dipeptidyl peptidases, tripeptidases, carboxypeptidases, peptidyl-di-peptidases, dipeptidases, and omega peptidases, cleave residues at the termini of their substrates. Endopeptidases, including serine proteases, cysteine proteases, and metalloproteases, cleave at residues within the peptide. Four principal categories of mammalian proteases have been identified based on active site structure, mechanism of action, and overall three-dimensional structure.

(See Beynon, R. J. and J. S. Bond (1994) Proteolytic Enzymes : A Practical Approach. Oxford University Press, New York NY, pp. 1-5.)

Serine Proteases The serine proteases (SPs) are a large, widespread family of proteolytic enzymes that include the digestive enzymes trypsin and chymotrypsin, components of the complement and blood-clotting cascades, and enzymes that control the degradation and turnover of macromolecules within the cell and in the extracellular matrix. Most of the more than 20 subfamilies can be grouped into six clans, each with a common ancestor. These six clans are hypothesized to have descended from at least four evolutionarily distinct ancestors. SPs are named for the presence of a serine residue found in the active catalytic site of most families. The active site is defined by the catalytic triad, a set of conserved asparagine, histidine, and serine residues critical for catalysis. These residues form a charge relay network that facilitates substrate binding. Other residues outside the active site form an oxyanion hole that stabilizes the tetrahedral transition intermediate formed during catalysis. SPs have a wide range of substrates and can be subdivided into subfamilies on the basis of their substrate specificity. The main subfamilies are named for the residue (s) after which they cleave: trypases (after arginine or lysine), aspases (after aspartate), chymases (after phenylalanine or leucine), metases (methionine), and serases (after serine) (Rawlings, N. D. and A. J. Barrett (1994) Methods Enzymol. 244: 19-61).

Most mammalian serine proteases are synthesized as zymogens, inactive precursors that are activated by proteolysis. For example, trypsinogen is converted to its active form, trypsin, by enteropeptidase. Enteropeptidase is an intestinal protease that removes an N-terminal fragment from trypsinogen. The remaining active fragment is trypsin, which in turn activates the precursors of the other pancreatic enzymes. Likewise, proteolysis of prothrombin, the precursor of thrombin, generates three separate polypeptide fragments. The N-terminal fragment is released while the other two fragments, which comprise active thrombin, remain associated through disulfide bonds.

The two largest SP subfamilies are the chymotrypsin (S1) and subtilisin (S8) families. Some members of the chymotrypsin family contain two structural domains unique to this family. Kringle domains are triple-looped, disulfide cross-linked domains found in varying copy number. Kringle domains are thought to play a role in binding mediators such as membranes, other proteins or phospholipids, and in the regulation of proteolytic activity (PROSITE PDOC00020). Apple domains are 90 amino-acid repeated domains, each containing six conserved cysteines. Three disulfide bonds link the first and sixth, second and fifth, and third and fourth cysteines (PROSITE PDOC00376).

Apple domains are involved in protein-protein interactions. S1 family members include trypsin, chymotrypsin, coagulation factors IX-XII, complement factors B, C, and D, granzymes, kallikrein, and tissue-and urokinase-plasminogen activators. The subtilisin family has members found in the eubacteria, archaebacteria, eukaryotes, and viruses. Subtilisins include the proprotein-processing

endopeptidases kexin and furin and the pituitary prohormone convertases PC1, PC2, PC3, PC6, and PACE4 (Rawlings and Barrett, supra).

SPs have functions in many normal processes and some have been implicated in the etiology or treatment of disease. Enterokinase, the initiator of intestinal digestion, is found in the intestinal brush border, where it cleaves the acidic propeptide from trypsinogen to yield active trypsin (Kitamoto, Y. et al. (1994) Proc. Natl. Acad. Sci. USA 91: 7588-7592). Prolylcarboxypeptidase, a lysosomal serine peptidase that cleaves peptides such as angiotensin II and III and [des-Arg9] bradykinin, shares sequence homology with members of both the serine carboxypeptidase and prolylendopeptidase families (Tan, F. et al. (1993) J. Biol. Chem. 268: 16631-16638). The protease neuropsin may influence synapse formation and neuronal connectivity in the hippocampus in response to neural signaling (Chen, Z. -L. et al. (1995) J. Neurosci. 15: 5088-5097). Tissue plasminogen activator is useful for acute management of stroke (Zivin, J. A. (1999) Neurology 53: 14-19) and myocardial infarction (Ross, A. M. (1999) Clin. Cardiol. 22: 165-171). Some receptors (PAR, for proteinase-activated receptor), highly expressed throughout the digestive tract, are activated by proteolytic cleavage of an extracellular domain. The major agonists for PARs, thrombin, trypsin, and mast cell tryptase, are released in allergy and inflammatory conditions. Control of PAR activation by proteases has been suggested as a promising therapeutic target (Vergnolle, N. (2000) Aliment. Pharmacol. Ther. 14: 257- 266; Rice, K. D. et al. (1998) Curr. Pharm. Des. 4: 381-396). Prostate-specific antigen (PSA) is a kallikrein-like serine protease synthesized and secreted exclusively by epithelial cells in the prostate gland. Serum PSA is elevated in prostate cancer and is the most sensitive physiological marker for monitoring cancer progression and response to therapy. PSA can also identify the prostate as the origin of a metastatic tumor (Brawer, M. K. and P. H. Lange (1989) Urology 33: 11-16).

The signal peptidase is a specialized class of SP found in all prokaryotic and eukaryotic cell types that serves in the processing of signal peptides from certain proteins. Signal peptides are amino-terminal domains of a protein which direct the protein from its ribosomal assembly site to a particular cellular or extracellular location. Once the protein has been exported, removal of the signal sequence by a signal peptidase and posttranslational processing, e. g. , glycosylation or phosphorylation, activate the protein. Signal peptidases exist as multi-subunit complexes in both yeast and mammals.

The canine signal peptidase complex is composed of five subunits, all associated with the microsomal membrane and containing hydrophobic regions that span the membrane one or more times (Shelness, G. S. and G. Blobel (1990) J. Biol. Chem. 265: 9512-9519). Some of these subunits serve to fix the complex in its proper position on the membrane while others contain the actual catalytic activity.

Thrombin is a serine protease with an essential role in the process of blood coagulation.

Prothrombin, synthesized in the liver, is converted to active thrombin by Factor Xa. Activated

thrombin then cleaves soluble fibrinogen to polymer-forming fibrin, a primary component of blood clots. In addition, thrombin activates Factor XIIIa, which plays a role in cross-linking fibrin.

Thrombin also stimulates platelet aggregation through proteolytic processing of a 41-residue amino-terminal peptide from protease-activated receptor 1 (PAR-1), formerly known as the thrombin receptor. The cleavage of the amino-terminal peptide exposes a new amino terminus and may also be associated with PAR-1 internalization (Stubbs, M. T. and W. Bode (1994) Curr. Opin. Struct. Biol.

4: 823-832; and Ofoso, F. A. et al. (1998) Biochem. J. 336: 283-285). In addition to stimulating platelet activation through cleavage of the PAR-1 receptor, thrombin also induces platelet aggregation following cleavage of glycoprotein V, also on the surface of platelets. Glycoprotein V appears to be the major thrombin substrate on intact platelets. Platelets deficient for glycoprotein V are hypersensitive to thrombin, which is still required to cleave PAR-1. While platelet aggregation is required for normal hemostasis in mammals, excessive platelet aggregation can result in arterial thrombosis, atherosclerotic arteries, acute myocardial infarction, and stroke (Ramakrishnan, V. et al.

(1999) Proc. Natl. Acad. Sci. U. S. A. 96: 13336-13341 and references within).

Proteases in another family have a serine in their active site and are dependent on the hydrolysis of ATP for their activity. These proteases contain proteolytic core domains and regulatory ATPase domains which can be identified by the presence of the P-loop, an ATP/GTP-binding motif (PROSITE PDOC00803). Members of this family include the eukaryotic mitochondrial matrix proteases, Clp protease and the proteasome. Clp protease was originally found in plant chloroplasts but is believed to be widespread in both prokaryotic and eukaryotic cells. The gene for early-onset torsion dystonia encodes a protein related to Clp protease (Ozelius, L. J. et al. (1998) Adv. Neurol.

78: 93-105).

The proteasome is an intracellular protease complex found in some bacteria and in all eukaryotic cells, and plays an important role in cellular physiology. The proteasome is a large (-2000 kDa) multisubunit complex composed of a central catalytic core containing a variety of proteases arranged in four seven-membered rings with the active sites facing inwards into the central cavity, and terminal ATPase subunits covering the outer port of the cavity and regulating substrate entry (for review, see Schmidt, M. et al. (1999) Curr. Opin. Chem. Biol. 3: 584-591). Proteasomes are associated with the ubiquitin conjugation system (UCS), a major pathway for the degradation of cellular proteins of all types, including proteins that function to activate or repress cellular processes such as transcription and cell cycle progression (Ciechanover, A. (1994) Cell 79: 13-21). In the UCS pathway, proteins targeted for degradation are conjugated to ubiquitin, a small heat stable protein. The ubiquitinated protein is then recognized and degraded by the proteasome. The resultant ubiquitin- peptide complex is hydrolyzed by a ubiquitin carboxyl terminal hydrolase, and free ubiquitin is released

for reutilization by the UCS. Ubiquitin-proteasome systems are implicated in the degradation of mitotic cyclic kinases, oncoproteins, tumor suppressor genes (p53), cell surface receptors associated with signal transduction, transcriptional regulators, and mutated or damaged proteins (Ciechanover, supra). This pathway has been implicated in a number of diseases, including cystic fibrosis, Angelman's syndrome, and Liddle syndrome (reviewed in Schwartz, A. L. and A. Ciechanover (1999) Annu. Rev. Med. 50: 57-74). A murine proto-oncogene, Unp, encodes a nuclear ubiquitin protease whose overexpression leads to oncogenic transformation of NIH3T3 cells. The human homolog of this gene is consistently elevated in small cell tumors and adenocarcinomas of the lung (Gray, D. A.

(1995) Oncogene 10: 2179-2183). Ubiquitin carboxyl terminal hydrolase is involved in the differentiation of a lymphoblastic leukemia cell line to a non-dividing mature state (Maki, A. et al.

(1996) Differentiation 60: 59-66). In neurons, ubiquitin carboxyl terminal hydrolase (PGP 9.5) expression is strong in the abnormal structures that occur in human neurodegenerative diseases (Lowe, J. et al. (1990) J. Pathol. 161: 153-160).

Cysteine Proteases Cysteine proteases (CPs) are involved in diverse cellular processes ranging from the processing of precursor proteins to intracellular degradation. Nearly half of the CPs known are present only in viruses. CPs have a cysteine as the major catalytic residue at the active site where catalysis proceeds via a thioester intermediate and is facilitated by nearby histidine and asparagine residues. A glutamine residue is also important, as it helps to form an oxyanion hole. Two important CP families include the papain-like enzymes (Cl) and the calpains (C2). Papain-like family members are generally lysosomal or secreted and therefore are synthesized with signal peptides as well as propeptides. Most members bear a conserved motif in the propeptide that may have structural significance (Karrer, K. M. et al. (1993) Proc. Natl. Acad. Sci. USA 90: 3063-3067). Three- dimensional structures of papain family members show a bilobed molecule with the catalytic site located between the two lobes. Papains include cathepsins B, C, H, L, and S, certain plant allergens and dipeptidyl peptidase (for a review, see Rawlings, N. D. and A. J. Barrett (1994) Methods Enzymol.

244: 461-486).

Some CPs are expressed ubiquitously, while others are produced only by cells of the immune system. Of particular note, CPs are produced by monocytes, macrophages and other cells which migrate to sites of inflammation and secrete molecules involved in tissue repair. Overabundance of these repair molecules plays a role in certain disorders. In autoimmune diseases such as rheumatoid arthritis, secretion of the cysteine peptidase cathepsin C degrades collagen, laminin, elastin and other structural proteins found in the extracellular matrix of bones. Bone weakened by such degradation is also more susceptible to tumor invasion and metastasis. Cathepsin L expression may also contribute

to the influx of mononuclear cells which exacerbates the destruction of the rheumatoid synovium (Keyszer, G. M. (1995) Arthritis Rheum. 38: 976-984).

Calpains are calcium-dependent cytosolic endopeptidases which contain both an N-terminal catalytic domain and a C-terminal calcium-binding domain. Calpain is expressed as a proenzyme heterodimer consisting of a catalytic subunit unique to each isoform and a regulatory subunit common to different isoforms. Each subunit bears a calcium-binding EF-hand domain. The regulatory subunit also contains a hydrophobic glycine-rich domain that allows the enzyme to associate with cell membranes. Calpains are activated by increased intracellular calcium concentration, which induces a change in conformation and limited autolysis. The resultant active molecule requires a lower calcium concentration for its activity (Chan, S. L. and M. P. Mattson (1999) J. Neurosci. Res. 58: 167-190).

Calpain expression is predominantly neuronal, although it is present in other tissues. Several chronic neurodegenerative disorders, including ALS, Parkinson's disease and Alzheimer's disease are associated with increased calpain expression (Chan and Mattson, supra). Calpain-mediated breakdown of the cytoskeleton has been proposed to contribute to brain damage resulting from head injury (McCracken, E. et al. (1999) J. Neurotrauma 16: 749-761). Calpain-3 is predominantly expressed in skeletal muscle, and is responsible for limb-girdle muscular dystrophy type 2A (Minami, N. et al. (1999) J. Neurol. Sci. 171: 31-37).

Another family of thiol proteases is the caspases, which are involved in the initiation and execution phases of apoptosis. A pro-apoptotic signal can activate initiator caspases that trigger a proteolytic caspase cascade, leading to the hydrolysis of target proteins and the classic apoptotic death of the cell. Two active site residues, a cysteine and a histidine, have been implicated in the catalytic mechanism. Caspases are among the most specific endopeptidases, cleaving after aspartate residues.

Caspases are synthesized as inactive zymogens consisting of one large (p20) and one small (plO) subunit separated by a small spacer region, and a variable N-terminal prodomain. This prodomain interacts with cofactors that can positively or negatively affect apoptosis. An activating signal causes autoproteolytic cleavage of a specific aspartate residue (D297 in the caspase-1 numbering convention) and removal of the spacer and prodomain, leaving a plO/p20 heterodimer. Two of these heterodimers interact via their small subunits to form the catalytically active tetramer. The long prodomains of some caspase family members have been shown to promote dimerization and auto-processing of procaspases. Some caspases contain a"death effector domain"in their prodomain by which they can be recruited into self-activating complexes with other caspases and FADD protein associated death receptors or the TNF receptor complex. In addition, two dimers from different caspase family members can associate, changing the substrate specificity of the resultant tetramer. Endogenous caspase inhibitors (inhibitor of apoptosis proteins, or IAPs) also exist. All these interactions have clear

effects on the control of apoptosis (reviewed in Chan and Mattson, supra ; Salveson, G. S. and V. M.

Dixit (1999) Proc. Natl. Acad. Sci. USA 96: 10964-10967).

Caspases have been implicated in a number of diseases. Mice lacking some caspases have severe nervous system defects due to failed apoptosis in the neuroepithelium and suffer early lethality.

Others show severe defects in the inflammatory response, as caspases are responsible for processing IL-lb and possibly other inflammatory cytokines (Chan and Mattson, supra). Cowpox virus and baculoviruses target caspases to avoid the death of their host cell and promote successful infection. In addition, increases in inappropriate apoptosis have been reported in AIDS, neurodegenerative diseases and ischemic injury, while a decrease in cell death is associated with cancer (Salveson and Dixit, supra ; Thompson, C. B. (1995) Science 267: 1456-1462).

Aspartvl proteases Aspartyl proteases (APs) include the lysosomal proteases cathepsins D and E, as well as chymosin, renin, and the gastric pepsins. Most retroviruses encode an AP, usually as part of the pol polyprotein. APs, also called acid proteases, are monomeric enzymes consisting of two domains, each domain containing one half of the active site with its own catalytic aspartic acid residue. APs are most active in the range of pH 2-3, at which one of the aspartate residues is ionized and the other neutral. The pepsin family of APs contains many secreted enzymes, and all are likely to be synthesized with signal peptides and propeptides. Most family members have three disulfide loops, the first-5 residue loop following the first aspartate, the second 5-6 residue loop preceding the second aspartate, and the third and largest loop occurring toward the C terminus. Retropepsins, on the other hand, are analogous to a single domain of pepsin, and become active as homodimers with each retropepsin monomer contributing one half of the active site. Retropepsins are required for processing the viral polyproteins.

APs have roles in various tissues, and some have been associated with disease. Renin mediates the first step in processing the hormone angiotensin, which is responsible for regulating electrolyte balance and blood pressure (reviewed in Crews, D. E. and S. R. Williams (1999) Hum. Biol.

71: 475-503). Abnormal regulation and expression of cathepsins are evident in various inflammatory disease states. Expression of cathepsin D is elevated in synovial tissues from patients with rheumatoid arthritis and osteoarthritis. The increased expression and differential regulation of the cathepsins are linked to the metastatic potential of a variety of cancers (Chambers, A. F. et al. (1993) Crit. Rev.

Oncol. 4: 95-114).

Metalloproteases Metalloproteases require a metal ion for activity, usually manganese or zinc. Examples of manganese metalloenzymes include aminopeptidase P and human proline dipeptidase (PEPD).

Aminopeptidase P can degrade bradykinin, a nonapeptide activated in a variety of inflammatory responses. Aminopeptidase P has been implicated in coronary ischemia/reperfusion injury.

Administration of aminopeptidase P inhibitors has been shown to have a cardioprotective effect in rats (Ersahin, C. et al (1999) J. Cardiovasc. Pharmacol. 34: 604-611).

Most zinc-dependent metalloproteases share a common sequence in the zinc-binding domain.

The active site is made up of two histidines which act as zinc ligands and a catalytic glutamic acid C- terminal to the first histidine. Proteins containing this signature sequence are known as the metzincins and include aminopeptidase N, angiotensin-converting enzyme, neurolysin, the matrix metalloproteases and the adamalysins (ADAMS). An alternate sequence is found in the zinc carboxypeptidases, in which all three conserved residues-two histidines and a glutamic acid-are involved in zinc binding.

A number of the neutral metalloendopeptidases, including angiotensin converting enzyme and the aminopeptidases, are involved in the metabolism of peptide hormones. High aminopeptidase B activity, for example, is found in the adrenal glands and neurohypophyses of hypertensive rats (Prieto, I. et al. (1998) Horm. Metab. Res. 30: 246-248). Oligopeptidase M/neurolysin can hydrolyze bradykinin as well as neurotensin (Serizawa, A. et al. (1995) J. Biol. Chem 270: 2092-2098).

Neurotensin is a vasoactive peptide that can act as a neurotransmitter in the brain, where it has been implicated in limiting food intake (Tritos, N. A. et al. (1999) Neuropeptides 33: 339-349).

The matrix metalloproteases (MMPs) are a family of at least 23 enzymes that can degrade components of the extracellular matrix (ECM). They are Zn2+ endopeptidases with an N-terminal catalytic domain. Nearly all members of the family have a hinge peptide and a C-terminal domain which can bind to substrate molecules in the ECM or to inhibitors produced by the tissue (TIMPs, for tissue inhibitor of metalloprotease ; Campbell, I. L. and A. Pagenstecher (1999) Trends Neurosci.

22: 285-287). The presence of fibronectin-like repeats, transmembrane domains, or C-terminal hemopexinase-like domains can be used to separate MMPs into collagenase, gelatinase, stromelysin and membrane-type MMP subfamilies. In the inactive form, the Zn2+ ion in the active site interacts with a cysteine in the pro-sequence. Activating factors disrupt the Zn2+-cysteine interaction, or "cysteine switch, "exposing the active site. This partially activates the enzyme, which then cleaves off its propeptide and becomes fully active. MMPs are often activated by the serine proteases plasmin and furin. MMPs are often regulated by stoichiometric, noncovalent interactions with inhibitors; the balance of protease to inhibitor, then, is very important in tissue homeostasis (reviewed in Yong, V. W. et al. (1998) Trends Neurosci. 21: 75-80).

MMPs are implicated in a number of diseases including osteoarthritis (Mitchell, P. et al.

(1996) J. Clin. Invest. 97: 761-768), atherosclerotic plaque rupture (Sukhova, G. K. et al. (1999) Circulation 99: 2503-2509), aortic aneurysm (Schneiderman, J. et al. (1998) Am. J. Path. 152: 703-710),

non-healing wounds (Saarialho-Kere, U. K. et al. (1994) J. Clin. Invest. 94: 79-88), bone resorption (Blavier, L. and J. M. Delaisse (1995) J. Cell Sci. 108: 3649-3659), age-related macular degeneration (Steen, B. et al. (1998) Invest. Ophthalmol. Vis. Sci. 39: 2194-2200), emphysema (Finlay, G. A. et al.

(1997) Thorax 52: 502-506), myocardial infarction (Rohde, L. E. et al. (1999) Circulation 99: 3063-3070) and dilated cardiomyopathy (Thomas, C. V. et al. (1998) Circulation 97: 1708-1715). MMP inhibitors prevent metastasis of mammary carcinoma and experimental tumors in rat, and Lewis lung carcinoma, hemangioma, and human ovarian carcinoma xenografts in mice (Eccles, S. A. et al. (1996) Cancer Res. 56: 2815-2822; Anderson et al. (1996) Cancer Res. 56: 715-718; Volpert, O. V. et al. (1996) J.

Clin. Invest. 98: 671-679; Taraboletti, G. et al. (1995) J. Natl. Cancer Inst. 87: 293-298; Davies, B. et al. (1993) Cancer Res. 53: 2087-2091). MMPs may be active in Alzheimer's disease. A number of MMPs are implicated in multiple sclerosis, and administration of MMP inhibitors can relieve some of its symptoms (reviewed in Yong et al., supra).

Another family of metalloproteases is the ADAMs, for A Disintegrin and Metalloprotease Domain, which they share with their close relatives the adamalysins, snake venom metalloproteases (SVMPs). ADAMs combine features of both cell surface adhesion molecules and proteases, containing a prodomain, a protease domain, a disintegrin domain, a cysteine rich domain, an epidermal growth factor repeat, a transmembrane domain, and a cytoplasmic tail. The first three domains listed above are also found in the SVMPs. The ADAMs possess four potential functions: proteolysis, adhesion, signaling and fusion. The ADAMs share the metzincin zinc binding sequence and are inhibited by some MMP antagonists such as TIMP-1.

ADAMs are implicated in such processes as sperm-egg binding and fusion, myoblast fusion, and protein-ectodomain processing or shedding of cytokines, cytokine receptors, adhesion proteins and other extracellular protein domains (Schlöndorff, J. and C. P. Blobel (1999) J. Cell. Sci. 112: 3603- 3617). The Kuzbanian protein cleaves a substrate in the NOTCH pathway (possibly NOTCH itself), activating the program for lateral inhibition in Drosophila neural development. Two ADAMs, TACE (ADAM 17) and ADAM 10, are proposed to have analogous roles in the processing of amyloid precursor protein in the brain (Schlondorff and Blobel, supra). TACE has also been identified as the TNF activating enzyme (Black, R. A. et al. (1997) Nature 385: 729-733). TNF is a pleiotropic cytokine that is important in mobilizing host defenses in response to infection or trauma, but can cause severe damage in excess and is often overproduced in autoimmune disease. TACE cleaves membrane- bound pro-TNF to release a soluble form. Other ADAMs may be involved in a similar type of processing of other membrane-bound molecules.

Proteins of the ADAMTS sub-family have all of the features of ADAM family metalloproteases and contain an additional thrombospondin domain (TS). The prototypic ADAMTS

was identified in mouse, and found to be expressed in heart and kidney and upregulated by proinflammatory stimuli (Kuno, K. et al. (1997) J. Biol. Chem. 272: 556-562). To date eleven members are recognized by the Human Genome Organization (HUGO; http ://www. gene. ucl. ac. uk/users/hester/adamts. html#Approved). Members of this family have the ability to degrade aggrecan, a high molecular weight proteoglycan which provides cartilage with important mechanical properties including compressibility, and which is lost during the development of arthritis. Enzymes which degrade aggrecan are thus considered attractive targets to prevent and slow the degradation of articular cartilage (See, e. g. , Tortorella, M. D. (1999) Science 284: 1664-1666; Abbaszade, 1. (1999) J. Biol. Chem. 274: 23443-23450). Other members are reported to have antiangiogenic potential (Kuno et al., supra) and/or procollagen processing (Colige, A. et al. (1997) Proc. Natl. Acad. Sci. USA 94: 2374-2379).

Protease inhibitors Protease inhibitors and other regulators of protease activity control the activity and effects of proteases. Protease inhibitors have been shown to control pathogenesis in animal models of proteolytic disorders (Murphy, G. (1991) Agents Actions Suppl. 35: 69-76). Low levels of the cystatins, low molecular weight inhibitors of the cysteine proteases, correlate with malignant progression of tumors (Calkins, C. et al. (1995) Biol. Biochem. Hoppe Seyler 376: 71-80). The cystatin superfamily of protease inhibitors is characterized by a particular pattern of linearly arranged and tandemly repeated disulfide loops (Kellermann, J. et al. (1989) J. Biol. Chem. 264: 14121-14128).

Serpins are inhibitors of mammalian plasma serine proteases. Many serpins serve to regulate the blood clotting cascade and/or the complement cascade in mammals. Sp32 is a positive regulator of the mammalian acrosomal protease, acrosin, that binds the proenzyme, proacrosin, and thereby aides in packaging the enzyme into the acrosomal matrix (Baba, T. et al. (1994) J. Biol. Chem. 269: 10133- 10140). The Kunitz family of serine protease inhibitors are characterized by one or more"Kunitz domains"containing a series of cysteine residues that are regularly spaced over approximately 50 amino acid residues and form three intrachain disulfide bonds. Members of this family include aprotinin, tissue factor pathway inhibitor (TFPI-1 and TFPI-2), inter-a-trypsin inhibitor, and bikunin (Marlor, C. W. et al. (1997) J. Biol. Chem. 272: 12202-12208). Members of this family are potent inhibitors (in the nanomolar range) against serine proteases such as kallikrein and plasmin. Aprotinin has clinical utility in reduction of perioperative blood loss.

A major portion of all proteins synthesized in eukaryotic cells are synthesized on the cytosolic surface of the endoplasmic reticulum (ER). Before these immature proteins are distributed to other organelles in the cell or are secreted, they must be transported into the interior lumen of the ER where

post-translational modifications are performed. These modifications include protein folding and the formation of disulfide bonds, and N-linked glycosylations.

Protein Isomerases Protein folding in the ER is aided by two principal types of protein isomerases, protein disulfide isomerase (PDI), and peptidyl-prolyl isomerase (PPI). PDI catalyzes the oxidation of free sulfhydryl groups in cysteine residues to form intramolecular disulfide bonds in proteins. PPI, an enzyme that catalyzes the isomerization of certain proline imidic bonds in oligopeptides and proteins, is considered to govern one of the rate limiting steps in the folding of many proteins to their final functional conformation. The cyclophilins represent a major class of PPI that was originally identified as the major receptor for the immunosuppressive drug cyclosporin A (Handschumacher, R. E. et al. (1984) Science 226: 544-547).

Protein Glycosylation The glycosylation of most soluble secreted and membrane-bound proteins by oligosaccharides linked to asparagine residues in proteins is also performed in the ER. This reaction is catalyzed by a membrane-bound enzyme, oligosaccharyl transferase. Although the exact purpose of this"N-linked" glycosylation is unknown, the presence of oligosaccharides tends to make a glycoprotein resistant to protease digestion. In addition, oligosaccharides attached to cell-surface proteins called selectins are known to function in cell-cell adhesion processes (Alberts, B. et al. (1994) Molecular Biology of the Cell Garland Publishing Co. , New York, NY, p. 608)."O-linked"glycosylation of proteins also occurs in the ER by the addition of N-acetylgalactosamine to the hydroxyl group of a serine or threonine residue followed by the sequential addition of other sugar residues to the first. This process is catalyzed by a series of glycosyltransferases, each specific for a particular donor sugar nucleotide and acceptor molecule (Lodish, H. et al. (1995) Molecular Cell Biology, W. H. Freeman and Co. , New York, NY, pp. 700-708). In many cases, both N-and O-linked oligosaccharides appear to be required for the secretion of proteins or the movement of plasma membrane glycoproteins to the cell surface.

An additional glycosylation mechanism operates in the ER specifically to target lysosomal enzymes to lysosomes and prevent their secretion. Lysosomal enzymes in the ER receive an N-linked oligosaccharide, like plasma membrane and secreted proteins, but are then phosphorylated on one or two mannose residues. The phosphorylation of mannose residues occurs in two steps, the first step being the addition of an N-acetylglucosamine phosphate residue by N-acetylglucosamine phosphotransferase, and the second the removal of the N-acetylglucosamine group by phosphodiesterase. The phosphorylated mannose residue then targets the lysosomal enzyme to a mannose 6-phosphate receptor which transports it to a lysosome vesicle (Lodish et al. supra, pp. 708- 711).

Chaperones Molecular chaperones are proteins that aid in the proper folding of immature proteins and refolding of improperly folded ones, the assembly of protein subunits, and in the transport of unfolded proteins across membranes. Chaperones are also called heat-shock proteins (hsp) because of their tendency to be expressed in dramatically increased amounts following brief exposure of cells to elevated temperatures. This latter property most likely reflects their need in the refolding of proteins that have become denatured by the high temperatures. Chaperones may be divided into several classes according to their location, function, and molecular weight, and include hsp60, TCP1, hsp70, hsp40 (also called DnaJ), and hsp90. For example, hsp90 binds to steroid hormone receptors, represses transcription in the absence of the ligand, and provides proper folding of the ligand-binding domain of the receptor in the presence of the hormone (Burston, S. G. and A. R. Clarke (1995) Essays Biochem. 29: 125-136). Hsp60 and hsp70 chaperones aid in the transport and folding of newly synthesized proteins. Hsp70 acts early in protein folding, binding a newly synthesized protein before it leaves the ribosome and transporting the protein to the mitochondria or ER before releasing the folded protein. Hsp60, along with hsplO, binds misfolded proteins and gives them the opportunity to refold correctly. All chaperones share an affinity for hydrophobic patches on incompletely folded proteins and the ability to hydrolyze ATP. The energy of ATP hydrolysis is used to release the hsp-bound protein in its properly folded state (Alberts et al., supra, pp. 214,571-572).

Expression profiling Microarrays are analytical tools used in bioanalysis. A microarray has a plurality of molecules spatially distributed over, and stably associated with, the surface of a solid support. Microarrays of polypeptides, polynucleotides, and/or antibodies have been developed and find use in a variety of applications, such as gene sequencing, monitoring gene expression, gene mapping, bacterial identification, drug discovery, and combinatorial chemistry.

One area in particular in which microarrays find use is in gene expression analysis. Array technology can provide a simple way to explore the expression of a single polymorphic gene or the expression profile of a large number of related or unrelated genes. When the expression of a single gene is examined, arrays are employed to detect the expression of a specific gene or its variants.

When an expression profile is examined, arrays provide a platform for identifying genes that are tissue specific, are affected by a substance being tested in a toxicology assay, are part of a signaling cascade, carry out housekeeping functions, or are specifically related to a particular genetic predisposition, condition, disease, or disorder.

Breast cancer is the most frequently diagnosed type of cancer in American women and the second most frequent cause of cancer death. The lifetime risk of an American woman developing

breast cancer is 1 in 8, and one-third of women diagnosed with breast cancer die of the disease. A number of risk factors have been identified, including hormonal and genetic factors. One genetic defect associated with breast cancer results in a loss of heterozygosity (LOH) at multiple loci such as p53, Rb, BRCA1, and BRCA2. Another genetic defect is gene amplification involving genes such as c-myc and c-erbB2 (Her2-neu gene). Steroid and growth factor pathways are also altered in breast cancer, notably the estrogen, progesterone, and epidermal growth factor (EGF) pathways. Breast cancer evolves through a multi-step process whereby premalignant mammary epithelial cells undergo a relatively defined sequence of events leading to tumor formation. An early event in tumor development is ductal hyperplasia. Cells undergoing rapid neoplastic growth gradually progress to invasive carcinoma and become metastatic to the lung, bone, and potentially other organs. Variables that may influence the process of tumor progression and malignant transformation include genetic factors, environmental factors, growth factors, and hormones.

The relationship between expression of epidermal growth factor (EGF) and its receptor, EGFR, to human mammary carcinoma has been particularly well studied. (See Khazaie, K. et al.

(1993) Cancer and Metastasis Rev. 12: 255-274, and references cited therein for a review of this area. ) Overexpression of EGFR, particularly coupled with down-regulation of the estrogen receptor, is a marker of poor prognosis in breast cancer patients. In addition, EGFR expression in breast tumor metastases is frequently elevated relative to the primary tumor, suggesting that EGFR is involved in tumor progression and metastasis. This is supported by accumulating evidence that EGF has effects on cell functions related to metastatic potential, such as cell motility, chemotaxis, secretion and differentiation. Changes in expression of other members of the erbB receptor family, of which EGFR is one, have also been implicated in breast cancer. The abundance of erbB receptors, such as HER- 2/neu, HER-3, and HER-4, and their ligands in breast cancer points to their functional importance in the pathogenesis of the disease, and may therefore provide targets for therapy of the disease (Bacus, S. S. et al. (1994) Am. J. Clin. Pathol. 102: S13-S24). Other known markers of breast cancer include a human secreted frizzled protein mRNA that is downregulated in breast tumors; the matrix Gla protein which is overexpressed is human breast carcinoma cells; Drgl or RTP, a gene whose expression is diminished in colon, breast, and prostate tumors; maspin, a tumor suppressor gene downregulated in invasive breast carcinomas; and CaN19, a member of the S100 protein family, all of which are down regulated in mammary carcinoma cells relative to normal mammary epithelial cells (Zhou, Z. et al. (1998) Int. J. Cancer 78: 95-99; Chen, L. et al. (1990) Oncogene 5: 1391-1395; Ulrix, W. et al (1999) FEBS Lett 455: 23-26; Sager, R. et al. (1996) Curr. Top. Microbiol. Immunol. 213: 51- 64; and Lee, S. W. et al. (1992) Proc. Natl. Acad. Sci. USA 89: 2504-2508).

Cell lines derived from human mammary epithelial cells at various stages of breast cancer provide a useful model to study the process of malignant transformation and tumor progression as it has been shown that these cell lines retain many of the properties of their parental tumors for lengthy culture periods (Wistuba, I. I. et al. (1998) Clin. Cancer Res. 4: 2931-2938). Such a model is particularly useful for comparing phenotypic and molecular characteristics of human mammary epithelial cells at various stages of malignant transformation.

Ovarian cancer is the leading cause of death from a gynecologic cancer. The majority of ovarian cancers are derived from epithelial cells, and 70% of patients with epithelial ovarian cancers present with late-stage disease. As a result, the long-term survival rates for this disease is very low.

Identification of early-stage markers for ovarian cancer would significantly increase the survival rate.

Genetic variations involved in ovarian cancer development include mutation of p53 and microsatellite instability. Gene expression patterns likely vary when normal ovary is compared to ovarian tumors.

While soft tissue sarcomas are relatively rare, more than 50% of new patients diagnosed with the disease will die from it. The molecular pathways leading to the development of sarcomas are relatively unknown, due to the rarity of the disease and variation in pathology. Colon cancer evolves through a multi-step process whereby pre-malignant colonocytes undergo a relatively defined sequence of events leading to tumor formation. Several factors participate in the process of tumor progression and malignant transformation including genetic factors, mutations, and selection.

To understand the nature of gene alterations in colorectal cancer, a number of studies have focused on the inherited syndromes. Familial adenomatous polyposis (FAP), is caused by mutations in the adenomatous polyposis coli gene (APC), resulting in truncated or inactive forms of the protein.

This tumor suppressor gene has been mapped to chromosome 5q. Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations in mis-match repair genes. Although hereditary colon cancer syndromes occur in a small percentage of the population and most colorectal cancers are considered sporadic, knowledge from studies of the hereditary syndromes can be generally applied.

For instance, somatic mutations in APC occur in at least 80% of sporadic colon tumors. APC mutations are thought to be the initiating event in the disease. Other mutations occur subsequently.

Approximately 50% of colorectal cancers contain activating mutations in ras, while 85% contain inactivating mutations in p53. Changes in all of these genes lead to gene expression changes in colon cancer.

Lung cancer is the leading cause of cancer death in the United States, affecting more than 100, 000 men and 50,000 women each year. Nearly 90% of the patients diagnosed with lung cancer are cigarette smokers. Tobacco smoke contains thousands of noxious substances that induce carcinogen metabolizing enzymes and covalent DNA adduct formation in the exposed bronchial

epithelium. In nearly 80% of patients diagnosed with lung cancer, metastasis has already occurred.

Most commonly lung cancers metastasize to pleura, brain, bone, pericardium, and liver. This adversely affects the overall five-year survival rate which is 37% for squamous carcinoma, 27% for adenocarcinoma and large cell carcinoma, and less than 1% for small cell carcinomas. Earlier diagnosis and an systematic approach to identification, staging, and treatment could positively affect patient outcome (DeVita et al. (1997) Cancer: Principles and Practice of Oncology, Lippincott- Raven, Philadelphia PA) and Fauci et al. (1998) Harrison's Principals of Internal Medicine, McGraw Hill, New York, NY).

Lung cancers progress through a series of morphologically distinct stages from hyperplasia to invasive carcinoma. Malignant lung cancers are divided into two groups comprising four histopathological classes. The nonsmall cell lung carcinoma (NSCLC) group includes squamous cell carcinomas, adenocarcinomas, and large cell carcinomas and accounts for about 70% of all lung cancer cases. Adenocarcinomas typically arise in the peripheral airways and often form mucin secreting glands. Squamous cell carcinomas typically arise in proximal airways. The histogenesis of squamous cell carcinomas may be related to chronic inflammation and injury to the bronchial epithelium, leading to squamous metaplasia. The small cell lung carcinoma (SCLC) group accounts for about 20% of lung cancer cases. SCLCs typically arise in proximal airways and exhibit a number of paraneoplastic syndromes including inappropriate production of adrenocorticotropin and anti-diuretic hormone.

Lung cancer cells accumulate numerous genetic lesions, many of which are associated with cytologically visible chromosomal aberrations. The high frequency of chromosomal deletions associated with lung cancer may reflect the role of multiple tumor suppressor loci in the etiology of this disease. Several studies report deletions of regions of chromosome 11 in NSCLC (Bepler, G. and Garcia-Blanco, M. A. (1994) Proc. Natl. Acad. Sci. USA 91: 5513-7; Iizuka, M. , et al. (1995) Genes, Chromosomes & Cancer 13: 40-46; Rasio, D. (1995) Cancer Research 55: 3988-91). Deletions in other chromosome arms such as 3p, 9p and 17p are also common. Other frequently observed genetic lesions include overexpression of telomerase, activation of oncogenes such as K-ras and c-myc, and inactivation of tumor suppressor genes such as RB, p53 and pl6 (Toomey, D. et al. (2001) Cancer 92: 2648-57; Zajac-Kaye M. (2001) Lung Cancer 34: S43-6 ; Wright, G. et al. (2000) Current Opinion in Oncology 12: 143-8; Kohno, T. and Yokota, J. (1999) Carcinogenesis 20: 1403-10).

Once cancer cells arise in the prostate, they are stimulated by testosterone to a more rapid growth. Thus, removal of the testes can indirectly reduce both rapid growth and metastasis of the cancer. Over 95 percent of prostatic cancers are adenocarcinomas which originate in the prostatic

acini. The remaining 5 percent are divided between squamous cell and transitional cell carcinomas, both of which arise in the prostatic ducts or other parts of the prostate gland.

As with most tumors, prostate cancer develops through a multistage progression ultimately resulting in an aggressive tumor phenotype. The initial step in tumor progression involves the hyperproliferation of normal luminal and/or basal epithelial cells. Androgen responsive cells become hyperplastic and evolve into early-stage tumors. Although early-stage tumors are often androgen sensitive and respond to androgen ablation, a population of androgen independent cells evolve from the hyperplastic population. These cells represent a more advanced form of prostate tumor that may become invasive and potentially become metastatic to the bone, brain, or lung. A variety of genes may be differentially expressed during tumor progression. For example, loss of heterozygosity (LOH) is frequently observed on chromosome 8p in prostate cancer. Fluorescence in situ hybridization (FISH) revealed a deletion for at least 1 locus on 8p in 29 (69%) tumors, with a significantly higher frequency of the deletion on 8p21. 2-p21.1 in advanced prostate cancer than in localized prostate cancer, implying that deletions on 8p22-p21. 3 play an important role in tumor differentiation, while 8p21. 2-p21. 1 deletion plays a role in progression of prostate cancer (Oba, K. et al. (2001) Cancer Genet. Cytogenet. 124: 20-26).

A primary diagnostic marker for prostate cancer is prostate specific antigen (PSA). PSA is a tissue-specific serine protease almost exclusively produced by prostatic epithelial cells. The quantity of PSA correlates with the number and volume of the prostatic epithelial cells, and consequently, the levels of PSA are an excellent indicator of abnormal prostate growth. Men with prostate cancer exhibit an early linear increase in PSA levels followed by an exponential increase prior to diagnosis.

However, since PSA levels are also influenced by factors such as inflammation, androgen and other growth factors, some scientists maintain that changes in PSA levels are not useful in detecting individual cases of prostate cancer.

Current areas of cancer research provide additional prospects for markers as well as potential therapeutic targets for prostate cancer. Several growth factors have been shown to play a critical role in tumor development, growth, and progression. The growth factors Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), and Tumor Growth Factor alpha (TGFa) are important in the growth of normal as well as hyperproliferative prostate epithelial cells, particularly at early stages of tumor development and progression, and affect signaling pathways in these cells in various ways (Lin J et al.

(1999) Cancer Res. 59: 2891-2897; Putz T et al. (1999) Cancer Res 59: 227-233). The TGF-ß family of growth factors are generally expressed at increased levels in human cancers and the high expression levels in many cases correlates with advanced stages of malignancy and poor survival (Gold LI (1999) Crit Rev Oncog 10: 303-360). Finally, there are human cell lines representing both the

androgen-dependent stage of prostate cancer (LNCap) as well as the androgen-independent, hormone refractory stage of the disease (PC3 and DU-145) that have proved useful in studying gene expression patterns associated with the progression of prostate cancer, and the effects of cell treatments on these expressed genes (Chung TD (1999) Prostate 15: 199-207).

Leukocytes comprise lymphocytes, granulocytes, and monocytes. Lymphocytes include T- and B-cells, which specifically recognize and respond to foreign pathogens. T-cells fight viral infections and activate other leukocytes, while B-cells secrete antibodies that neutralize bacteria and other microbes. Granulocytes and monocytes are primarily migratory, phagocytic cells that exit the bloodstream to fight infection in tissues. Monocytes, which are derived from immature promonocytes, further differentiate into macrophages that engulf and digest microorganisms and damaged or dead cells. Monocytes and macrophages modulate the immune response by secreting signaling molecules such as growth factors and cytokines. Tumor necrosis factor-a (TNF-a), for example, is a macrophage-secreted protein with anti-tumor and anti-viral activity. In addition, monocytes and macrophages are recruited to sites of infection and inflammation by signaling proteins secreted by other leukocytes. The differentiation of the monocyte blood cell lineage can be studied in vitro using cultured cell lines. For example, THP-1 is a human promonocyte cell line that can be activated by treatment with both phorbol ester such as phorbol myristate acetate (PMA), and lipopolysaccharide (LPS). PMA is a broad activator of the protein kinase C-dependent pathways.

The differentiation of the monocyte blood cell lineage can be studied in vitro using cultured cell lines. For example, Jurkat is an acute T-cell leukemia cell line that grows actively in the absence of external stimuli. Jurkat has been extensively used for the study of signalling in human T-cells. Human peripheral blood mononuclear cells (PBMCs) can be classified into discrete cellular populations representing the major cellular components of the immune system. PBMCs contain about 52% lymphocytes (12% B lymphocytes, 40% T lymphocytes {25% CD4+ and 15% CD8+}), 20% NK cells, 25% monocytes, and 3% various cells that include dendritic cells and progenitor cells. The proportions, as well as the biology of these cellular components tend to vary slightly between healthy individuals, depending on factors such as age, gender, past medical history, and genetic background.

PMA is a broad activator of the protein kinase C-dependent pathways. Ionomycin is a calcium ionophore that permits the entry of calcium in the cell, hence increasing the cytosolic calcium concentration. The combination of PMA and ionomycin activates two of the major signaling pathways used by mammalian cells to interact with their environment. In T cells, the combination of PMA and ionomycin mimics the type of secondary signaling events elicited during optimal B cell activation. In PBMCs, the combination of PMA and ionomycin mimics the secondary signaling events elicited during activation of lymphocytes, NK cells, and monocytes.

Human umbilical vein endothelial cells (HUVECs) are a primary cell line derived from the endothelium of the human umbilical vein. HUVECs have been used extensively to study the functional biology of human endothelial cells in vitro. Activation of vascular endothelium is a central event in a wide range of both physiological and pathophysiological processes, such as vascular tone regulation, coagulation and thrombosis, atherosclerosis, and inflammation. Both IFN-y and TNF-a are considered proinflammatory cytokines. Cross-talk can exist between the signal transduction pathways of two cytokines; for example, signal transduction cascades initiated by two different cytokines lead to the activation of NFkB Monocytes are involved in the initiation and maintenance of inflammatory immune responses.

The outer membrane of gram-negative bacteria expresses lipopolysaccharide (LPS) complexes called endotoxins. Toxicity is associated with the lipid component (Lipid A) of LPS, and immunogenicity is associated with the polysaccharide components of LPS. LPS elicits a variety of inflammatory responses, and because it activates complement by the alternative (properdin) pathway, it is often part of the pathology of gram-negative bacterial infections. For the most part, endotoxins remain associated with the cell wall until the bacteria disintegrate. LPS released into the bloodstream by lysing gram- negative bacteria is first bound by certain plasma proteins identified as LPS-binding proteins. The LPS-binding protein complex interacts with CD14 receptors on monocytes, macrophages, B cells, and other types of receptors on endothelial cells. Activation of human B cells with LPS results in mitogenesis as well as immunoglobulin synthesis. In monocytes and macrophages three types of events are triggered during their interaction with LPS: 1) Production of cytokines, including IL-1, IL-6, IL-8, TNF-a, and platelet-activating factor, which stimulate production of prostaglandins and leukotrienes that mediate inflammation and septic shock; 2) Activation of the complement cascade; and 3) Activation of the coagulation cascade.

ECV304 is a cell line derived from the endothelium of the human umbilical vein. This cell model has been extensively used to study the functional biology of human endothelial cells in vitro.

T-cells require two distinct signals to achieve optimal activation: the"antigenic"signal delivered through the binding of the TCR-CD3 complex, and the costimulatory signal delivered through the binding of the CD28 molecules. Upon binding of the TCR-CD3 complex alone, T cells achieve only a partial state of activation. However, it is important to note that the signaling requirements of T- cells depend greatly on the cycling state of those cells.

Interleukin 1 beta (IL-1 (I) is a cytokine associated with acute inflammatory responses and is generally considered the prototypical pro-inflammatory cytokine. However, IL-lß functions are not limited to the inflammatory response since this molecule is involved in processes such as fever induction, metabolic regulation, and bone remodeling. Both cells of the immune system (monocytes,

dendritic cells, NK cells, platelets, and neutrophils) and somatic cells (osteoblasts, neurons, Schwann's cells, oligodendrocytes, and adrenal cortical cells) can produce IL-1 (3. IL-1 (3 has been shown to induce its own production in monocytes; induce the production of adhesion molecules and chemokines in endothelial cells; and in conjunction with IL-12, induce interferon-y production by NK Cells. IL-1 (3 is produced as a single chain pro-molecule that needs to be cleaved by a specialized protease, IL-lp Converting Enzyme (ICE), to acquire its function.

Interleukin 2 (IL-2) is a protein with a variety of immunologic functions, most notably the ability to promote the proliferation and maturation of activated T cells. Some of the biological activities attributed to IL-2 include: induction of secretion of IFN-y and TNF-a and-p from PBMCs ; stimulation of the rate of synthesis of c-myc RNA and transferrin receptor; activation of neutrophils; stimulation of proliferation and maturation of activated helper T cells; stimulation of proliferation of activated and natural killer cells and tumor-infiltrating lymphocytes, as well as enhancement of the ability to kill target cells; induction of IL-2 receptor expression on T cells; stimulation of antibody-producing B cell proliferation.

Interleukin 3 (IL-3) is a pleiotropic factor produced primarily by activated T cells that can stimulate the proliferation and differentiation of pluripotent hematopoietic stem cells and various lineage-committed progenitors. IL-3 also affects the functional activity of mature mast cells, basophils, eosinophils, and macrophages. Because of its multiple functions and targets, IL-3 was originally studied under different names, including mast cell growth factor, P-cell stimulating factor, burst promoting activity, multi-colony stimulating factor, thy-1 inducing factor, and WEHI-3 growth factor. In addition to activated T cells, other cell types such as human thymic epithelial cells, activated murine mast cells, murine keratinocytes, and neurons/astrocytes can also produce IL-3. IL-3 exerts its biological activities by binding to specific cell surface receptors. The high affinity receptor responsible for IL-3 signaling is composed of at least two subunits, an IL-3 specific a-chain that binds IL-3 with low affinity and a common (3-chain that is shared by the IL-5 and GM-CSF high-affinity receptors. Although the P-chain itself does not bind IL-3, it confers high-affinity IL-3 binding in the presence of the a-chain. Receptors for IL-3 are present on bone marrow progenitors, macrophages, mast cells, eosinophils, megakaryocytes, basophils, and various myeloid leukemic cells.

Interleukin 4 (IL-4) is a pleiotropic cytokine produced by activated T cells, mast cells, and basophils. It was initially identified as a B cell differentiation factor (BCDF) and a B cell stimulatory factor (BSF1). Subsequent to the molecular cloning and expression of both human and mouse IL-4, numerous other functions have been ascribed to B cells and other hematopoietic and non- hematopoietic cells including T lymphocytes, monocytes, macrophages, mast cells, myeloid and erythroid progenitors, fibroblasts, endothelial cells, etc. IL-4 exhibits anti-tumor effects both in vivo

and in vitro. Recently, IL-4 was identified as an important regulator for the CD4+ subset (Thl-like vs. Th2-like) development. The biological effects of IL-4 are mediated by the binding of IL-4 to specific cell surface receptors. The functional high-affinity receptor for IL-4 consists of a ligand- binding subunit (IL-4 R) and a second subunit (ß chain) that can modulate the ligand binding affinity of the receptor complex. In certain cell types, the gamma chain of the IL-2 receptor complex is a functional ? chain of the IL-4 receptor complex. Signaling of IL-4 through its receptor leads to the activation of Signal Transducer and Activator of Transcription 6 (STAT6).

Interleukin 5 (IL-5) is a T cell-derived factor that promotes the proliferation, differentiation, and activation of eosinophils. IL-5 has also been known as T cell replacing factor (TRF), B cell growth factor II (BCGFII), B cell differentiation factor m (BCDF m), eosinophil differentiation factor (EDF), and eosinophil colony-stimulating factor (Eo-CSF). IL-5 exerts its activity on target cells by binding to specific cell surface receptors. The functional high-affinity receptor for human IL-5 is composed of a low-affinity IL-5 binding a-subunit and a non-binding common p-subunit that is shared with the high-affinity receptors for GM-CSF and IL-3.

Interleukin 6 (IL-6) is a multifunctional protein that plays important roles in host defense, acute phase reactions, immune responses, and hematopoiesis. According to the type of biological responses being studied, IL-6 was previously named interferon-b2,26-kDa protein, B cell stimulatory factor-2 (BSF-2), hybridoma/plasmacytoma growth factor, hepatocyte stimulating factor, cytotoxic T cell differentiation factor, and macrophage-granulocyte inducing factor 2A (MGI-2A). The IL-6 designation was adopted after these variously named proteins were found to be identical on the basis of their amino acid and/or nucleotide sequences. IL-6 is expressed by a variety of normal and transformed cells including T cells, B cells, monocytes/macrophages, fibroblasts, hepatocytes, keratinocytes, astrocytes, vascular endothelial cells, and various tumor cells. The production of IL-6 is upregulated by numerous signals including mitogenic or antigenic stimulation, LPS, calcium ionophore, IL-1, IL-2, IFN, TNF, PDGF, and viruses. IL-4 and IL-13 inhibit IL-6 expression in monocytes.

Interleukin 7 (IL-7), previously known as pre-B-cell growth factor and lymphopoietin-1, was originally purified on the basis of its ability to promote the proliferation of precursor B-cells. It has been shown that IL-7 can also stimulate the proliferation of thymocytes, T cell progenitors, and mature CD4 + and CD8 + T cells. IL-7 can induce the formation of lymphokine-activated killer (LAK) cells as well as the development of cytotoxic T lymphocytes (CTL). Among myeloid lineage cells, IL-7 can upregulate the production of pro-inflammatory cytokines and stimulate the tumoricidal activity of monocytes/macrophages. IL-7 is expressed by adherent stromal cells from various tissues. IL-7 bioactivities are mediated by the binding of IL-7 to functional high-affinity receptor complexes. The ligand binding subunit (IL-7 R) of the IL-7 receptor complex has been cloned from human and mouse

sources. Recently, the y chain of the IL-2 receptor complex has been shown to be an essential component for IL-7 signal transduction. Both IL-7 R and IL-2 R y are members of the hematopoietin receptor superfamily. Cells known to express IL-7 receptors include pre-B cells, T cells, and bone marrow cells.

Interleukin 8 (IL-8) was originally discovered and purified independently by a number of laboratories as a neutrophil chemotactic and activating factor. It was also referred to as neutrophil chemotactic factor (NCF), neutrophil activating protein (NAP), monocyte-derived neutrophil chemotactic factor (MDNCF), T-lymphocyte chemotactic factor (TCF), granulocyte chemotactic protein (GCP), and leukocyte adhesion inhibitor (LAI). Many cell types, including monocyte/macrophages, T cells, neutrophils, fibroblasts, endothelial cells, keratinocytes, hepatocytes, chondrocytes, and various tumor cell lines can produce L-8 in response to a wide variety of pro- inflammatory stimuli such as exposure to IL-1, TNF, LPS, and viruses. IL-8 is a member of the alpha (C-X-C) subfamily of chemokines, which also includes platelet factor 4, GRO, IP-10, etc. IL-8 is a potent chemoattractant for neutrophils and has a wide range of other pro-inflammatory effects. IL-8 causes degranulation of neutrophil-specific granules and azurophilic granules. IL-8 induces expression of the cell adhesion molecules CD11/CD18 and enhances the adherence of neutrophils to endothelial cells and sub-endothelial matrix proteins. Besides neutrophils, IL-8 is also chemotactic for basophils, T cells, and eosinophils. L-8 has been reported to be a co-mitogen for keratinocytes and was also shown to be an autocrine growth factor for melanoma cells. Recently, IL-8 was reported to be angiogenic both in vivo and in vitro.

Interleukin 10 (L-10), initially designated cytokine synthesis inhibitory factor (CSIF), was originally identified as a product of murine T helper 2 (Th2) clones that inhibited the cytokine production by Thl clones, which are dependent upon stimulation with antigen in the presence of antigen presenting cells (APC). The human homolog of murine IL-10 was subsequently cloned by cross-hybridization. Human L-10 is produced by CD4 + T cell clones as well as by some CD8 + T cell clones. In addition, human B cells, EBV-transformed lymphoblastoid cell lines, and monocytes can also produce IL-10 upon activation. IL-10 is a pleiotrophic cytokine that can exert either immunostimulatory or immunosupressive effects on a variety of cell types. It is a potent immunosuppressant of macrophage functions. In vitro, IL-10 can inhibit the accessory function and antigen-presenting capacity of monocytes by, among other effects, downregulating class II MHC expression. Thus, IL-10 can inhibit monocyte/macrophage-dependent, antigen-specific proliferation of mouse Thl clones as well as human ThO-, Thl-, and Th2-like T cells. IL-10 can also inhibit the monocyte/macrophage-dependent, antigen stimulated cytokine synthesis (especially IFN-y) by human PBMNC and NK cells. Additionally, IL-10 is a potent inhibitor of monocyte/macrophage activation

and its resultant cytotoxic effects. It can suppress the production of numerous cytokines including TNF-a, IL-1, IL-6, and IL-10, as well as the synthesis of superoxide anion, reactive oxygen intermediates, and reactive nitrogen intermediates by activated monocytes/macrophages. As an immunostimulatory cytokine, IL-10 can act on B cells to enhance their viability, cell proliferation, Ig secretion, and class II MHC expression. Aside from B lymphocytes, IL-10 is also a growth co- stimulator for thymocytes and mast cells, as well as an enhancer of cytotoxic T cell development.

Interleukin 12 (IL-12), also known as natural killer cell stimulatory factor (NKSF) or cytotoxic lymphocyte maturation factor (CLMF), is a pleiotropic cytokine originally identified in the medium of activated human B lymphoblastoid cell lines. IL-12 is produced by macrophages and B lymphocytes and has been shown to have multiple effects on T cells and natural killer (NK) cells.

These include inducing production of IFN-y and TNF by resting and activated T and NK cells, enhancing the cytotoxic activity of resting NK and T cells, inducing and synergizing with IL-2 in the generation of lymphokine-activated killer (LAK) cells, acting as a comitogen to stimulate proliferation of resting T cells, and inducing proliferation of activated T and NK cells. Current evidence indicates that IL-12, produced by macrophages in response to infectious agents, is a central mediator of the cell- mediated immune response by its actions on the development, proliferation, and activities of TH1 cells.

In its role as the initiator of cell-mediated immunity, it has been suggested that IL-12 has therapeutic potential as a stimulator of cell-mediated immune responses to microbial pathogens, metastatic cancers, and viral infections such as AIDS.

Interleukin 18 (IL-18), also known as interferon-gamma-inducing factor (IGIF) and IL-1 y, is a recently described cytokine that shares some biologic activities with IL-12 and structural similarities with the IL-1 family of proteins. IL-18 was originally cloned from liver cells and has since been shown to be expressed by monocyte/macrophages, osteoblasts, and keratinocytes. Human IL-18 cDNA encodes a 193 amino acid residue biologically inactive precursor molecule (pro-IL-18) that requires cleavage by a specific protease--ICE--to acquire its function. Like IL-12, human IL-18 has been shown to enhance NK cell activity in PBMC cultures. Human IL-18 has also been found to induce the production of IFN-y and GM-CSF while inhibiting the production of IL-10 by PBMCs. On enriched human T cells, human IL-18 can enhance Thl cytokine production and stimulate cell proliferation via an IL-2-dependent pathway.

Granulocyte Colony Stimulating Factor (G-CSF) is a pleiotropic cytokine best known for its specific effects on the proliferation, differentiation, and activation of hematopoietic cells of the neutrophilic granulocyte lineage. Activated monocytes and macrophages are the primary sources of G-CSF in the body. Fibroblasts, endothelial cells, astrocytes, and bone marrow stromal cells can also produce this cytokine upon activation. In vitro, G-CSF stimulates growth, differentiation, and

functions of cells from the neutrophil lineage. Consistent with its in vitro functions, G-CSF plays important roles in defending against infection, in inflammation and repair, and in maintaining steady state hematopoiesis.

Granulocyte-Monocyte Colony Stimulating Factor (GM-CSF) Granulocyte-monocyte colony stimulating factor (GM-CSF) was first described as a factor that can support the in vitro colony formation of granulocyte-macrophage progenitors. In addition, GM-CSF is a growth factor for erythroid, megakaryocyte, and eosinophil progenitors. Lymphocytes (T and B), monocytes, macrophages, mast cells, endothelial cells, and fibroblasts can produce GM-CSF upon activation. GM- CSF exerts its biological effects by binding to specific cell surface receptors. The high affinity receptors required for human GM-CSF signal transduction are heterodimers consisting of a GM-CSF- specific a chain and a common P chain that is shared by the high-affinity receptors for IL-3 and IL-5.

Interferon gamma (IFN-y), also known as Type II interferon or immune interferon, is a cytokine produced primarily by T-lymphocytes and natural killer cells. IFN-y was originally characterized based on its antiviral activities. The protein also exerts antiproliferative, immunoregulatory, and proinflammatory activities and is thus important in host defense mechanisms.

IFN-y induces the production of cytokines; and upregulates the expression of class I and II MHC antigens, Fc receptor, and leukocyte adhesion molecules. It modulates macrophage effector functions, influences isotype switching, and potentiates the secretion of immunoglobulins by B cells. IFN-y also augments TH1 cell expansion and may be required for TH1 cell differentiation. The IFN-y receptor is present on almost all cell types except mature erythrocytes and has been cloned and characterized.

The IFN-y receptor is structurally related to the recently cloned IL-10 receptor.

Leptin is a protein product of the mouse obesity gene. Mice with mutations in the obesity gene that block the synthesis of leptin tend to be obese and diabetic and exhibit reduced activity, metabolism, and body temperature. Human leptin shares approximately 84% sequence identity with the mouse protein. Human leptin cDNA encodes a 167 amino acid residue protein with a 21 amino acid residue signal sequence that is cleaved to yield the 146 amino acid residue mature protein. The expression of leptin mRNA is restricted to adipose tissue. A high-affinity receptor for leptin (OB-R) with homology to gpl30 and the G-CSF receptor has recently been cloned. OB-R mRNA is expressed in the choroid plexus and in the hypothalamus. OB-R is also an isoform of B219, a sequence that is expressed in at least four isoforms in very primitive hematopoietic cell populations and in a variety of lymphohematopoietic cell lines. The possible roles of leptin in body weight regulation, hematopoiesis, and reproduction are being investigated.

Leukemia inhibitory factor (LIF) was initially identified as a factor that inhibits the proliferation and induces the differentiation to macrophages of the murine myeloid leukemic cell line Ml.

Subsequent to its purification and molecular cloning, LIF was recognized to be a pleiotropic factor with multiple effects on both hematopoietic and non-hematopoietic cells. LIF has overlapping biological functions with OSM, IL-6, IL-11, and CNTF. All these cytokines use gpl30 as a component in their signal transducing receptor complexes. Human LIF cDNA encodes a 202 amino acid residue polypeptide with a 22 amino acid residue signal peptide that is cleaved to yield a 180 amino acid residue mature human LIF.

Tumor Growth Factor beta (TGF-ß) is a stable, multifunctional polypeptide growth factor.

While specific receptors for this protein have been found on almost all mammalian cell types thus far examined, the effect of the molecule varies depending on the cell type and growth conditions.

Generally, TGF-ß is stimulatory for cells of mesenchymal origin and inhibitory for cells of epithelial or neuroectodermal origin. TGF-P has been found in the highest concentration in human platelets and mammalian bone, but is produced by many cell types in smaller amounts.

Tumor necrosis factor alpha (TNF-a), also called cachectin, is produced by neutrophils, activated lymphocytes, macrophages, NK cells, LAK cells, astrocytes, endothelial cells, smooth muscle cells, and some transformed cells. TNF-a occurs as a secreted, soluble form and as a membrane-anchored form, both of which are biologically active. Two types of receptors for TNF-a have been described and virtually all cell types studied show the presence of one or both of these receptor types. TNF-a and TNF-p are extremely pleiotropic factors due to the ubiquity of their receptors, to their ability to activate multiple signal transduction pathways, and to their ability to induce or suppress the expression of a wide number of genes. TNF-a and TNF-P play a critical role in mediation of the inflammatory response and in mediation of resistance to infections and tumor growth.

Osteosarcoma is the most common malignant bone tumor in children. Approximately 80% of patients present with non-metastatic disease. After the diagnosis is made by an initial biopsy, treatment involves the use of 3-4 courses of neoadjuvant chemotherapy before definitive surgery, followed by post-operative chemotherapy. With currently available treatment regimens, approximately 30-40% of patients with non-metastatic disease relapse after therapy. Currently, there is no prognostic factor that can be used at the time of initial diagnosis to predict which patients will have a high risk of relapse. The only significant prognostic factor predicting the outcome in a patient with non-metastatic osteosarcoma is the histopathologic response of the primary tumor resected at the time of definitive surgery. The degree of necrosis in the primary tumor is a reflection of the tumor response to neoadjuvant chemotherapy. A higher degree of necrosis (good or favorable response) is associated with a lower risk of relapse and a better outcome. Patients with a lower degree of necrosis (poor or unfavorable response) have a much higher risk of relapse and poor outcome even after complete resection of the primary tumor. Unfortunately, poor outcome cannot be altered despite

modification of post-operative chemotherapy to account for the resistance of the primary tumor to neoadjuvant chemotherapy. Thus, there is an urgent need to identify prognostic factors that can be used at the time of diagnosis to recognize the subtypes of osteosarcomas that have various risks of relapse, so that more appropriate chemotherapy can be used at the outset to improve the outcome.

We hypothesize that global gene expression analysis is a systematic and unbiased approach to recognize such tumor subtypes.

Characterization of region-specific gene expression in the human brain provides a context and background for molecular neurobiology on a variety of neurological disorders. For example, Alzheimer's disease (AD) is a progressive, neurodestructive process of the human neocortex, characterized by the deterioration of memory and higher cognitive function. A progressive and irreversible brain disorder, AD is characterized by three major pathogenic episodes involving (a) an aberrant processing and deposition of beta-amyloid precursor protein (betaAPP) to form neurotoxic beta-amyloid (betaA) peptides and an aggregated insoluble polymer of betaA that forms the senile plaque, (b) the establishment of intraneuronal neuritic tau pathology yielding widespread deposits of agyrophilic neurofibrillary tangles (NFT) and (c) the initiation and proliferation of a brain-specific inflammatory response. These three seemingly disperse attributes of AD etiopathogenesis are linked by the fact that proinflammatory microglia, reactive astrocytes and their associated cytokines and chemokines are associated with the biology of the microtubule associated protein tau, betaA speciation and aggregation. Missense mutations in the presenilin genes PS1 and PS2, implicated in early onset familial AD, cause abnormal betaAPP processing with resultant overproduction of betaA42 and related neurotoxic peptides. Specific betaA fragments such as betaA42 can further potentiate proinflammatory mechanisms. Expression of the inducible oxidoreductase cyclooxygenase-2 and cytosolic phospholipase A2 (cPLA2) are strongly activated during cerebral ischemia and trauma, epilepsy and AD, indicating the induction of proinflammatory gene pathways as a response to brain injury. Neurotoxic metals such as aluminum and zinc, both implicated in AD etiopathogenesis, and arachidonic acid, a major metabolite of brain cPLA2 activity, each polymerize hyperphosphorylated tau to form NFT-like bundles. Studies have identified a reduced risk for AD in patients aged over 70 years who were previously treated with non-steroidal anti-inflammatory drugs for non-CNS afflictions that include arthritis. (For a review of the interrelationships between the mechanisms of PS1, PS2 and betaAPP gene expression, tau and betaA deposition and the induction, regulation and proliferation in AD of the neuroinflammatory response, see Lukiw W. J, and Bazan N. G. (2000) Neurochem. Res.

2000 25 : 1173-1184).

Tangier disease (TD) is a genetic disorder characterized by near absence of circulating high density lipoprotein (HDL) and the accumulation of cholesterol esters in many tissues, including tonsils,

lymph nodes, liver, spleen, thymus, and intestine. Low levels of HDL represent a clear predictor of premature coronary artery disease and homozygous TD correlates with a four-to six-fold increase in cardiovascular disease compared to controls. HDL plays a cardio-protective role in reverse cholesterol transport, the flux of cholesterol from peripheral cells such as tissue macrophages through plasma lipoproteins to the liver. The HDL protein, apolipoprotein A-1, plays a major role in this process, interacting with the cell surface to remove excess cholesterol and phospholipids. This pathway is severely impaired in TD and the defect lies in a specific gene, the ABC1 transporter. This gene is a member of the family of ATP-binding cassette transporters, which utilize ATP hydrolysis to transport a variety of substrates across membranes.

The human C3A cell line is a clonal derivative of HepG2/C3 (hepatoma cell line, isolated from a 15-year-old male with liver tumor), which was selected for strong contact inhibition of growth. The use of a clonal population enhances the reproducibility of the cells. C3A cells have many characteristics of primary human hepatocytes in culture: i) expression of insulin receptor and insulin- like growth factor II receptor; ii) secretion of a high ratio of serum albumin compared with a- fetoprotein iii) conversion of ammonia to urea and glutamine; iv) metabolism of aromatic amino acids; and v) proliferation in glucose-free and insulin-free medium. The C3A cell line is now well established as an in vitro model of the mature human liver (Mickelson et al. (1995) Hepatology 22: 866- 875; Nagendra et al. (1997) Am J Physiol 272: G408-G416).

Gemfibrozil is a fibric acid antilipemic agent that lowers serum triglycerides and produces favorable changes in lipoproteins. Gemfibrozil is effective in reducing the risk of coronary heart disease in men (Frick, M. H. , et al. (1987) New Engl. J. Med; 317: 1237-1245). The compound can inhibit peripheral lipolysis and decrease hepatic extraction of free fatty acids, which, decreases hepatic triglyceride production. Gemfibrozil also inhibits the synthesis and increases the clearance of apolipoprotein B, a carrier molecule for VLDL. Gemfibrozil has variable effects on LDL cholesterol.

Although it causes moderate reductions in patients with type IIa hyperlipoproteinemia, changes in patients with either type IIb or type IV hyperlipoproteinemia are unpredictable. In general, the HMG- CoA reductase inhibitors are more effective than gemfibrozil in reducing LDL cholesterol. At the molecular level gemfibozil may function as a peroxisome proliferator-activated receptor (PPAR) agonist. Gemfibrozil is rapidly and completely absorbed from the GI tract and undergoes enterohepatic recirculation. Gemfibrozil is metabolized by the liver and excreted by the kidneys, mainly as metabolites, one of which possesses pharmacologic activity. Gemfibozil causes peroxisome proliferation and hepatocarcinogenesis in rats, which is a cause for concern generally for fibric acid derivative drugs. In humans, fibric acid derivatives are known to increase the risk of gall bladder disease although gemfibrozil is better tolerated than other fibrates. The relative safety of gemfibrozil

in humans compared to rodent species including rats may be attributed to differences in metabolism and clearance of the compound in different species (Dix, K. J. , et al. , (1999) Drug Metab. Distrib. 27 (1) 138-146; Thomas, B. F. , et al. , (1999) Drug Metab. Distrib. 27 (1) 147-157).

There is a need in the art for new compositions, including nucleic acids and proteins, for the diagnosis, prevention, and treatment of gastrointestinal, cardiovascular, autoimmune/inflammatory, cell proliferative, developmental, epithelial, neurological, and reproductive disorders.

SUMMARY OF THE INVENTION Various embodiments of the invention provide purified polypeptides, protein modification and maintenance molecules, referred to collectively as'PMMM'and individually as'PMMM-1,' <BR> <BR> <BR> <BR> 'PMMM-2,''PMMM-3,''PMMM-4,''PMMM-5,''PMMM-6,''PMMM-7,''PMMM- 8,''PMMM-<BR> <BR> <BR> <BR> <BR> 9,''PMMM-10,''PMMM-1 1,''PMMM-12,''PMMM-13,''PMMM-14,''PMMM-15,''PMMM-<BR> <BR> <BR> <BR> <BR> <BR> 16,''PMMM-17,''PMMM-18,''PMMM-19,''PMMM-20,''PMMM-21,''PMMM- 22,''PMMM-<BR> <BR> <BR> <BR> <BR> 23,''PMMM-24,''PMMM-25,''PMMM-26,''PMMM-27,''PMMM-28,''PMMM- 29,''PMMM-<BR> <BR> <BR> <BR> <BR> <BR> 30,''PMMM-3 1,''PMMM-32,''PMMM-33,''PMMM-34,''PMMM-35,''PMMM-36,''PMMM-& lt;BR> <BR> <BR> <BR> <BR> <BR> 37,''PMMM-38,''PMMM-39,''PMMM-40,''PMMM-4 1,''PMMM-42,''PMMM-43,''PMMM-<BR> <BR> <BR> <BR> <BR> 44,''PMMM-45,''PMMM-46,''PMMM-47,''PMMM-48,''PMMM-49,''PMMM- 50,''PMMM-<BR> <BR> <BR> <BR> <BR> <BR> 51,''PMMM-52,''PMMM-53,''PMMM-54,''PMMM-55,''PMMM-56,''PMMM- 57,''PMMM-<BR> <BR> <BR> <BR> <BR> <BR> 5 8,''PMMM-59,''PMMM-60,''PMMM-6 1,''PMMM-62,''PMMM-63,''PMMM-64,''PMMM- 65,''PMMM-66,''PMMM-67,''PMMM-68,''PMMM-69,''PMMM-70,'and'PM MM-7 and methods for using these proteins and their encoding polynucleotides for the detection, diagnosis, and treatment of diseases and medical conditions. Embodiments also provide methods for utilizing the purified protein modification and maintenance molecules and/or their encoding polynucleotides for facilitating the drug discovery process, including determination of efficacy, dosage, toxicity, and pharmacology. Related embodiments provide methods for utilizing the purified protein modification and maintenance molecules and/or their encoding polynucleotides for investigating the pathogenesis of diseases and medical conditions.

An embodiment provides an isolated polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO : 1- 71, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, and d) an immunogenic fragment of a polypeptide

having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-71. Another embodiment provides an isolated polypeptide comprising an amino acid sequence of SEQ ID NO: 1-71.

Still another embodiment provides an isolated polynucleotide encoding a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71. In another embodiment, the polynucleotide encodes a polypeptide selected from the group consisting of SEQ ID NO : 1-71. In an alternative embodiment, the polynucleotide is selected from the group consisting of SEQ ID N0 : 72-142.

Still another embodiment provides a recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide encoding a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-71.

Another embodiment provides a cell transformed with the recombinant polynucleotide. Yet another embodiment provides a transgenic organism comprising the recombinant polynucleotide.

Another embodiment provides a method for producing a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71.

The method comprises a) culturing a cell under conditions suitable for expression of the polypeptide, wherein said cell is transformed with a recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide encoding the polypeptide, and b) recovering the polypeptide so expressed.

Yet another embodiment provides an isolated antibody which specifically binds to a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-71.

Still yet another embodiment provides an isolated polynucleotide selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO : 72-142, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical or at least about 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO : 72-142, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a) -d). In other embodiments, the polynucleotide can comprise at least about 20,30, 40, 60,80, or 100 contiguous nucleotides.

Yet another embodiment provides a method for detecting a target polynucleotide in a sample, said target polynucleotide being selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO : 72-142, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical or at least about 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO : 72-142, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a) -d). The method comprises a) hybridizing the sample with a probe comprising at least 20 contiguous nucleotides comprising a sequence complementary to said target polynucleotide in the sample, and which probe specifically hybridizes to said target polynucleotide, under conditions whereby a hybridization complex is formed between said probe and said target polynucleotide or fragments thereof, and b) detecting the presence or absence of said hybridization complex. In a related embodiment, the method can include detecting the amount of the hybridization complex. In still other embodiments, the probe can comprise at least about 20,30, 40,60, 80, or 100 contiguous nucleotides.

Still yet another embodiment provides a method for detecting a target polynucleotide in a sample, said target polynucleotide being selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO : 72-142, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical or at

least about 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO : 72-142, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a) -d). The method comprises a) amplifying said target polynucleotide or fragment thereof using polymerase chain reaction amplification, and b) detecting the presence or absence of said amplified target polynucleotide or fragment thereof. In a related embodiment, the method can include detecting the amount of the amplified target polynucleotide or fragment thereof.

Another embodiment provides a composition comprising an effective amount of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, and a pharmaceutically acceptable excipient. In one embodiment, the composition can comprise an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71. Other embodiments provide a method of treating a disease or condition associated with decreased or abnormal expression of functional PMMM, comprising administering to a patient in need of such treatment the composition.

Yet another embodiment provides a method for screening a compound for effectiveness as an agonist of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-71, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71. The method comprises a) exposing a sample comprising the polypeptide to a compound, and b) detecting agonist activity in the sample. Another embodiment provides a composition comprising an agonist compound identified by the method and a pharmaceutically acceptable excipient. Yet another embodiment provides a method of treating a disease or condition associated with decreased expression of functional PMMM, comprising administering to a patient in need of such treatment the composition.

Still yet another embodiment provides a method for screening a compound for effectiveness as an antagonist of a polypeptide selected from the group consisting of a) a polypeptide comprising an

amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71. The method comprises a) exposing a sample comprising the polypeptide to a compound, and b) detecting antagonist activity in the sample. Another embodiment provides a composition comprising an antagonist compound identified by the method and a pharmaceutically acceptable excipient. Yet another embodiment provides a method of treating a disease or condition associated with overexpression of functional PMMM, comprising administering to a patient in need of such treatment the composition.

Another embodiment provides a method of screening for a compound that specifically binds to a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71. The method comprises a) combining the polypeptide with at least one test compound under suitable conditions, and b) detecting binding of the polypeptide to the test compound, thereby identifying a compound that specifically binds to the polypeptide.

Yet another embodiment provides a method of screening for a compound that modulates the activity of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO : 1-71. The method comprises a) combining the polypeptide with at least one test compound under conditions permissive for the activity of the polypeptide, b) assessing the activity of the polypeptide in the presence of the test compound, and c) comparing the activity of the polypeptide in the presence of the test compound with the activity of the polypeptide in the absence of the test compound, wherein a change in the activity of the polypeptide in

the presence of the test compound is indicative of a compound that modulates the activity of the polypeptide.

Still yet another embodiment provides a method for screening a compound for effectiveness in altering expression of a target polynucleotide, wherein said target polynucleotide comprises a polynucleotide sequence selected from the group consisting of SEQ ID NO : 72-142, the method comprising a) exposing a sample comprising the target polynucleotide to a compound, b) detecting altered expression of the target polynucleotide, and c) comparing the expression of the target polynucleotide in the presence of varying amounts of the compound and in the absence of the compound.

Another embodiment provides a method for assessing toxicity of a test compound, said method comprising a) treating a biological sample containing nucleic acids with the test compound; b) hybridizing the nucleic acids of the treated biological sample with a probe comprising at least 20 contiguous nucleotides of a polynucleotide selected from the group consisting of i) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO : 72-142, ii) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical or at least about 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO : 72-142, iii) a polynucleotide having a sequence complementary to i), iv) a polynucleotide complementary to the polynucleotide of ii), and v) an RNA equivalent of i) -iv). Hybridization occurs under conditions whereby a specific hybridization complex is formed between said probe and a target polynucleotide in the biological sample, said target polynucleotide selected from the group consisting of i) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO : 72-142, ii) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical or at least about 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO : 72-142, iii) a polynucleotide complementary to the polynucleotide of i), iv) a polynucleotide complementary to the polynucleotide of ii), and v) an RNA equivalent of i)-iv).

Alternatively, the target polynucleotide can comprise a fragment of a polynucleotide selected from the group consisting of i) -v) above; c) quantifying the amount of hybridization complex; and d) comparing the amount of hybridization complex in the treated biological sample with the amount of hybridization complex in an untreated biological sample, wherein a difference in the amount of hybridization complex in the treated biological sample is indicative of toxicity of the test compound.

BRIEF DESCRIPTION OF THE TABLES Table 1 summarizes the nomenclature for full length polynucleotide and polypeptide embodiments of the invention.

Table 2 shows the GenBank identification number and annotation of the nearest GenBank homolog, and the PROTEOME database identification numbers and annotations of PROTEOME database homologs, for polypeptide embodiments of the invention. The probability scores for the matches between each polypeptide and its homolog (s) are also shown.

Table 3 shows structural features of polypeptide embodiments, including predicted motifs and domains, along with the methods, algorithms, and searchable databases used for analysis of the polypeptides.

Table 4 lists the cDNA and/or genomic DNA fragments which were used to assemble polynucleotide embodiments, along with selected fragments of the polynucleotides.

Table 5 shows representative cDNA libraries for polynucleotide embodiments.

Table 6 provides an appendix which describes the tissues and vectors used for construction of the cDNA libraries shown in Table 5.

Table 7 shows the tools, programs, and algorithms used to analyze polynucleotides and polypeptides, along with applicable descriptions, references, and threshold parameters.

Table 8 shows single nucleotide polymorphisms found in polynucleotide sequences of the invention, along with allele frequencies in different human populations.

DESCRIPTION OF THE INVENTION Before the present proteins, nucleic acids, and methods are described, it is understood that embodiments of the invention are not limited to the particular machines, instruments, materials, and methods described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the invention.

As used herein and in the appended claims, the singular forms"a,""an,"and"the"include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to"a host cell"includes a plurality of such host cells, and a reference to"an antibody"is a reference to one or more antibodies and equivalents thereof known to those skilled in the art, and so forth.

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs.

Although any machines, materials, and methods similar or equivalent to those described herein can be used to practice or test the present invention, the preferred machines, materials and methods are now described. All publications mentioned herein are cited for the purpose of describing and disclosing the cell lines, protocols, reagents and vectors which are reported in the publications and which might be

used in connection with various embodiments of the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

DEFINITIONS "PMMM"refers to the amino acid sequences of substantially purified PMMM obtained from any species, particularly a mammalian species, including bovine, ovine, porcine, murine, equine, and human, and from any source, whether natural, synthetic, semi-synthetic, or recombinant.

The term"agonist"refers to a molecule which intensifies or mimics the biological activity of PMMM. Agonists may include proteins, nucleic acids, carbohydrates, small molecules, or any other compound or composition which modulates the activity of PMMM either by directly interacting with PMMM or by acting on components of the biological pathway in which PMMM participates.

An"allelic variant"is an alternative form of the gene encoding PMMM. Allelic variants may result from at least one mutation in the nucleic acid sequence and may result in altered mRNAs or in polypeptides whose structure or function may or may not be altered. A gene may have none, one, or many allelic variants of its naturally occurring form. Common mutational changes which give rise to allelic variants are generally ascribed to natural deletions, additions, or substitutions of nucleotides.

Each of these types of changes may occur alone, or in combination with the others, one or more times in a given sequence.

"Altered"nucleic acid sequences encoding PMMM include those sequences with deletions, insertions, or substitutions of different nucleotides, resulting in a polypeptide the same as PMMM or a polypeptide with at least one functional characteristic of PMMM. Included within this definition are polymorphisms which may or may not be readily detectable using a particular oligonucleotide probe of the polynucleotide encoding PMMM, and improper or unexpected hybridization to allelic variants, with a locus other than the normal chromosomal locus for the polynucleotide encoding PMMM. The encoded protein may also be"altered, "and may contain deletions, insertions, or substitutions of amino acid residues which produce a silent change and result in a functionally equivalent PMMM.

Deliberate amino acid substitutions may be made on the basis of one or more similarities in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues, as long as the biological or immunological activity of PMMM is retained. For example, negatively charged amino acids may include aspartic acid and glutamic acid, and positively charged amino acids may include lysine and arginine. Amino acids with uncharged polar side chains having similar hydrophilicity values may include: asparagine and glutamine; and serine and threonine. Amino acids with uncharged side chains having similar hydrophilicity values may include: leucine, isoleucine, and valine; glycine and alanine; and phenylalanine and tyrosine.

The terms"amino acid"and"amino acid sequence"can refer to an oligopeptide, a peptide, a polypeptide, or a protein sequence, or a fragment of any of these, and to naturally occurring or synthetic molecules. Where"amino acid sequence"is recited to refer to a sequence of a naturally occurring protein molecule, "amino acid sequence"and like terms are not meant to limit the amino acid sequence to the complete native amino acid sequence associated with the recited protein molecule.

"Amplification"relates to the production of additional copies of a nucleic acid. Amplification may be carried out using polymerase chain reaction (PCR) technologies or other nucleic acid amplification technologies well known in the art.

The term"antagonist"refers to a molecule which inhibits or attenuates the biological activity of PMMM. Antagonists may include proteins such as antibodies, anticalins, nucleic acids, carbohydrates, small molecules, or any other compound or composition which modulates the activity of PMMM either by directly interacting with PMMM or by acting on components of the biological pathway in which PMMM participates.

The term"antibody"refers to intact immunoglobulin molecules as well as to fragments thereof, such as Fab, F (ab') 2, and Fv fragments, which are capable of binding an epitopic determinant.

Antibodies that bind PMMM polypeptides can be prepared using intact polypeptides or using fragments containing small peptides of interest as the immunizing antigen. The polypeptide or oligopeptide used to immunize an animal (e. g. , a mouse, a rat, or a rabbit) can be derived from the translation of RNA, or synthesized chemically, and can be conjugated to a carrier protein if desired.

Commonly used carriers that are chemically coupled to peptides include bovine serum albumin, thyroglobulin, and keyhole limpet hemocyanin (KLH). The coupled peptide is then used to immunize the animal.

The term"antigenic determinant"refers to that region of a molecule (i. e. , an epitope) that makes contact with a particular antibody. When a protein or a fragment of a protein is used to immunize a host animal, numerous regions of the protein may induce the production of antibodies which bind specifically to antigenic determinants (particular regions or three-dimensional structures on the protein). An antigenic determinant may compete with the intact antigen (i. e. , the immunogen used to elicit the immune response) for binding to an antibody.

The term"aptamer"refers to a nucleic acid or oligonucleotide molecule that binds to a specific molecular target. Aptamers are derived from an in vitro evolutionary process (e. g. , SELEX (Systematic Evolution of Ligands by EXponential Enrichment), described in U. S. Patent No.

5,270, 163), which selects for target-specific aptamer sequences from large combinatorial libraries.

Aptamer compositions may be double-stranded or single-stranded, and may include deoxyribonucleotides, ribonucleotides, nucleotide derivatives, or other nucleotide-like molecules. The

nucleotide components of an aptamer may have modified sugar groups (e. g. , the 2'-OH group of a ribonucleotide may be replaced by 2'-F or 2'-NH2), which may improve a desired property, e. g., resistance to nucleases or longer lifetime in blood. Aptamers may be conjugated to other molecules, e. g. , a high molecular weight carrier to slow clearance of the aptamer from the circulatory system.

Aptamers may be specifically cross-linked to their cognate ligands, e. g. , by photo-activation of a cross-linker (Brody, E. N. and L. Gold (2000) J. Biotechnol. 74: 5-13).

The term"intramer"refers to an aptamer which is expressed in vivo. For example, a vaccinia virus-based RNA expression system has been used to express specific RNA aptamers at high levels in the cytoplasm of leukocytes (Blind, M. et al. (1999) Proc. Natl. Acad. Sci. USA 96: 3606-3610).

The term"spiegelmer"refers to an aptamer which includes L-DNA, L-RNA, or other left- handed nucleotide derivatives or nucleotide-like molecules. Aptamers containing left-handed nucleotides are resistant to degradation by naturally occurring enzymes, which normally act on substrates containing right-handed nucleotides.

The term"antisense"refers to any composition capable of base-pairing with the"sense" (coding) strand of a polynucleotide having a specific nucleic acid sequence. Antisense compositions may include DNA; RNA; peptide nucleic acid (PNA); oligonucleotides having modified backbone linkages such as phosphorothioates, methylphosphonates, or benzylphosphonates; oligonucleotides having modified sugar groups such as 2'-methoxyethyl sugars or 2'-methoxyethoxy sugars; or oligonucleotides having modified bases such as 5-methyl cytosine, 2'-deoxyuracil, or 7-deaza-2'- deoxyguanosine. Antisense molecules may be produced by any method including chemical synthesis or transcription. Once introduced into a cell, the complementary antisense molecule base-pairs with a naturally occurring nucleic acid sequence produced by the cell to form duplexes which block either transcription or translation. The designation"negative"or"minus"can refer to the antisense strand, and the designation"positive"or"plus"can refer to the sense strand of a reference DNA molecule.

The term"biologically active"refers to a protein having structural, regulatory, or biochemical functions of a naturally occurring molecule. Likewise,"immunologically active"or"immunogenic" refers to the capability of the natural, recombinant, or synthetic PMMM, or of any oligopeptide thereof, to induce a specific immune response in appropriate animals or cells and to bind with specific antibodies.

"Complementary"describes the relationship between two single-stranded nucleic acid sequences that anneal by base-pairing. For example, 5'-AGT-3'pairs with its complement, 3'-TCA-5'.

A"composition comprising a given polynucleotide"and a"composition comprising a given polypeptide"can refer to any composition containing the given polynucleotide or polypeptide. The composition may comprise a dry formulation or an aqueous solution. Compositions comprising polynucleotides encoding PMMM or fragments of PMMM may be employed as hybridization probes.

The probes may be stored in freeze-dried form and may be associated with a stabilizing agent such as a carbohydrate. In hybridizations, the probe may be deployed in an aqueous solution containing salts (e. g., NaCI), detergents (e. g. , sodium dodecyl sulfate; SDS), and other components (e. g. , Denhardt's solution, dry milk, salmon sperm DNA, etc.).

"Consensus sequence"refers to a nucleic acid sequence which has been subjected to repeated DNA sequence analysis to resolve uncalled bases, extended using the XL-PCR kit (Applied Biosystems, Foster City CA) in the 5'and/or the 3'direction, and resequenced, or which has been assembled from one or more overlapping cDNA, EST, or genomic DNA fragments using a computer program for fragment assembly, such as the GELVIEW fragment assembly system (Accelrys, Burlington MA) or Phrap (University of Washington, Seattle WA). Some sequences have been both extended and assembled to produce the consensus sequence.

"Conservative amino acid substitutions"are those substitutions that are predicted to least interfere with the properties of the original protein, i. e. , the structure and especially the function of the protein is conserved and not significantly changed by such substitutions. The table below shows amino acids which may be substituted for an original amino acid in a protein and which are regarded as conservative amino acid substitutions.

Original Residue Conservative Substitution Ala Gly, Ser Arg His, Lys Asn Asp, Gln, His Asp Asn, Glu Cys Ala, Ser Gln Asn, Glu, His Glu Asp, Gln, His Gly Ala His Asn, Arg, Gln, Glu Ile Leu, Val Leu Ile, Val Lys Arg, Gln, Glu Met Leu, Ile Phe His, Met, Leu, Trp, Tyr Ser Cys, Thr Thr Ser, Val Trp Phe, Tyr Tyr His, Phe, Trp Val Ile, Leu, Thr

Conservative amino acid substitutions generally maintain (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a beta sheet or alpha helical conformation, (b) the charge or hydrophobicity of the molecule at the site of the substitution, and/or (c) the bulk of the side chain.

A"deletion"refers to a change in the amino acid or nucleotide sequence that results in the absence of one or more amino acid residues or nucleotides.

The term"derivative"refers to a chemically modified polynucleotide or polypeptide.

Chemical modifications of a polynucleotide can include, for example, replacement of hydrogen by an alkyl, acyl, hydroxyl, or amino group. A derivative polynucleotide encodes a polypeptide which retains at least one biological or immunological function of the natural molecule. A derivative polypeptide is one modified by glycosylation, pegylation, or any similar process that retains at least one biological or immunological function of the polypeptide from which it was derived.

A"detectable label"refers to a reporter molecule or enzyme that is capable of generating a measurable signal and is covalently or noncovalently joined to a polynucleotide or polypeptide.

"Differential expression"refers to increased or upregulated; or decreased, downregulated, or absent gene or protein expression, determined by comparing at least two different samples. Such comparisons may be carried out between, for example, a treated and an untreated sample, or a diseased and a normal sample.

"Exon shuffling"refers to the recombination of different coding regions (exons). Since an exon may represent a structural or functional domain of the encoded protein, new proteins may be assembled through the novel reassortment of stable substructures, thus allowing acceleration of the evolution of new protein functions.

A"fragment"is a unique portion of PMMM or a polynucleotide encoding PMMM which can be identical in sequence to, but shorter in length than, the parent sequence. A fragment may comprise up to the entire length of the defined sequence, minus one nucleotide/amino acid residue. For example, a fragment may comprise from about 5 to about 1000 contiguous nucleotides or amino acid residues. A fragment used as a probe, primer, antigen, therapeutic molecule, or for other purposes, may be at least 5,10, 15,16, 20,25, 30,40, 50,60, 75,100, 150,250 or at least 500 contiguous nucleotides or amino acid residues in length. Fragments may be preferentially selected from certain regions of a molecule. For example, a polypeptide fragment may comprise a certain length of contiguous amino acids selected from the first 250 or 500 amino acids (or first 25% or 50%) of a polypeptide as shown in a certain defined sequence. Clearly these lengths are exemplary, and any length that is supported by the specification, including the Sequence Listing, tables, and figures, may be encompassed by the present embodiments.

A fragment of SEQ ID NO : 72-142 can comprise a region of unique polynucleotide sequence that specifically identifies SEQ ID NO : 72-142, for example, as distinct from any other sequence in the genome from which the fragment was obtained. A fragment of SEQ ID NO : 72-142 can be employed in one or more embodiments of methods of the invention, for example, in hybridization and amplification technologies and in analogous methods that distinguish SEQ ID NO : 72-142 from related polynucleotides. The precise length of a fragment of SEQ ID NO : 72-142 and the region of SEQ ID NO : 72-142 to which the fragment corresponds are routinely determinable by one of ordinary skill in the art based on the intended purpose for the fragment.

A fragment of SEQ ID NO : 1-71 is encoded by a fragment of SEQ ID NO : 72-142. A fragment of SEQ ID NO : 1-71 can comprise a region of unique amino acid sequence that specifically identifies SEQ ID NO : 1-71. For example, a fragment of SEQ ID NO : 1-71 can be used as an immunogenic peptide for the development of antibodies that specifically recognize SEQ ID NO : 1-71.

The precise length of a fragment of SEQ ID NO : 1-71 and the region of SEQ ID NO : 1-71 to which the fragment corresponds can be determined based on the intended purpose for the fragment using one or more analytical methods described herein or otherwise known in the art.

A"full length"polynucleotide is one containing at least a translation initiation codon (e. g., methionine) followed by an open reading frame and a translation termination codon. A"full length" polynucleotide sequence encodes a"full length"polypeptide sequence.

"Homology"refers to sequence similarity or, alternatively, sequence identity, between two or more polynucleotide sequences or two or more polypeptide sequences.

The terms"percent identity"and"% identity, "as applied to polynucleotide sequences, refer to the percentage of identical nucleotide matches between at least two polynucleotide sequences aligned using a standardized algorithm. Such an algorithm may insert, in a standardized and reproducible way, gaps in the sequences being compared in order to optimize alignment between two sequences, and therefore achieve a more meaningful comparison of the two sequences.

Percent identity between polynucleotide sequences may be determined using one or more computer algorithms or programs known in the art or described herein. For example, percent identity can be determined using the default parameters of the CLUSTAL V algorithm as incorporated into the MEGALIGN version 3.12e sequence alignment program. This program is part of the LASERGENE software package, a suite of molecular biological analysis programs (DNASTAR, Madison WI). CLUSTAL V is described in Higgins, D. G. and P. M. Sharp (1989; CABIOS 5 : 151- 153) and in Higgins, D. G. et al. (1992; CABIOS 8: 189-191). For pairwise alignments of polynucleotide sequences, the default parameters are set as follows: Ktuple=2, gap penalty=5, window=4, and"diagonals saved"=4. The"weighted"residue weight table is selected as the default.

Alternatively, a suite of commonly used and freely available sequence comparison algorithms which can be used is provided by the National Center for Biotechnology Information (NCBI) Basic Local Alignment Search Tool (BLAST) (Altschul, S. F. et al. (1990) J. Mol. Biol. 215: 403-410), which is available from several sources, including the NCBI, Bethesda, MD, and on the Internet at http ://www. ncbi. nlm. nih. gov/BLAST/. The BLAST software suite includes various sequence analysis programs including"blastn, "that is used to align a known polynucleotide sequence with other polynucleotide sequences from a variety of databases. Also available is a tool called"BLAST 2 Sequences"that is used for direct pairwise comparison of two nucleotide sequences. "BLAST 2 Sequences"can be accessed and used interactively at http://www. ncbi. nlm. nih. gov/gorf/bl2. html. The "BLAST 2 Sequences"tool can be used for both blastn and blastp (discussed below). BLAST programs are commonly used with gap and other parameters set to default settings. For example, to compare two nucleotide sequences, one may use blastn with the"BLAST 2 Sequences"tool Version 2.0. 12 (April-21-2000) set at default parameters. Such default parameters may be, for example: Matrix : BLOSUM62 Rewardfor match : 1 Penalty for mismatch :-2 Open Gap : 5 and Extension Gap : 2 penalties Gap x drop-off : 50 Expect : 10 Word Size : 11 Filter : on Percent identity may be measured over the length of an entire defined sequence, for example, as defined by a particular SEQ ID number, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined sequence, for instance, a fragment of at least 20, at least 30, at least 40, at least 50, at least 70, at least 100, or at least 200 contiguous nucleotides. Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in the tables, figures, or Sequence Listing, may be used to describe a length over which percentage identity may be measured.

Nucleic acid sequences that do not show a high degree of identity may nevertheless encode similar amino acid sequences due to the degeneracy of the genetic code. It is understood that changes in a nucleic acid sequence can be made using this degeneracy to produce multiple nucleic acid sequences that all encode substantially the same protein.

The phrases"percent identity"and"% identity, "as applied to polypeptide sequences, refer to the percentage of identical residue matches between at least two polypeptide sequences aligned using

a standardized algorithm. Methods of polypeptide sequence alignment are well-known. Some alignment methods take into account conservative amino acid substitutions. Such conservative substitutions, explained in more detail above, generally preserve the charge and hydrophobicity at the site of substitution, thus preserving the structure (and therefore function) of the polypeptide. The phrases"percent similarity"and"% similarity, "as applied to polypeptide sequences, refer to the percentage of residue matches, including identical residue matches and conservative substitutions, between at least two polypeptide sequences aligned using a standardized algorithm. In contrast, conservative substitutions are not included in the calculation of percent identity between polypeptide sequences.

Percent identity between polypeptide sequences may be determined using the default parameters of the CLUSTAL V algorithm as incorporated into the MEGALIGN version 3.12e sequence alignment program (described and referenced above). For pairwise alignments of polypeptide sequences using CLUSTAL V, the default parameters are set as follows: Ktuple=1, gap penalty=3, window=5, and"diagonals saved"=5. The PAM250 matrix is selected as the default residue weight table.

Alternatively the NCBI BLAST software suite may be used. For example, for a pairwise comparison of two polypeptide sequences, one may use the"BLAST 2 Sequences"tool Version 2.0. 12 (April-21-2000) with blastp set at default parameters. Such default parameters may be, for example: Matrix : BLOSUM62 Open Gap : 11 and Extension Gap : 1 penalties Gap x drop-off : 50 Expect : 10 Word Size: 3 Filter: on Percent identity may be measured over the length of an entire defined polypeptide sequence, for example, as defined by a particular SEQ ID number, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined polypeptide sequence, for instance, a fragment of at least 15, at least 20, at least 30, at least 40, at least 50, at least 70 or at least 150 contiguous residues. Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in the tables, figures or Sequence Listing, may be used to describe a length over which percentage identity may be measured.

"Human artificial chromosomes" (HACs) are linear microchromosomes which may contain DNA sequences of about 6 kb to 10 Mb in size and which contain all of the elements required for chromosome replication, segregation and maintenance.

The term"humanized antibody"refers to an antibody molecule in which the amino acid sequence in the non-antigen binding regions has been altered so that the antibody more closely resembles a human antibody, and still retains its original binding ability.

"Hybridization"refers to the process by which a polynucleotide strand anneals with a complementary strand through base pairing under defined hybridization conditions. Specific hybridization is an indication that two nucleic acid sequences share a high degree of complementarity.

Specific hybridization complexes form under permissive annealing conditions and remain hybridized after the"washing"step (s). The washing step (s) is particularly important in determining the stringency of the hybridization process, with more stringent conditions allowing less non-specific binding, i. e. , binding between pairs of nucleic acid strands that are not perfectly matched. Permissive conditions for annealing of nucleic acid sequences are routinely determinable by one of ordinary skill in the art and may be consistent among hybridization experiments, whereas wash conditions may be varied among experiments to achieve the desired stringency, and therefore hybridization specificity.

Permissive annealing conditions occur, for example, at 68°C in the presence of about 6 x SSC, about 1% (w/v) SDS, and about 100 yg/ml sheared, denatured salmon sperm DNA.

Generally, stringency of hybridization is expressed, in part, with reference to the temperature under which the wash step is carried out. Such wash temperatures are typically selected to be about 5°C to 20°C lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength and pH) at which 50% of the target sequence hybridizes to a perfectly matched probe. An equation for calculating Tm and conditions for nucleic acid hybridization are well known and can be found in Sambrook, J. and D. W.

Russell (2001; Molecular Cloning : A Laboratory Manual, 3rd ed. , vol. 1-3, Cold Spring Harbor Press, Cold Spring Harbor NY, ch. 9).

High stringency conditions for hybridization between polynucleotides of the present invention include wash conditions of 68°C in the presence of about 0.2 x SSC and about 0. 1% SDS, for 1 hour.

Alternatively, temperatures of about 65°C, 60°C, 55°C, or 42°C may be used. SSC concentration may be varied from about 0.1 to 2 x SSC, with SDS being present at about 0.1%. Typically, blocking reagents are used to block non-specific hybridization. Such blocking reagents include, for instance, sheared and denatured salmon sperm DNA at about 100-200 llg/ml. Organic solvent, such as formamide at a concentration of about 35-50% v/v, may also be used under particular circumstances, such as for RNA: DNA hybridizations. Useful variations on these wash conditions will be readily

apparent to those of ordinary skill in the art. Hybridization, particularly under high stringency conditions, may be suggestive of evolutionary similarity between the nucleotides. Such similarity is strongly indicative of a similar role for the nucleotides and their encoded polypeptides.

The term"hybridization complex"refers to a complex formed between two nucleic acids by virtue of the formation of hydrogen bonds between complementary bases. A hybridization complex may be formed in solution (e. g., Cot or Rot analysis) or formed between one nucleic acid present in solution and another nucleic acid immobilized on a solid support (e. g. , paper, membranes, filters, chips, pins or glass slides, or any other appropriate substrate to which cells or their nucleic acids have been fixed).

The words"insertion"and"addition"refer to changes in an amino acid or polynucleotide sequence resulting in the addition of one or more amino acid residues or nucleotides, respectively.

"Immune response"can refer to conditions associated with inflammation, trauma, immune disorders, or infectious or genetic disease, etc. These conditions can be characterized by expression of various factors, e. g. , cytokines, chemokines, and other signaling molecules, which may affect cellular and systemic defense systems.

An"immunogenic fragment"is a polypeptide or oligopeptide fragment of PMMM which is capable of eliciting an immune response when introduced into a living organism, for example, a mammal. The term"immunogenic fragment"also includes any polypeptide or oligopeptide fragment of PMMM which is useful in any of the antibody production methods disclosed herein or known in the art.

The term"microarray"refers to an arrangement of a plurality of polynucleotides, polypeptides, antibodies, or other chemical compounds on a substrate.

The terms"element"and"array element"refer to a polynucleotide, polypeptide, antibody, or other chemical compound having a unique and defined position on a microarray.

The term"modulate"refers to a change in the activity of PMMM. For example, modulation may cause an increase or a decrease in protein activity, binding characteristics, or any other biological, functional, or immunological properties of PMMM.

The phrases"nucleic acid"and"nucleic acid sequence"refer to a nucleotide, oligonucleotide, polynucleotide, or any fragment thereof. These phrases also refer to DNA or RNA of genomic or synthetic origin which may be single-stranded or double-stranded and may represent the sense or the antisense strand, to peptide nucleic acid (PNA), or to any DNA-like or RNA-like material.

"Operably linked"refers to the situation in which a first nucleic acid sequence is placed in a functional relationship with a second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding

sequence. Operably linked DNA sequences may be in close proximity or contiguous and, where necessary to join two protein coding regions, in the same reading frame.

"Peptide nucleic acid" (PNA) refers to an antisense molecule or anti-gene agent which comprises an oligonucleotide of at least about 5 nucleotides in length linked to a peptide backbone of amino acid residues ending in lysine. The terminal lysine confers solubility to the composition. PNAs preferentially bind complementary single stranded DNA or RNA and stop transcript elongation, and may be pegylated to extend their lifespan in the cell.

"Post-translational modification"of an PMMM may involve lipidation, glycosylation, phosphorylation, acetylation, racemization, proteolytic cleavage, and other modifications known in the art. These processes may occur synthetically or biochemically. Biochemical modifications will vary by cell type depending on the enzymatic milieu of PMMM.

"Probe"refers to nucleic acids encoding PMMM, their complements, or fragments thereof, which are used to detect identical, allelic or related nucleic acids. Probes are isolated oligonucleotides or polynucleotides attached to a detectable label or reporter molecule. Typical labels include radioactive isotopes, ligands, chemiluminescent agents, and enzymes. "Primers"are short nucleic acids, usually DNA oligonucleotides, which may be annealed to a target polynucleotide by complementary base-pairing. The primer may then be extended along the target DNA strand by a DNA polymerase enzyme. Primer pairs can be used for amplification (and identification) of a nucleic acid, e. g. , by the polymerase chain reaction (PCR).

Probes and primers as used in the present invention typically comprise at least 15 contiguous nucleotides of a known sequence. In order to enhance specificity, longer probes and primers may also be employed, such as probes and primers that comprise at least 20,25, 30,40, 50,60, 70,80, 90,100, or at least 150 consecutive nucleotides of the disclosed nucleic acid sequences. Probes and primers may be considerably longer than these examples, and it is understood that any length supported by the specification, including the tables, figures, and Sequence Listing, may be used.

Methods for preparing and using probes and primers are described in, for example, Sambrook, J. and D. W. Russell (2001; Molecular Cloning : A Laboratory Manual, 3rd ed. , vol. 1-3, Cold Spring Harbor Press, Cold Spring Harbor NY), Ausubel, F. M. et al. (1999; Short Protocols in Molecular Biology. 4th ed., John Wiley & Sons, New York NY), and Innis, M. et al. (1990; PCR Protocols. A Guide to Methods and Applications, Academic Press, San Diego CA). PCR primer pairs can be derived from a known sequence, for example, by using computer programs intended for that purpose such as Primer (Version 0.5, 1991, Whitehead Institute for Biomedical Research, Cambridge MA).

Oligonucleotides for use as primers are selected using software known in the art for such purpose. For example, OLIGO 4.06 software is useful for the selection of PCR primer pairs of up to

100 nucleotides each, and for the analysis of oligonucleotides and larger polynucleotides of up to 5,000 nucleotides from an input polynucleotide sequence of up to 32 kilobases. Similar primer selection programs have incorporated additional features for expanded capabilities. For example, the PrimOU primer selection program (available to the public from the Genome Center at University of Texas South West Medical Center, Dallas TX) is capable of choosing specific primers from megabase sequences and is thus useful for designing primers on a genome-wide scope. The Primer3 primer selection program (available to the public from the Whitehead Institute/MIT Center for Genome Research, Cambridge MA) allows the user to input a"mispriming library, "in which sequences to avoid as primer binding sites are user-specified. Primer3 is useful, in particular, for the selection of oligonucleotides for microarrays. (The source code for the latter two primer selection programs may also be obtained from their respective sources and modified to meet the user's specific needs. ) The PrimeGen program (available to the public from the UK Human Genome Mapping Project Resource Centre, Cambridge UK) designs primers based on multiple sequence alignments, thereby allowing selection of primers that hybridize to either the most conserved or least conserved regions of aligned nucleic acid sequences. Hence, this program is useful for identification of both unique and conserved oligonucleotides and polynucleotide fragments. The oligonucleotides and polynucleotide fragments identified by any of the above selection methods are useful in hybridization technologies, for example, as PCR or sequencing primers, microarray elements, or specific probes to identify fully or partially complementary polynucleotides in a sample of nucleic acids. Methods of oligonucleotide selection are not limited to those described above.

A"recombinant nucleic acid"is a nucleic acid that is not naturally occurring or has a sequence that is made by an artificial combination of two or more otherwise separated segments of sequence. This artificial combination is often accomplished by chemical synthesis or, more commonly, by the artificial manipulation of isolated segments of nucleic acids, e. g. , by genetic engineering techniques such as those described in Sambrook and Russell (supra). The term recombinant includes nucleic acids that have been altered solely by addition, substitution, or deletion of a portion of the nucleic acid. Frequently, a recombinant nucleic acid may include a nucleic acid sequence operably linked to a promoter sequence. Such a recombinant nucleic acid may be part of a vector that is used, for example, to transform a cell.

Alternatively, such recombinant nucleic acids may be part of a viral vector, e. g. , based on a vaccinia virus, that could be use to vaccinate a mammal wherein the recombinant nucleic acid is expressed, inducing a protective immunological response in the mammal.

A"regulatory element"refers to a nucleic acid sequence usually derived from untranslated regions of a gene and includes enhancers, promoters, introns, and 5'and 3'untranslated regions

(UTRs). Regulatory elements interact with host or viral proteins which control transcription, translation, or RNA stability.

"Reporter molecules"are chemical or biochemical moieties used for labeling a nucleic acid, amino acid, or antibody. Reporter molecules include radionuclides; enzymes; fluorescent, chemiluminescent, or chromogenic agents; substrates; cofactors; inhibitors; magnetic particles; and other moieties known in the art.

An"RNA equivalent, "in reference to a DNA molecule, is composed of the same linear sequence of nucleotides as the reference DNA molecule with the exception that all occurrences of the nitrogenous base thymine are replaced with uracil, and the sugar backbone is composed of ribose instead of deoxyribose.

The term"sample"is used in its broadest sense. A sample suspected of containing PMMM, nucleic acids encoding PMMM, or fragments thereof may comprise a bodily fluid; an extract from a cell, chromosome, organelle, or membrane isolated from a cell; a cell; genomic DNA, RNA, or cDNA, in solution or bound to a substrate; a tissue; a tissue print; etc.

The terms"specific binding"and"specifically binding"refer to that interaction between a protein or peptide and an agonist, an antibody, an antagonist, a small molecule, or any natural or synthetic binding composition. The interaction is dependent upon the presence of a particular structure of the protein, e. g. , the antigenic determinant or epitope, recognized by the binding molecule. For example, if an antibody is specific for epitope"A, "the presence of a polypeptide comprising the epitope A, or the presence of free unlabeled A, in a reaction containing free labeled A and the antibody will reduce the amount of labeled A that binds to the antibody.

The term"substantially purified"refers to nucleic acid or amino acid sequences that are removed from their natural environment and are isolated or separated, and are at least about 60% free, preferably at least about 75% free, and most preferably at least about 90% free from other components with which they are naturally associated.

A"substitution"refers to the replacement of one or more amino acid residues or nucleotides by different amino acid residues or nucleotides, respectively.

"Substrate"refers to any suitable rigid or semi-rigid support including membranes, filters, chips, slides, wafers, fibers, magnetic or nonmagnetic beads, gels, tubing, plates, polymers, microparticles and capillaries. The substrate can have a variety of surface forms, such as wells, trenches, pins, channels and pores, to which polynucleotides or polypeptides are bound.

A"transcript image"or"expression profile"refers to the collective pattern of gene expression by a particular cell type or tissue under given conditions at a given time.

"Transformation"describes a process by which exogenous DNA is introduced into a recipient cell. Transformation may occur under natural or artificial conditions according to various methods well known in the art, and may rely on any known method for the insertion of foreign nucleic acid sequences into a prokaryotic or eukaryotic host cell. The method for transformation is selected based on the type of host cell being transformed and may include, but is not limited to, bacteriophage or viral infection, electroporation, heat shock, lipofection, and particle bombardment. The term"transformed cells"includes stably transformed cells in which the inserted DNA is capable of replication either as an autonomously replicating plasmid or as part of the host chromosome, as well as transiently transformed cells which express the inserted DNA or RNA for limited periods of time.

A"transgenic organism, "as used herein, is any organism, including but not limited to animals and plants, in which one or more of the cells of the organism contains heterologous nucleic acid introduced by way of human intervention, such as by transgenic techniques well known in the art. The nucleic acid is introduced into the cell, directly or indirectly by introduction into a precursor of the cell, by way of deliberate genetic manipulation, such as by microinjection or by infection with a recombinant virus. In another embodiment, the nucleic acid can be introduced by infection with a recombinant viral vector, such as a lentiviral vector (Lois, C. et al. (2002) Science 295: 868-872). The term genetic manipulation does not include classical cross-breeding, or in vitro fertilization, but rather is directed to the introduction of a recombinant DNA molecule. The transgenic organisms contemplated in accordance with the present invention include bacteria, cyanobacteria, fungi, plants and animals. The isolated DNA of the present invention can be introduced into the host by methods known in the art, for example infection, transfection, transformation or transconjugation. Techniques for transferring the DNA of the present invention into such organisms are widely known and provided in references such as Sambrook and Russell (supra).

A"variant"of a particular nucleic acid sequence is defined as a nucleic acid sequence having at least 40% sequence identity to the particular nucleic acid sequence over a certain length of one of the nucleic acid sequences using blastn with the"BLAST 2 Sequences"tool Version 2.0. 9 (May-07- 1999) set at default parameters. Such a pair of nucleic acids may show, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% or greater sequence identity over a certain defined length. A variant may be described as, for example, an "allelic" (as defined above),"splice,""species,"or"polymorphic"variant. A splice variant may have significant identity to a reference molecule, but will generally have a greater or lesser number of polynucleotides due to alternate splicing during mRNA processing. The corresponding polypeptide may possess additional functional domains or lack domains that are present in the reference molecule.

Species variants are polynucleotides that vary from one species to another. The resulting polypeptides will generally have significant amino acid identity relative to each other. A polymorphic variant is a variation in the polynucleotide sequence of a particular gene between individuals of a given species.

Polymorphic variants also may encompass"single nucleotide polymorphisms" (SNPs) in which the polynucleotide sequence varies by one nucleotide base. The presence of SNPs may be indicative of, for example, a certain population, a disease state, or a propensity for a disease state.

A"variant"of a particular polypeptide sequence is defined as a polypeptide sequence having at least 40% sequence identity or sequence similarity to the particular polypeptide sequence over a certain length of one of the polypeptide sequences using blastp with the"BLAST 2 Sequences"tool Version 2.0. 9 (May-07-1999) set at default parameters. Such a pair of polypeptides may show, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% or greater sequence identity or sequence similarity over a certain defined length of one of the polypeptides.

THE INVENTION Various embodiments of the invention include new human protein modification and maintenance molecules (PMMM), the polynucleotides encoding PMMM, and the use of these compositions for the diagnosis, treatment, or prevention of gastrointestinal, cardiovascular, autoimmune/inflammatory, cell proliferative, developmental, epithelial, neurological, and reproductive disorders.

Table 1 summarizes the nomenclature for the full length polynucleotide and polypeptide embodiments of the invention. Each polynucleotide and its corresponding polypeptide are correlated to a single Incyte project identification number (Incyte Project ID). Each polypeptide sequence is denoted by both a polypeptide sequence identification number (Polypeptide SEQ ID NO:) and an Incyte polypeptide sequence number (Incyte Polypeptide ID) as shown. Each polynucleotide sequence is denoted by both a polynucleotide sequence identification number (Polynucleotide SEQ ID NO:) and an Incyte polynucleotide consensus sequence number (Incyte Polynucleotide ID) as shown.

Column 6 shows the Incyte ID numbers of physical, full length clones corresponding to the polypeptide and polynucleotide sequences of the invention. The full length clones encode polypeptides which have at least 95% sequence identity to the polypeptide sequences shown in column 3.

Table 2 shows sequences with homology to polypeptide embodiments of the invention as identified by BLAST analysis against the GenBank protein (genpept) database and the PROTEOME database. Columns 1 and 2 show the polypeptide sequence identification number (Polypeptide SEQ

ID NO:) and the corresponding Incyte polypeptide sequence number (Incyte Polypeptide ID) for polypeptides of the invention. Column 3 shows the GenBank identification number (GenBank ID NO:) of the nearest GenBank homolog and the PROTEOME database identification numbers (PROTEOME ID NO:) of the nearest PROTEOME database homologs. Column 4 shows the probability scores for the matches between each polypeptide and its homolog (s). Column 5 shows the annotation of the GenBank and PROTEOME database homolog (s) along with relevant citations where applicable, all of which are expressly incorporated by reference herein.

Table 3 shows various structural features of the polypeptides of the invention. Columns 1 and 2 show the polypeptide sequence identification number (SEQ ID NO:) and the corresponding Incyte polypeptide sequence number (Incyte Polypeptide ID) for each polypeptide of the invention. Column 3 shows the number of amino acid residues in each polypeptide. Column 4 shows potential phosphorylation sites, and column 5 shows potential glycosylation sites, as determined by the MOTIFS program of the GCG sequence analysis software package (Accelrys, Burlington MA). Column 6 shows amino acid residues comprising signature sequences, domains, and motifs. Column 7 shows analytical methods for protein structure/function analysis and in some cases, searchable databases to which the analytical methods were applied.

Together, Tables 2 and 3 summarize the properties of polypeptides of the invention, and these properties establish that the claimed polypeptides are protein modification and maintenance molecules.

For example, SEQ ID NO : 4 is 98% identical, from residue M231 to residue Q861, to human UHX1 protein (GenBank ID gl276912), a ubiquitin C-terminal hydrolase, as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2. ) The BLAST probability score is 0.0, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID NO : 4 also has homology to proteins that are ubiquitin-specific proteases which may play a role in oncogenesis, as determined by BLAST analysis using the PROTEOME database. SEQ ID NO : 4 also contains a ubiquitin carboxyl-terminal hydrolases family domain as determined by searching for statistically significant matches in the hidden Markov model (HMM) -based PFAM database of conserved protein families/domains. (See Table 3. ) Data from BLIMPS, MOTIFS, and additional BLAST analyses against the PRODOM and DOMO databases provide further corroborative evidence that SEQ ID NO : 4 is a ubiquitin-specific protease. In an alternative example, SEQ ID NO : 26 is 94% identical, from residue MI to residue L269, to human cathepsin G (GenBank ID gl79915) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2. ) The BLAST probability score is 1.6E-132, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID NO : 26 also has homology to cathepsin G, as determined by BLAST analysis using the PROTEOME database. SEQ ID NO : 26 also contains a

trypsin domain and a trypsin-like serine protease domain as determined by searching for statistically significant matches in the hidden Markov model (HMM) -based PFAM and SMART databases of conserved protein families/domains. (See Table 3. ) Data from BLIMPS, MOTIFS, and PROFILESCAN analyses, and BLAST analyses against the PRODOM and DOMO databases, provide further corroborative evidence that SEQ ID NO : 26 is a cathepsin. In an alternative example, SEQ ID NO : 58 is 86% identical, from residue MI to residue S719, to mouse calpain 12 (GenBank ID gel0303329) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2. ) The BLAST probability score is 0.0, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID NO : 58 also has homology to proteins that mediate cell adhesion, migration, signal transduction, regulate the cell cycle, apoptosis, and cellular differentiation and are upregulated in muscle from progressive muscular dystrophy and amyotrophic lateral sclerosis patients, and are members of the calpain family of cysteine proteases. SEQ ID NO : 58 has high similarity to a region of calpain 2, which is the large subunit of the cysteine-type protease m-calpain, as determined by BLAST analysis using the PROTEOME database. SEQ ID NO : 58 also contains a calpain large subunit, domain III, calpain family cysteine protease, and calpain-like thiol protease family domains as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM/SMART database of conserved protein families/domains. (See Table 3. ) Data from BLIMPS and MOTIFS analyses, and BLAST analyses against the PRODOM and DOMO databases, provide further corroborative evidence that SEQ ID NO : 58 is a member of the calpain family of cysteine proteases. SEQ ID NO : 1-3, SEQ ID NO : 5-25, SEQ ID NO : 27-57, and SEQ ID NO : 59-71 were analyzed and annotated in a similar manner. The algorithms and parameters for the analysis of SEQ ID NO : 1-71 are described in Table 7.

As shown in Table 4, the full length polynucleotide embodiments were assembled using cDNA sequences or coding (exon) sequences derived from genomic DNA, or any combination of these two types of sequences. Column 1 lists the polynucleotide sequence identification number (Polynucleotide SEQ ID NO:), the corresponding Incyte polynucleotide consensus sequence number (Incyte ID) for each polynucleotide of the invention, and the length of each polynucleotide sequence in basepairs.

Column 2 shows the nucleotide start (5') and stop (3') positions of the cDNA and/or genomic sequences used to assemble the full length polynucleotide embodiments, and of fragments of the polynucleotides which are useful, for example, in hybridization or amplification technologies that identify SEQ ID NO : 72-142 or that distinguish between SEQ ID NO : 72-142 and related polynucleotides.

The polynucleotide fragments described in Column 2 of Table 4 may refer specifically, for example, to Incyte cDNAs derived from tissue-specific cDNA libraries or from pooled cDNA

libraries. Alternatively, the polynucleotide fragments described in column 2 may refer to GenBank cDNAs or ESTs which contributed to the assembly of the full length polynucleotides. In addition, the polynucleotide fragments described in column 2 may identify sequences derived from the ENSEMBL (The Sanger Centre, Cambridge, UK) database (i. e., those sequences including the designation "ENST"). Alternatively, the polynucleotide fragments described in column 2 may be derived from the NCBI RefSeq Nucleotide Sequence Records Database (i. e., those sequences including the designation"NM"or"NT") or the NCBI RefSeq Protein Sequence Records (i. e., those sequences including the designation"NP"). Alternatively, the polynucleotide fragments described in column 2 may refer to assemblages of both cDNA and Genscan-predicted exons brought together by an"exon stitching"algorithm. For example, a polynucleotide sequence identified as FL_XXXXXX_N, _N2_YYYYY_N3_N4 represents a"stitched"sequence in which : CXXXX is the identification number of the cluster of sequences to which the algorithm was applied, and YYYYY is the number of the prediction generated by the algorithm, and N, 2 3, if present, represent specific exons that may have been manually edited during analysis (See Example V). Alternatively, the polynucleotide fragments in column 2 may refer to assemblages of exons brought together by an "exon-stretching"algorithm. For example, a polynucleotide sequence identified as FLXXXXXXgAAAAAgBBBlJVis a"stretched"sequence, with XXXXXY being the Incyte project identification number, gAAAAA being the GenBank identification number of the human genomic sequence to which the"exon-stretching"algorithm was applied, gBBBBB being the GenBank identification number or NCBI RefSeq identification number of the nearest GenBank protein homolog, and N referring to specific exons (See Example V). In instances where a RefSeq sequence was used as a protein homolog for the"exon-stretching"algorithm, a RefSeq identifier (denoted by"NM," "NP, "or"NT") may be used in place of the GenBank identifier (i. e., gBBBBB).

Alternatively, a prefix identifies component sequences that were hand-edited, predicted from genomic DNA sequences, or derived from a combination of sequence analysis methods. The following Table lists examples of component sequence prefixes and corresponding sequence analysis methods associated with the prefixes (see Example IV and Example V). Prefix Type of analysis and/or examples of programs GNN, GFG, Exon prediction from genomic sequences using, for example, ENST GENSCAN (Stanford University, CA, USA) or FGENES (Computer Genomics Group, The Sanger Centre, Cambridge, UK). GBI Hand-edited analysis of genomic sequences. FL Stitched or stretched genomic sequences (see Example V). INCY Full length transcript and exon prediction from mapping of EST sequences to the genome. Genomic location and EST composition data are combined to predict the exons and resulting transcript.

In some cases, Incyte cDNA coverage redundant with the sequence coverage shown in Table 4 was obtained to confirm the final consensus polynucleotide sequence, but the relevant Incyte cDNA identification numbers are not shown.

Table 5 shows the representative cDNA libraries for those full length polynucleotides which were assembled using Incyte cDNA sequences. The representative cDNA library is the Incyte cDNA library which is most frequently represented by the Incyte cDNA sequences which were used to assemble and confirm the above polynucleotides. The tissues and vectors which were used to construct the cDNA libraries shown in Table 5 are described in Table 6.

Table 8 shows single nucleotide polymorphisms (SNPs) found in polynucleotide sequences of the invention, along with allele frequencies in different human populations. Columns 1 and 2 show the polynucleotide sequence identification number (SEQ ID NO:) and the corresponding Incyte project identification number (PID) for polynucleotides of the invention. Column 3 shows the Incyte identification number for the EST in which the SNP was detected (EST ID), and column 4 shows the identification number for the SNP (SNP ID). Column 5 shows the position within the EST sequence at which the SNP is located (EST SNP), and column 6 shows the position of the SNP within the full- length polynucleotide sequence (CB1 SNP). Column 7 shows the allele found in the EST sequence.

Columns 8 and 9 show the two alleles found at the SNP site. Column 10 shows the amino acid encoded by the codon including the SNP site, based upon the allele found in the EST. Columns 11-14 show the frequency of allele 1 in four different human populations. An entry of n/d (not detected) indicates that the frequency of allele 1 in the population was too low to be detected, while n/a (not available) indicates that the allele frequency was not determined for the population.

The invention also encompasses PMMM variants. Various embodiments of PMMM variants can have at least about 80%, at least about 90%, or at least about 95% amino acid sequence identity to the PMMM amino acid sequence, and can contain at least one functional or structural characteristic of PMMM.

Various embodiments also encompass polynucleotides which encode PMMM. In a particular embodiment, the invention encompasses a polynucleotide sequence comprising a sequence selected from the group consisting of SEQ ID NO : 72-142, which encodes PMMM. The polynucleotide sequences of SEQ ID NO : 72-142, as presented in the Sequence Listing, embrace the equivalent RNA

sequences, wherein occurrences of the nitrogenous base thymine are replaced with uracil, and the sugar backbone is composed of ribose instead of deoxyribose.

The invention also encompasses variants of a polynucleotide encoding PMMM. In particular, such a variant polynucleotide will have at least about 70%, or alternatively at least about 85%, or even at least about 95% polynucleotide sequence identity to a polynucleotide encoding PMMM. A particular aspect of the invention encompasses a variant of a polynucleotide comprising a sequence selected from the group consisting of SEQ ID N0 : 72-142 which has at least about 70%, or alternatively at least about 85%, or even at least about 95% polynucleotide sequence identity to a nucleic acid sequence selected from the group consisting of SEQ ID N0 : 72-142. Any one of the polynucleotide variants described above can encode a polypeptide which contains at least one functional or structural characteristic of PMMM.

In addition, or in the alternative, a polynucleotide variant of the invention is a splice variant of a polynucleotide encoding PMMM. A splice variant may have portions which have significant sequence identity to a polynucleotide encoding PMMM, but will generally have a greater or lesser number of polynucleotides due to additions or deletions of blocks of sequence arising from alternate splicing during mRNA processing. A splice variant may have less than about 70%, or alternatively less than about 60%, or alternatively less than about 50% polynucleotide sequence identity to a polynucleotide encoding PMMM over its entire length; however, portions of the splice variant will have at least about 70%, or alternatively at least about 85%, or alternatively at least about 95%, or alternatively 100% polynucleotide sequence identity to portions of the polynucleotide encoding PMMM. For example, a polynucleotide comprising a sequence of SEQ ID N0 : 72 and a polynucleotide comprising a sequence of SEQ ID N0 : 84 are splice variants of each other; a polynucleotide comprising a sequence of SEQ ID NO : 75 and a polynucleotide comprising a sequence of SEQ ID N0 : 109 are splice variants of each other; a polynucleotide comprising a sequence of SEQ ID N0 : 89 and a polynucleotide comprising a sequence of SEQ ID N0 : 90 are splice variants of each other; a polynucleotide comprising a sequence of SEQ ID N0 : 91 and a polynucleotide comprising a sequence of SEQ ID NO: 102 are splice variants of each other; a polynucleotide comprising a sequence of SEQ ID NO: 105, a polynucleotide comprising a sequence of SEQ ID N0 : 106 and a polynucleotide comprising a sequence of SEQ ID NO : 107 are splice variants of each other; and a polynucleotide comprising a sequence of SEQ ID NO : 114 and a polynucleotide comprising a sequence of SEQ ID NO: 115 are splice variants of each other. Any one of the splice variants described above can encode a polypeptide which contains at least one functional or structural characteristic of PMMM.

It will be appreciated by those skilled in the art that as a result of the degeneracy of the genetic code, a multitude of polynucleotide sequences encoding PMMM, some bearing minimal

similarity to the polynucleotide sequences of any known and naturally occurring gene, may be produced. Thus, the invention contemplates each and every possible variation of polynucleotide sequence that could be made by selecting combinations based on possible codon choices. These combinations are made in accordance with the standard triplet genetic code as applied to the polynucleotide sequence of naturally occurring PMMM, and all such variations are to be considered as being specifically disclosed.

Although polynucleotides which encode PMMM and its variants are generally capable of hybridizing to polynucleotides encoding naturally occurring PMMM under appropriately selected conditions of stringency, it may be advantageous to produce polynucleotides encoding PMMM or its derivatives possessing a substantially different codon usage, e. g. , inclusion of non-naturally occurring codons. Codons may be selected to increase the rate at which expression of the peptide occurs in a particular prokaryotic or eukaryotic host in accordance with the frequency with which particular codons are utilized by the host. Other reasons for substantially altering the nucleotide sequence encoding PMMM and its derivatives without altering the encoded amino acid sequences include the production of RNA transcripts having more desirable properties, such as a greater half-life, than transcripts produced from the naturally occurring sequence.

The invention also encompasses production of polynucleotides which encode PMMM and PMMM derivatives, or fragments thereof, entirely by synthetic chemistry. After production, the synthetic polynucleotide may be inserted into any of the many available expression vectors and cell systems using reagents well known in the art. Moreover, synthetic chemistry may be used to introduce mutations into a polynucleotide encoding PMMM or any fragment thereof.

Embodiments of the invention can also include polynucleotides that are capable of hybridizing to the claimed polynucleotides, and, in particular, to those having the sequences shown in SEQ ID NO : 72-142 and fragments thereof, under various conditions of stringency (Wahl, G. M. and S. L.

Berger (1987) Methods Enzymol. 152: 399-407; Kimmel, A. R. (1987) Methods Enzymol. 152: 507-511).

Hybridization conditions, including annealing and wash conditions, are described in"Definitions." Methods for DNA sequencing are well known in the art and may be used to practice any of the embodiments of the invention. The methods may employ such enzymes as the Klenow fragment of DNA polymerase I, SEQUENASE (US Biochemical, Cleveland OH), Taq polymerase (Applied Biosystems), thermostable T7 polymerase (Amersham Biosciences, Piscataway NJ), or combinations of polymerases and proofreading exonucleases such as those found in the ELONGASE amplification system (Invitrogen, Carlsbad CA). Preferably, sequence preparation is automated with machines such as the MICROLAB 2200 liquid transfer system (Hamilton, Reno NV), PTC200 thermal cycler (MJ Research, Watertown MA) and ABI CATALYST 800 thermal cycler (Applied Biosystems).

Sequencing is then carried out using either the ABI 373 or 377 DNA sequencing system (Applied Biosystems), the MEGABACE 1000 DNA sequencing system (Amersham Biosciences), or other systems known in the art. The resulting sequences are analyzed using a variety of algorithms which are well known in the art (Ausubel et al., supra, ch. 7; Meyers, R. A. (1995) Molecular Biology and Biotechnolosv. Wiley VCH, New York NY, pp. 856-853).

The nucleic acids encoding PMMM may be extended utilizing a partial nucleotide sequence and employing various PCR-based methods known in the art to detect upstream sequences, such as promoters and regulatory elements. For example, one method which may be employed, restriction-site PCR, uses universal and nested primers to amplify unknown sequence from genomic DNA within a cloning vector (Sarkar, G. (1993) PCR Methods Applic. 2: 318-322). Another method, inverse PCR, uses primers that extend in divergent directions to amplify unknown sequence from a circularized template. The template is derived from restriction fragments comprising a known genomic locus and surrounding sequences (Triglia, T. et al. (1988) Nucleic Acids Res. 16: 8186). A third method, capture PCR, involves PCR amplification of DNA fragments adjacent to known sequences in human and yeast artificial chromosome DNA (Lagerstrom, M. et al. (1991) PCR Methods Applic. 1: 111-119). In this method, multiple restriction enzyme digestions and ligations may be used to insert an engineered double-stranded sequence into a region of unknown sequence before performing PCR. Other methods which may be used to retrieve unknown sequences are known in the art (Parker, J. D. et al.

(1991) Nucleic Acids Res. 19: 3055-3060). Additionally, one may use PCR, nested primers, and PROMOTERFINDER libraries (Clontech, Palo Alto CA) to walk genomic DNA. This procedure avoids the need to screen libraries and is useful in finding intron/exon junctions. For all PCR-based methods, primers may be designed using commercially available software, such as OLIGO 4.06 primer analysis software (National Biosciences, Plymouth MN) or another appropriate program, to be about 22 to 30 nucleotides in length, to have a GC content of about 50% or more, and to anneal to the template at temperatures of about 68°C to 72°C.

When screening for full length cDNAs, it is preferable to use libraries that have been size-selected to include larger cDNAs. In addition, random-primed libraries, which often include sequences containing the 5'regions of genes, are preferable for situations in which an oligo d (T) library does not yield a full-length cDNA. Genomic libraries may be useful for extension of sequence into 5'non-transcribed regulatory regions.

Capillary electrophoresis systems which are commercially available may be used to analyze the size or confirm the nucleotide sequence of sequencing or PCR products. In particular, capillary sequencing may employ flowable polymers for electrophoretic separation, four different nucleotide- specific, laser-stimulated fluorescent dyes, and a charge coupled device camera for detection of the

emitted wavelengths. Output/light intensity may be converted to electrical signal using appropriate software (e. g. , GENOTYPER and SEQUENCE NAVIGATOR, Applied Biosystems), and the entire process from loading of samples to computer analysis and electronic data display may be computer controlled. Capillary electrophoresis is especially preferable for sequencing small DNA fragments which may be present in limited amounts in a particular sample.

In another embodiment of the invention, polynucleotides or fragments thereof which encode PMMM may be cloned in recombinant DNA molecules that direct expression of PMMM, or fragments or functional equivalents thereof, in appropriate host cells. Due to the inherent degeneracy of the genetic code, other polynucleotides which encode substantially the same or a functionally equivalent polypeptides may be produced and used to express PMMM.

The polynucleotides of the invention can be engineered using methods generally known in the art in order to alter PMMM-encoding sequences for a variety of purposes including, but not limited to, modification of the cloning, processing, and/or expression of the gene product. DNA shuffling by random fragmentation and PCR reassembly of gene fragments and synthetic oligonucleotides may be used to engineer the nucleotide sequences. For example, oligonucleotide-mediated site-directed mutagenesis may be used to introduce mutations that create new restriction sites, alter glycosylation patterns, change codon preference, produce splice variants, and so forth.

The nucleotides of the present invention may be subjected to DNA shuffling techniques such as MOLECULARBREEDING (Maxygen Inc. , Santa Clara CA; described in U. S. Patent No.

5,837, 458; Chang, C.-C. et al. (1999) Nat. Biotechnol. 17: 793-797; Christians, F. C. et al. (1999) Nat.

Biotechnol. 17: 259-264; and Crameri, A. et al. (1996) Nat. Biotechnol. 14: 315-319) to alter or improve the biological properties of PMMM, such as its biological or enzymatic activity or its ability to bind to other molecules or compounds. DNA shuffling is a process by which a library of gene variants is produced using PCR-mediated recombination of gene fragments. The library is then subjected to selection or screening procedures that identify those gene variants with the desired properties. These preferred variants may then be pooled and further subjected to recursive rounds of DNA shuffling and selection/screening. Thus, genetic diversity is created through"artificial"breeding and rapid molecular evolution. For example, fragments of a single gene containing random point mutations may be recombined, screened, and then reshuffled until the desired properties are optimized. Alternatively, fragments of a given gene may be recombined with fragments of homologous genes in the same gene family, either from the same or different species, thereby maximizing the genetic diversity of multiple naturally occurring genes in a directed and controllable manner.

In another embodiment, polynucleotides encoding PMMM may be synthesized, in whole or in part, using one or more chemical methods well known in the art (Caruthers, M. H. et al. (1980)

Nucleic Acids Symp. Ser. 7: 215-223; Horn, T. et al. (1980) Nucleic Acids Symp. Ser. 7: 225-232).

Alternatively, PMMM itself or a fragment thereof may be synthesized using chemical methods known in the art. For example, peptide synthesis can be performed using various solution-phase or solid-phase techniques (Creighton, T. (1984) Proteins, Structures and Molecular Properties, WH Freeman, New York NY, pp. 55-60; Roberge, J. Y. et al. (1995) Science 269: 202-204). Automated synthesis may be achieved using the ABI 431A peptide synthesizer (Applied Biosystems).

Additionally, the amino acid sequence of PMMM, or any part thereof, may be altered during direct synthesis and/or combined with sequences from other proteins, or any part thereof, to produce a variant polypeptide or a polypeptide having a sequence of a naturally occurring polypeptide.

The peptide may be substantially purified by preparative high performance liquid chromatography (Chiez, R. M. and F. Z. Regnier (1990) Methods Enzymol. 182: 392-421). The composition of the synthetic peptides may be confirmed by amino acid analysis or by sequencing (Creighton, supra, pp. 28-53).

In order to express a biologically active PMMM, the polynucleotides encoding PMMM or derivatives thereof may be inserted into an appropriate expression vector, i. e. , a vector which contains the necessary elements for transcriptional and translational control of the inserted coding sequence in a suitable host. These elements include regulatory sequences, such as enhancers, constitutive and inducible promoters, and 5'and 3'untranslated regions in the vector and in polynucleotides encoding PMMM. Such elements may vary in their strength and specificity. Specific initiation signals may also be used to achieve more efficient translation of polynucleotides encoding PMMM. Such signals include the ATG initiation codon and adjacent sequences, e. g. the Kozak sequence. In cases where a polynucleotide sequence encoding PMMM and its initiation codon and upstream regulatory sequences are inserted into the appropriate expression vector, no additional transcriptional or translational control signals may be needed. However, in cases where only coding sequence, or a fragment thereof, is inserted, exogenous translational control signals including an in-frame ATG initiation codon should be provided by the vector. Exogenous translational elements and initiation codons may be of various origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of enhancers appropriate for the particular host cell system used (Scharf, D. et al. (1994) Results Probl.

Cell Differ. 20: 125-162).

Methods which are well known to those skilled in the art may be used to construct expression vectors containing polynucleotides encoding PMMM and appropriate transcriptional and translational control elements. These methods include in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination (Sambrook and Russell, supra, ch. 1-4, and 8; Ausubel et al., supra, ch. 1,3, and 15).

A variety of expression vector/host systems may be utilized to contain and express polynucleotides encoding PMMM. These include, but are not limited to, microorganisms such as bacteria transformed with recombinant bacteriophage, plasmid, or cosmid DNA expression vectors; yeast transformed with yeast expression vectors; insect cell systems infected with viral expression vectors (e. g. , baculovirus); plant cell systems transformed with viral expression vectors (e. g., cauliflower mosaic virus, CaMV, or tobacco mosaic virus, TMV) or with bacterial expression vectors (e. g. , Ti or pBR322 plasmids); or animal cell systems (Sambrook and Russell, supra ; Ausubel et al., supra ; Van Heeke, G. and S. M. Schuster (1989) J. Biol. Chem. 264: 5503-5509; Engelhard, E. K. et al.

(1994) Proc. Natl. Acad. Sci. USA 91: 3224-3227; Sandig, V. et al. (1996) Hum. Gene Ther. 7: 1937- 1945; Takamatsu, N. (1987) EMBO J. 6: 307-311 ; The McGraw Hill Yearbook of Science and Technology (1992) McGraw Hill, New York NY, pp. 191-196; Logan, J. and T. Shenk (1984) Proc.

Natl. Acad. Sci. USA 81: 3655-3659; Harrington, J. J. et al. (1997) Nat. Genet. 15: 345-355).

Expression vectors derived from retroviruses, adenoviruses, or herpes or vaccinia viruses, or from various bacterial plasmids, may be used for delivery of polynucleotides to the targeted organ, tissue, or cell population (Di Nicola, M. et al. (1998) Cancer Gen. Ther. 5: 350-356; Yu, M. et al. (1993) Proc.

Natl. Acad. Sci. USA 90: 6340-6344; Buller, R. M. et al. (1985) Nature 317: 813-815; McGregor, D. P. et al. (1994) Mol. Immunol. 31: 219-226; Verma, I. M. and N. Somia (1997) Nature 389: 239-242). The invention is not limited by the host cell employed.

In bacterial systems, a number of cloning and expression vectors may be selected depending upon the use intended for polynucleotides encoding PMMM. For example, routine cloning, subcloning, and propagation of polynucleotides encoding PMMM can be achieved using a multifunctional E. coli vector such as PBLUESCRIPT (Stratagene, La Jolla CA) or PSPORT1 plasmid (Invitrogen).

Ligation of polynucleotides encoding PMMM into the vector's multiple cloning site disrupts the lacZ gene, allowing a colorimetric screening procedure for identification of transformed bacteria containing recombinant molecules. In addition, these vectors may be useful for in vitro transcription, dideoxy sequencing, single strand rescue with helper phage, and creation of nested deletions in the cloned sequence (Van Heeke, G. and S. M. Schuster (1989) J. Biol. Chem. 264: 5503-5509). When large quantities of PMMM are needed, e. g. for the production of antibodies, vectors which direct high level expression of PMMM may be used. For example, vectors containing the strong, inducible SP6 or T7 bacteriophage promoter may be used.

Yeast expression systems may be used for production of PMMM. A number of vectors containing constitutive or inducible promoters, such as alpha factor, alcohol oxidase, and PGH promoters, may be used in the yeast Saccharomyces cerevisiae or Pichia pastoris. In addition, such vectors direct either the secretion or intracellular retention of expressed proteins and enable

integration of foreign polynucleotide sequences into the host genome for stable propagation (Ausubel et al., supra ; Bitter, G. A. et al. (1987) Methods Enzymol. 153: 516-544; Scorer, C. A. et al. (1994) Bio/Technology 12: 181-184).

Plant systems may also be used for expression of PMMM. Transcription of polynucleotides encoding PMMM may be driven by viral promoters, e. g. , the 35S and 19S promoters of CaMV used alone or in combination with the omega leader sequence from TMV (Takamatsu, N. (1987) EMBO J.

6: 307-311). Alternatively, plant promoters such as the small subunit of RUBISCO or heat shock promoters may be used (Coruzzi, G. et al. (1984) EMBO J. 3: 1671-1680; Broglie, R. et al. (1984) Science 224: 838-843; Winter, J. et al. (1991) Results Probl. Cell Differ. 17: 85-105). These constructs can be introduced into plant cells by direct DNA transformation or pathogen-mediated transfection (The McGraw Hill Yearbook of Science and Technology (1992) McGraw Hill, New York NY, pp.

191-196).

In mammalian cells, a number of viral-based expression systems may be utilized. In cases where an adenovirus is used as an expression vector, polynucleotides encoding PMMM may be ligated into an adenovirus transcription/translation complex consisting of the late promoter and tripartite leader sequence. Insertion in a non-essential E1 or E3 region of the viral genome may be used to obtain infective virus which expresses PMMM in host cells (Logan, J. and T. Shenk (1984) Proc.

Natl. Acad. Sci. USA 81: 3655-3659). In addition, transcription enhancers, such as the Rous sarcoma virus (RSV) enhancer, may be used to increase expression in mammalian host cells. SV40 or EBV- based vectors may also be used for high-level protein expression.

Human artificial chromosomes (HACs) may also be employed to deliver larger fragments of DNA than can be contained in and expressed from a plasmid. HACs of about 6 kb to 10 Mb are constructed and delivered via conventional delivery methods (liposomes, polycationic amino polymers, or vesicles) for therapeutic purposes (Harrington, J. J. et al. (1997) Nat. Genet. 15: 345-355).

For long term production of recombinant proteins in mammalian systems, stable expression of PMMM in cell lines is preferred. For example, polynucleotides encoding PMMM can be transformed into cell lines using expression vectors which may contain viral origins of replication and/or endogenous expression elements and a selectable marker gene on the same or on a separate vector.

Following the introduction of the vector, cells may be allowed to grow for about 1 to 2 days in enriched media before being switched to selective media. The purpose of the selectable marker is to confer resistance to a selective agent, and its presence allows growth and recovery of cells which successfully express the introduced sequences. Resistant clones of stably transformed cells may be propagated using tissue culture techniques appropriate to the cell type.

Any number of selection systems may be used to recover transformed cell lines. These include, but are not limited to, the herpes simplex virus thymidine kinase and adenine phosphoribosyltransferase genes, for use in tk-and apr~ cells, respectively (Wigler, M. et al. (1977) Cell 11: 223-232; Lowy, 1. et al. (1980) Cell 22: 817-823). Also, antimetabolite, antibiotic, or herbicide resistance can be used as the basis for selection. For example, dhfr confers resistance to methotrexate; neo confers resistance to the aminoglycosides neomycin and G-418; and als and pat confer resistance to chlorsulfuron and phosphinotricin acetyltransferase, respectively (Wigler, M. et al.

(1980) Proc. Natl. Acad. Sci. USA 77: 3567-3570; Colbere-Garapin, F. et al. (1981) J. Mol. Biol.

150: 1-14). Additional selectable genes have been described, e. g., trpB and hisD, which alter cellular requirements for metabolites (Hartman, S. C. and R. C. Mulligan (1988) Proc. Natl. Acad. Sci. USA 85: 8047-8051). Visible markers, e. g. , anthocyanins, green fluorescent proteins (GFP; Clontech), i- glucuronidase and its substrate P-glucuronide, or luciferase and its substrate luciferin may be used.

These markers can be used not only to identify transformants, but also to quantify the amount of transient or stable protein expression attributable to a specific vector system (Rhodes, C. A. (1995) Methods Mol. Biol. 55: 121-131).

Although the presence/absence of marker gene expression suggests that the gene of interest is also present, the presence and expression of the gene may need to be confirmed. For example, if the sequence encoding PMMM is inserted within a marker gene sequence, transformed cells containing polynucleotides encoding PMMM can be identified by the absence of marker gene function. Alternatively, a marker gene can be placed in tandem with a sequence encoding PMMM under the control of a single promoter. Expression of the marker gene in response to induction or selection usually indicates expression of the tandem gene as well.

In general, host cells that contain the polynucleotide encoding PMMM and that express PMMM may be identified by a variety of procedures known to those of skill in the art. These procedures include, but are not limited to, DNA-DNA or DNA-RNA hybridizations, PCR amplification, and protein bioassay or immunoassay techniques which include membrane, solution, or chip based technologies for the detection and/or quantification of nucleic acid or protein sequences.

Immunological methods for detecting and measuring the expression of PMMM using either specific polyclonal or monoclonal antibodies are known in the art. Examples of such techniques include enzyme-linked immunosorbent assays (ELISAs), radioimmunoassays (RIAs), and fluorescence activated cell sorting (FACS). A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering epitopes on PMMM is preferred, but a competitive binding assay may be employed. These and other assays are well known in the art (Hampton, R. et al. (1990) Serological Methods, a Laboratory Manual, APS Press, St. Paul MN, Sect.

IV; Coligan, J. E. et al. (1997) Current Protocols in Immunology, Greene Pub. Associates and Wiley- Interscience, New York NY; Pound, J. D. (1998) Immunochemical Protocols, Humana Press, Totowa NJ).

A wide variety of labels and conjugation techniques are known by those skilled in the art and may be used in various nucleic acid and amino acid assays. Means for producing labeled hybridization or PCR probes for detecting sequences related to polynucleotides encoding PMMM include oligolabeling, nick translation, end-labeling, or PCR amplification using a labeled nucleotide.

Alternatively, polynucleotides encoding PMMM, or any fragments thereof, may be cloned into a vector for the production of an mRNA probe. Such vectors are known in the art, are commercially available, and may be used to synthesize RNA probes in vitro by addition of an appropriate RNA polymerase such as T7, T3, or SP6 and labeled nucleotides. These procedures may be conducted using a variety of commercially available kits, such as those provided by Amersham Biosciences, Promega (Madison WI), and US Biochemical. Suitable reporter molecules or labels which may be used for ease of detection include radionuclides, enzymes, fluorescent, chemiluminescent, or chromogenic agents, as well as substrates, cofactors, inhibitors, magnetic particles, and the like.

Host cells transformed with polynucleotides encoding PMMM may be cultured under conditions suitable for the expression and recovery of the protein from cell culture. The protein produced by a transformed cell may be secreted or retained intracellularly depending on the sequence and/or the vector used. As will be understood by those of skill in the art, expression vectors containing polynucleotides which encode PMMM may be designed to contain signal sequences which direct secretion of PMMM through a prokaryotic or eukaryotic cell membrane.

In addition, a host cell strain may be chosen for its ability to modulate expression of the inserted polynucleotides or to process the expressed protein in the desired fashion. Such modifications of the polypeptide include, but are not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation, and acylation. Post-translational processing which cleaves a"prepro"or "pro"form of the protein may also be used to specify protein targeting, folding, and/or activity.

Different host cells which have specific cellular machinery and characteristic mechanisms for post-translational activities (e. g. , CHO, HeLa, MDCK, HEK293, and WI38) are available from the American Type Culture Collection (ATCC, Manassas VA) and may be chosen to ensure the correct modification and processing of the foreign protein.

In another embodiment of the invention, natural, modified, or recombinant polynucleotides encoding PMMM may be ligated to a heterologous sequence resulting in translation of a fusion protein in any of the aforementioned host systems. For example, a chimeric PMMM protein containing a heterologous moiety that can be recognized by a commercially available antibody may facilitate the

screening of peptide libraries for inhibitors of PMMM activity. Heterologous protein and peptide moieties may also facilitate purification of fusion proteins using commercially available affinity matrices. Such moieties include, but are not limited to, glutathione S-transferase (GST), maltose binding protein (MBP), thioredoxin (Trx), calmodulin binding peptide (CBP), 6-His, FLAG, c-myc, and hemagglutinin (HA). GST, MBP, Trx, CBP, and 6-His enable purification of their cognate fusion proteins on immobilized glutathione, maltose, phenylarsine oxide, calmodulin, and metal-chelate resins, respectively. FLAG, c-myc, and hemagglutinin (HA) enable immunoaffinity purification of fusion proteins using commercially available monoclonal and polyclonal antibodies that specifically recognize these epitope tags. A fusion protein may also be engineered to contain a proteolytic cleavage site located between the PMMM encoding sequence and the heterologous protein sequence, so that PMMM may be cleaved away from the heterologous moiety following purification. Methods for fusion protein expression and purification are discussed in Ausubel et al. (supra, ch. 10 and 16). A variety of commercially available kits may also be used to facilitate expression and purification of fusion proteins.

In another embodiment, synthesis of radiolabeled PMMM may be achieved in vitro using the TNT rabbit reticulocyte lysate or wheat germ extract system (Promega). These systems couple transcription and translation of protein-coding sequences operably associated with the T7, T3, or SP6 promoters. Translation takes place in the presence of a radiolabeled amino acid precursor, for example, 35S-methionine.

PMMM, fragments of PMMM, or variants of PMMM may be used to screen for compounds that specifically bind to PMMM. One or more test compounds may be screened for specific binding to PMMM. In various embodiments, 1,2, 3,4, 5,10, 20,50, 100, or 200 test compounds can be screened for specific binding to PMMM. Examples of test compounds can include antibodies, anticalins, oligonucleotides, proteins (e. g. , ligands or receptors), or small molecules.

In related embodiments, variants of PMMM can be used to screen for binding of test compounds, such as antibodies, to PMMM, a variant of PMMM, or a combination of PMMM and/or one or more variants PMMM. In an embodiment, a variant of PMMM can be used to screen for compounds that bind to a variant of PMMM, but not to PMMM having the exact sequence of a sequence of SEQ ID NO : 1-71. PMMM variants used to perform such screening can have a range of about 50% to about 99% sequence identity to PMMM, with various embodiments having 60%, 70%, 75%, 80%, 85%, 90%, and 95% sequence identity.

In an embodiment, a compound identified in a screen for specific binding to PMMM can be closely related to the natural ligand of PMMM, e. g. , a ligand or fragment thereof, a natural substrate, a structural or functional mimetic, or a natural binding partner (Coligan, J. E. et al. (1991) Current

Protocols in Immunology 1 (2): Chapter 5). In another embodiment, the compound thus identified can be a natural ligand of a receptor PMMM (Howard, A. D. et al. (2001) Trends Pharmacol. Sci. 22: 132- 140; Wise, A. et al. (2002) Drug Discovery Today 7: 235-246).

In other embodiments, a compound identified in a screen for specific binding to PMMM can be closely related to the natural receptor to which PMMM binds, at least a fragment of the receptor, or a fragment of the receptor including all or a portion of the ligand binding site or binding pocket. For example, the compound may be a receptor for PMMM which is capable of propagating a signal, or a decoy receptor for PMMM which is not capable of propagating a signal (Ashkenazi, A. and V. M.

Divit (1999) Curr. Opin. Cell Biol. 11: 255-260; Mantovani, A. et al. (2001) Trends Immunol. 22: 328- 336). The compound can be rationally designed using known techniques. Examples of such techniques include those used to construct the compound etanercept (ENBREL; Amgen Inc., Thousand Oaks CA), which is efficacious for treating rheumatoid arthritis in humans. Etanercept is an engineered p75 tumor necrosis factor (TNF) receptor dimer linked to the Fc portion of human IgG, (Taylor, P. C. et al. (2001) Curr. Opin. Immunol. 13: 611-616).

In one embodiment, two or more antibodies having similar or, alternatively, different specificities can be screened for specific binding to PMMM, fragments of PMMM, or variants of PMMM. The binding specificity of the antibodies thus screened can thereby be selected to identify particular fragments or variants of PMMM. In one embodiment, an antibody can be selected such that its binding specificity allows for preferential identification of specific fragments or variants of PMMM. In another embodiment, an antibody can be selected such that its binding specificity allows for preferential diagnosis of a specific disease or condition having increased, decreased, or otherwise abnormal production of PMMM In an embodiment, anticalins can be screened for specific binding to PMMM, fragments of PMMM, or variants of PMMM. Anticalins are ligand-binding proteins that have been constructed based on a lipocalin scaffold (Weiss, G. A. and H. B. Lowman (2000) Chem. Biol. 7: R177-R184 ; Skerra, A. (2001) J. Biotechnol. 74: 257-275). The protein architecture of lipocalins can include a beta-barrel having eight antiparallel beta-strands, which supports four loops at its open end. These loops form the natural ligand-binding site of the lipocalins, a site which can be re-engineered in vitro by amino acid substitutions to impart novel binding specificities. The amino acid substitutions can be made using methods known in the art or described herein, and can include conservative substitutions (e. g. , substitutions that do not alter binding specificity) or substitutions that modestly, moderately, or significantly alter binding specificity.

In one embodiment, screening for compounds which specifically bind to, stimulate, or inhibit PMMM involves producing appropriate cells which express PMMM, either as a secreted protein or on

the cell membrane. Preferred cells can include cells from mammals, yeast, Drosophila, or E. coli.

Cells expressing PMMM or cell membrane fractions which contain PMMM are then contacted with a test compound and binding, stimulation, or inhibition of activity of either PMMM or the compound is analyzed.

An assay may simply test binding of a test compound to the polypeptide, wherein binding is detected by a fluorophore, radioisotope, enzyme conjugate, or other detectable label. For example, the assay may comprise the steps of combining at least one test compound with PMMM, either in solution or affixed to a solid support, and detecting the binding of PMMM to the compound. Alternatively, the assay may detect or measure binding of a test compound in the presence of a labeled competitor.

Additionally, the assay may be carried out using cell-free preparations, chemical libraries, or natural product mixtures, and the test compound (s) may be free in solution or affixed to a solid support.

An assay can be used to assess the ability of a compound to bind to its natural ligand and/or to inhibit the binding of its natural ligand to its natural receptors. Examples of such assays include radio- labeling assays such as those described in U. S. Patent No. 5,914, 236 and U. S. Patent No. 6,372, 724.

In a related embodiment, one or more amino acid substitutions can be introduced into a polypeptide compound (such as a receptor) to improve or alter its ability to bind to its natural ligands (Matthews, D. J. and J. A. Wells. (1994) Chem. Biol. 1: 25-30). In another related embodiment, one or more amino acid substitutions can be introduced into a polypeptide compound (such as a ligand) to improve or alter its ability to bind to its natural receptors (Cunningham, B. C. and J. A. Wells (1991) Proc. Natl. Acad.

Sci. USA 88: 3407-3411; Lowman, H. B. et al. (1991) J. Biol. Chem. 266: 10982-10988).

PMMM, fragments of PMMM, or variants of PMMM may be used to screen for compounds that modulate the activity of PMMM. Such compounds may include agonists, antagonists, or partial or inverse agonists. In one embodiment, an assay is performed under conditions permissive for PMMM activity, wherein PMMM is combined with at least one test compound, and the activity of PMMM in the presence of a test compound is compared with the activity of PMMM in the absence of the test compound. A change in the activity of PMMM in the presence of the test compound is indicative of a compound that modulates the activity of PMMM. Alternatively, a test compound is combined with an in vitro or cell-free system comprising PMMM under conditions suitable for PMMM activity, and the assay is performed. In either of these assays, a test compound which modulates the activity of PMMM may do so indirectly and need not come in direct contact with the test compound. At least one and up to a plurality of test compounds may be screened.

In another embodiment, polynucleotides encoding PMMM or their mammalian homologs may be"knocked out"in an animal model system using homologous recombination in embryonic stem (ES) cells. Such techniques are well known in the art and are useful for the generation of animal models of

human disease (see, e. g. , U. S. Patent No. 5,175, 383 and U. S. Patent No. 5,767, 337). For example, mouse ES cells, such as the mouse 129/SvJ cell line, are derived from the early mouse embryo and grown in culture. The ES cells are transformed with a vector containing the gene of interest disrupted by a marker gene, e. g. , the neomycin phosphotransferase gene (neo ; Capecchi, M. R. (1989) Science 244: 1288-1292). The vector integrates into the corresponding region of the host genome by homologous recombination. Alternatively, homologous recombination takes place using the Cre-loxP system to knockout a gene of interest in a tissue-or developmental stage-specific manner (Marth, J. D.

(1996) Clin. Invest. 97: 1999-2002; Wagner, K. U. et al. (1997) Nucleic Acids Res. 25: 4323-4330).

Transformed ES cells are identified and microinjected into mouse cell blastocysts such as those from the C57BL/6 mouse strain. The blastocysts are surgically transferred to pseudopregnant dams, and the resulting chimeric progeny are genotyped and bred to produce heterozygous or homozygous strains. Transgenic animals thus generated may be tested with potential therapeutic or toxic agents.

Polynucleotides encoding PMMM may also be manipulated in vitro in ES cells derived from human blastocysts. Human ES cells have the potential to differentiate into at least eight separate cell lineages including endoderm, mesoderm, and ectodermal cell types. These cell lineages differentiate into, for example, neural cells, hematopoietic lineages, and cardiomyocytes (Thomson, J. A. et al.

(1998) Science 282: 1145-1147).

Polynucleotides encoding PMMM can also be used to create"knockin"humanized animals (pigs) or transgenic animals (mice or rats) to model human disease. With knockin technology, a region of a polynucleotide encoding PMMM is injected into animal ES cells, and the injected sequence integrates into the animal cell genome. Transformed cells are injected into blastulae, and the blastulae are implanted as described above. Transgenic progeny or inbred lines are studied and treated with potential pharmaceutical agents to obtain information on treatment of a human disease. Alternatively, a mammal inbred to overexpress PMMM, e. g. , by secreting PMMM in its milk, may also serve as a convenient source of that protein (Janne, J. et al. (1998) Biotechnol. Annu. Rev. 4: 55-74).

THERAPEUTICS Chemical and structural similarity, e. g. , in the context of sequences and motifs, exists between regions of PMMM and protein modification and maintenance molecules. In addition, examples of tissues expressing PMMM can be found in Table 6 and can also be found in Example XI. Therefore, PMMM appears to play a role in gastrointestinal, cardiovascular, autoimmune/inflammatory, cell proliferative, developmental, epithelial, neurological, and reproductive disorders. In the treatment of disorders associated with increased PMMM expression or activity, it is desirable to decrease the expression or activity of PMMM. In the treatment of disorders associated with decreased PMMM expression or activity, it is desirable to increase the expression or activity of PMMM.

Therefore, in one embodiment, PMMM or a fragment or derivative thereof may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of PMMM. Examples of such disorders include, but are not limited to, a gastrointestinal disorder, such as dysphagia, peptic esophagitis, esophageal spasm, esophageal stricture, esophageal carcinoma, dyspepsia, indigestion, gastritis, gastric carcinoma, anorexia, nausea, emesis, gastroparesis, antral or pyloric edema, abdominal angina, pyrosis, gastroenteritis, intestinal obstruction, infections of the intestinal tract, peptic ulcer, cholelithiasis, cholecystitis, cholestasis, pancreatitis, pancreatic carcinoma, biliary tract disease, hepatitis, hyperbilirubinemia, cirrhosis, passive congestion of the liver, hepatoma, infectious colitis, ulcerative colitis, ulcerative proctitis, Crohn's disease, Whipple's disease, Mallory-Weiss syndrome, colonic carcinoma, colonic obstruction, irritable bowel syndrome, short bowel syndrome, diarrhea, constipation, gastrointestinal hemorrhage, acquired immunodeficiency syndrome (AIDS) enteropathy, jaundice, hepatic encephalopathy, hepatorenal syndrome, hepatic steatosis, hemochromatosis, Wilson's disease, alpha,-antitrypsin deficiency, Reye's syndrome, primary sclerosing cholangitis, liver infarction, portal vein obstruction and thrombosis, centrilobular necrosis, peliosis hepatis, hepatic vein thrombosis, veno-occlusive disease, preeclampsia, eclampsia, acute fatty liver of pregnancy, intrahepatic cholestasis of pregnancy, and hepatic tumors including nodular hyperplasias, adenomas, and carcinomas; a cardiovascular disorder, such as arteriovenous fistula, atherosclerosis, hypertension, vasculitis, Raynaud's disease, aneurysms, arterial dissections, varicose veins, thrombophlebitis and phlebothrombosis, vascular tumors, and complications of thrombolysis, balloon angioplasty, vascular replacement, and coronary artery bypass graft surgery, congestive heart failure, ischemic heart disease, angina pectoris, myocardial infarction, hypertensive heart disease, degenerative valvular heart disease, calcific aortic valve stenosis, congenitally bicuspid aortic valve, mitral annular calcification, mitral valve prolapse, rheumatic fever and rheumatic heart disease, infective endocarditis, nonbacterial thrombotic endocarditis, endocarditis of systemic lupus erythematosus, carcinoid heart disease, cardiomyopathy, myocarditis, pericarditis, neoplastic heart disease, congenital heart disease, and complications of cardiac transplantation; an autoimmune/inflammatory disease, such as acquired immunodeficiency syndrome (AIDS), Addison's disease, adult respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis, anemia, asthma, atherosclerosis, atherosclerotic plaque rupture, autoimmune hemolytic anemia, autoimmune thyroiditis, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), bronchitis, cholecystitis, contact dermatitis, Crohn's disease, atopic dermatitis, dermatomyositis, diabetes mellitus, emphysema, episodic lymphopenia with lymphocytotoxins, erythroblastosis fetalis, erythema nodosum, atrophic gastritis, glomerulonephritis, Goodpasture's syndrome, gout, Graves'disease, Hashimoto's thyroiditis, hypereosinophilia, irritable bowel syndrome, multiple sclerosis, myasthenia gravis,

myocardial or pericardial inflammation, osteoarthritis, degradation of articular cartilage, osteoporosis, pancreatitis, polymyositis, psoriasis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic anaphylaxis, systemic lupus erythematosus, systemic sclerosis, thrombocytopenic purpura, ulcerative colitis, uveitis, Werner syndrome, complications of cancer, hemodialysis, and extracorporeal circulation, viral, bacterial, fungal, parasitic, protozoal, and helminthic infections, and trauma; a cell proliferative disorder such as actinic keratosis, arteriosclerosis, atherosclerosis, bursitis, cirrhosis, hepatitis, mixed connective tissue disease (MCTD), myelofibrosis, paroxysmal nocturnal hemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia, and cancers including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, cancers of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, colon, gall bladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, and uterus; a developmental disorder, such as renal tubular acidosis, anemia, Cushing's syndrome, achondroplastic dwarfism, Duchenne and Becker muscular dystrophy, bone resorption, epilepsy, gonadal dysgenesis, WAGR syndrome (Wilms'tumor, aniridia, genitourinary abnormalities, and mental retardation), Smith-Magenis syndrome, myelodysplastic syndrome, hereditary mucoepithelial dysplasia, hereditary keratodermas, hereditary neuropathies such as Charcot-Marie-Tooth disease and neurofibromatosis, hypothyroidism, hydrocephalus, seizure disorders such as Syndenham's chorea and cerebral palsy, spina bifida, anencephaly, craniorachischisis, congenital glaucoma, cataract, age-related macular degeneration, and sensorineural hearing loss; an epithelial disorder, such as dyshidrotic eczema, allergic contact dermatitis, keratosis pilaris, melasma, vitiligo, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, seborrheic keratosis, folliculitis, herpes simplex, herpes zoster, varicella, candidiasis, dermatophytosis, scabies, insect bites, cherry angioma, keloid, dermatofibroma, acrochordons, urticaria, transient acantholytic dermatosis, xerosis, eczema, atopic dermatitis, contact dermatitis, hand eczema, nummular eczema, lichen simplex chronicus, asteatotic eczema, stasis dermatitis and stasis ulceration, seborrheic dermatitis, psoriasis, lichen planus, pityriasis rosea, impetigo, ecthyma, dermatophytosis, tinea versicolor, warts, acne vulgaris, acne rosacea, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, bullous pemphigoid, herpes gestationis, dermatitis herpetiformis, linear IgA disease, epidermolysis bullosa acquisita, dermatomyositis, lupus erythematosus, scleroderma and morphea, erythroderma, alopecia, figurate skin lesions, telangiectasias, hypopigmentation, hyperpigmentation, vesicles/bullae, exanthems, cutaneous drug reactions, papulonodular skin lesions, chronic non-healing wounds, photosensitivity diseases, epidermolysis bullosa simplex, epidermolytic hyperkeratosis, epidermolytic and nonepidermolytic palmoplantar keratoderma, ichthyosis bullosa of Siemens, ichthyosis exfoliativa, keratosis palmaris et plantais, keratosis palmoplantaris, palmoplantar

keratoderma, keratosis punctata, Meesmann's corneal dystrophy, pachyonychia congenita, white sponge nevus, steatocystoma multiplex, epidermal nevi/epidermolytic hyperkeratosis type, monilethrix, trichothiodystrophy, chronic hepatitis/cryptogenic cirrhosis, and colorectal hyperplasia; a neurological disorder, such as epilepsy, ischemic cerebrovascular disease, stroke, cerebral neoplasms, Alzheimer's disease, Pick's disease, Huntington's disease, dementia, Parkinson's disease and other extrapyramidal disorders, amyotrophic lateral sclerosis and other motor neuron disorders, progressive neural muscular atrophy, retinitis pigmentosa, hereditary ataxias, multiple sclerosis and other demyelinating diseases, bacterial and viral meningitis, brain abscess, subdural empyema, epidural abscess, suppurative intracranial thrombophlebitis, myelitis and radiculitis, viral central nervous system disease, prion diseases including kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, nutritional and metabolic diseases of the nervous system, neurofibromatosis, tuberous sclerosis, cerebelloretinal hemangioblastomatosis, encephalotrigeminal syndrome, mental retardation and other developmental disorders of the central nervous system including Down syndrome, cerebral palsy, neuroskeletal disorders, autonomic nervous system disorders, cranial nerve disorders, spinal cord diseases, muscular dystrophy and other neuromuscular disorders, peripheral nervous system disorders, dermatomyositis and polymyositis, inherited, metabolic, endocrine, and toxic myopathies, myasthenia gravis, periodic paralysis, mental disorders including mood, anxiety, and schizophrenic disorders, seasonal affective disorder (SAD), akathesia, amnesia, catatonia, diabetic neuropathy, tardive dyskinesia, dystonias, paranoid psychoses, postherpetic neuralgia, Tourette's disorder, progressive supranuclear palsy, corticobasal degeneration, and familial frontotemporal dementia; and a reproductive disorder, such as infertility, including tubal disease, ovulatory defects, and endometriosis, a disorder of prolactin production, a disruption of the estrous cycle, a disruption of the menstrual cycle, polycystic ovary syndrome, ovarian hyperstimulation syndrome, an endometrial or ovarian tumor, a uterine fibroid, autoimmune disorders, an ectopic pregnancy, and teratogenesis; cancer of the breast, fibrocystic breast disease, and galactorrhea; a disruption of spermatogenesis, abnormal sperm physiology, cancer of the testis, cancer of the prostate, benign prostatic hyperplasia, prostatitis, Peyronie's disease, impotence, carcinoma of the male breast, and gynecomastia.

In another embodiment, a vector capable of expressing PMMM or a fragment or derivative thereof may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of PMMM including, but not limited to, those described above.

In a further embodiment, a composition comprising a substantially purified PMMM in conjunction with a suitable pharmaceutical carrier may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of PMMM including, but not limited to, those provided above.

In still another embodiment, an agonist which modulates the activity of PMMM may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of PMMM including, but not limited to, those listed above.

In a further embodiment, an antagonist of PMMM may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of PMMM. Examples of such disorders include, but are not limited to, those gastrointestinal, cardiovascular, autoimmune/inflammatory, cell proliferative, developmental, epithelial, neurological, and reproductive disorders described above. In one aspect, an antibody which specifically binds PMMM may be used directly as an antagonist or indirectly as a targeting or delivery mechanism for bringing a pharmaceutical agent to cells or tissues which express PMMM.

In an additional embodiment, a vector expressing the complement of the polynucleotide encoding PMMM may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of PMMM including, but not limited to, those described above.

In other embodiments, any protein, agonist, antagonist, antibody, complementary sequence, or vector embodiments may be administered in combination with other appropriate therapeutic agents.

Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles. The combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.

An antagonist of PMMM may be produced using methods which are generally known in the art. In particular, purified PMMM may be used to produce antibodies or to screen libraries of pharmaceutical agents to identify those which specifically bind PMMM. Antibodies to PMMM may also be generated using methods that are well known in the art. Such antibodies may include, but are not limited to, polyclonal, monoclonal, chimeric, and single chain antibodies, Fab fragments, and fragments produced by a Fab expression library. In an embodiment, neutralizing antibodies (i. e. , those which inhibit dimer formation) can be used therapeutically. Single chain antibodies (e. g. , from camels or llamas) may be potent enzyme inhibitors and may have application in the design of peptide mimetics, and in the development of immuno-adsorbents and biosensors (Muyldermans, S. (2001) J. Biotechnol.

74: 277-302).

For the production of antibodies, various hosts including goats, rabbits, rats, mice, camels, dromedaries, llamas, humans, and others may be immunized by injection with PMMM or with any fragment or oligopeptide thereof which has immunogenic properties. Depending on the host species, various adjuvants may be used to increase immunological response. Such adjuvants include, but are

not limited to, Freund's, mineral gels such as aluminum hydroxide, and surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, KLH, and dinitrophenol. Among adjuvants used in humans, BCG (bacilli Calmette-Guerin) and Corynebacterium parvum are especially preferable.

It is preferred that the oligopeptides, peptides, or fragments used to induce antibodies to PMMM have an amino acid sequence consisting of at least about 5 amino acids, and generally will consist of at least about 10 amino acids. It is also preferable that these oligopeptides, peptides, or fragments are substantially identical to a portion of the amino acid sequence of the natural protein.

Short stretches of PMMM amino acids may be fused with those of another protein, such as KLH, and antibodies to the chimeric molecule may be produced.

Monoclonal antibodies to PMMM may be prepared using any technique which provides for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, the hybridoma technique, the human B-cell hybridoma technique, and the EBV-hybridoma technique (Kohler, G. et al. (1975) Nature 256: 495-497; Kozbor, D. et al. (1985) J. Immunol. Methods 81: 31-42; Cote, R. J. et al. (1983) Proc. Natl. Acad. Sci. USA 80: 2026-2030; Cole, S. P. et al. (1984) Mol. Cell Biol. 62: 109-120).

In addition, techniques developed for the production of"chimeric antibodies, "such as the splicing of mouse antibody genes to human antibody genes to obtain a molecule with appropriate antigen specificity and biological activity, can be used (Morrison, S. L. et al. (1984) Proc. Natl. Acad.

Sci. USA 81: 6851-6855; Neuberger, M. S. et al. (1984) Nature 312: 604-608; Takeda, S. et al. (1985) Nature 314: 452-454). Alternatively, techniques described for the production of single chain antibodies may be adapted, using methods known in the art, to produce PMMM-specific single chain antibodies.

Antibodies with related specificity, but of distinct idiotypic composition, may be generated by chain shuffling from random combinatorial immunoglobulin libraries (Burton, D. R. (1991) Proc. Natl. Acad.

Sci. USA 88: 10134-10137).

Antibodies may also be produced by inducing in vivo production in the lymphocyte population or by screening immunoglobulin libraries or panels of highly specific binding reagents as disclosed in the literature (Orlandi, R. et al. (1989) Proc. Natl. Acad. Sci. USA 86: 3833-3837; Winter, G. et al.

(1991) Nature 349: 293-299).

Antibody fragments which contain specific binding sites for PMMM may also be generated.

For example, such fragments include, but are not limited to, F (ab') 2 fragments produced by pepsin digestion of the antibody molecule and Fab fragments generated by reducing the disulfide bridges of the F (ab') 2 fragments. Alternatively, Fab expression libraries may be constructed to allow rapid and

easy identification of monoclonal Fab fragments with the desired specificity (Huse, W. D. et al. (1989) Science 246: 1275-1281).

Various immunoassays may be used for screening to identify antibodies having the desired specificity. Numerous protocols for competitive binding or immunoradiometric assays using either polyclonal or monoclonal antibodies with established specificities are well known in the art. Such immunoassays typically involve the measurement of complex formation between PMMM and its specific antibody. A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering PMMM epitopes is generally used, but a competitive binding assay may also be employed (Pound, supra).

Various methods such as Scatchard analysis in conjunction with radioimmunoassay techniques may be used to assess the affinity of antibodies for PMMM. Affinity is expressed as an association constant, Ka which is defined as the molar concentration of PMMM-antibody complex divided by the molar concentrations of free antigen and free antibody under equilibrium conditions. The Ka determined for a preparation of polyclonal antibodies, which are heterogeneous in their affinities for multiple PMMM epitopes, represents the average affinity, or avidity, of the antibodies for PMMM.

The Ka determined for a preparation of monoclonal antibodies, which are monospecific for a particular PMMM epitope, represents a true measure of affinity. High-affinity antibody preparations with Ka ranging from about 109 to 10l2 L/mole are preferred for use in immunoassays in which the PMMM- antibody complex must withstand rigorous manipulations. Low-affinity antibody preparations with Ka ranging from about lO6 to 10'L/mole are preferred for use in immunopurification and similar procedures which ultimately require dissociation of PMMM, preferably in active form, from the antibody (Catty, D. (1988) Antibodies, Volume 1 : A Practical Approach, IRL Press, Washington DC; Liddell, J. E. and A. Cryer (1991) A Practical Guide to Monoclonal Antibodies, John Wiley & Sons, New York NY).

The titer and avidity of polyclonal antibody preparations may be further evaluated to determine the quality and suitability of such preparations for certain downstream applications. For example, a polyclonal antibody preparation containing at least 1-2 mg specific antibody/ml, preferably 5-10 mg specific antibody/ml, is generally employed in procedures requiring precipitation of PMMM-antibody complexes. Procedures for evaluating antibody specificity, titer, and avidity, and guidelines for antibody quality and usage in various applications, are generally available (Catty, supra ; Coligan et al., supra).

In another embodiment of the invention, polynucleotides encoding PMMM, or any fragment or complement thereof, may be used for therapeutic purposes. In one aspect, modifications of gene expression can be achieved by designing complementary sequences or antisense molecules (DNA,

RNA, PNA, or modified oligonucleotides) to the coding or regulatory regions of the gene encoding PMMM. Such technology is well known in the art, and antisense oligonucleotides or larger fragments can be designed from various locations along the coding or control regions of sequences encoding PMMM (Agrawal, S. , ed. (1996) Antisense Therapeutics, Humana Press, Totawa NJ).

In therapeutic use, any gene delivery system suitable for introduction of the antisense sequences into appropriate target cells can be used. Antisense sequences can be delivered intracellularly in the form of an expression plasmid which, upon transcription, produces a sequence complementary to at least a portion of the cellular sequence encoding the target protein (Slater, J. E. et al. (1998) J. Allergy Clin. Immunol. 102: 469-475; Scanlon, K. J. et al. (1995) 9: 1288-1296). Antisense sequences can also be introduced intracellularly through the use of viral vectors, such as retrovirus and adeno-associated virus vectors (Miller, A. D. (1990) Blood 76: 271; Ausubel et al., supra ; Uckert, W. and W. Walther (1994) Pharmacol. Ther. 63: 323-347). Other gene delivery mechanisms include liposome-derived systems, artificial viral envelopes, and other systems known in the art (Rossi, J. J.

(1995) Br. Med. Bull. 51: 217-225; Boado, R. J. et al. (1998) J. Pharm. Sci. 87: 1308-1315; Morris, M. C. et al. (1997) Nucleic Acids Res. 25: 2730-2736).

In another embodiment of the invention, polynucleotides encoding PMMM may be used for somatic or germline gene therapy. Gene therapy may be performed to (i) correct a genetic deficiency (e. g. , in the cases of severe combined immunodeficiency (SCID)-X1 disease characterized by X- linked inheritance (Cavazzana-Calvo, M. et al. (2000) Science 288: 669-672), severe combined immunodeficiency syndrome associated with an inherited adenosine deaminase (ADA) deficiency (Blaese, R. M. et al. (1995) Science 270: 475-480; Bordignon, C. et al. (1995) Science 270: 470-475), cystic fibrosis (Zabner, J. et al. (1993) Cell 75: 207-216; Crystal, R. G. et al. (1995) Hum. Gene Therapy 6: 643-666; Crystal, R. G. et al. (1995) Hum. Gene Therapy 6: 667-703), thalassamias, familial hypercholesterolemia, and hemophilia resulting from Factor VIII or Factor IX deficiencies (Crystal, R. G. (1995) Science 270: 404-410; Verma, I. M. and N. Somia (1997) Nature 389: 239-242) ), (ii) express a conditionally lethal gene product (e. g. , in the case of cancers which result from unregulated cell proliferation), or (iii) express a protein which affords protection against intracellular parasites (e. g., against human retroviruses, such as human immunodeficiency virus (HIV) (Baltimore, D. (1988) Nature 335: 395-396; Poeschla, E. et al. (1996) Proc. Natl. Acad. Sci. USA 93: 11395-11399), hepatitis B or C virus (HBV, HCV); fungal parasites, such as Candida albicans and Paracoccidioides brasiliensis ; and protozoan parasites such as Plasmodium falciparum and Trypanosoma cruzi). In the case where a genetic deficiency in PMMM expression or regulation causes disease, the expression of PMMM from an appropriate population of transduced cells may alleviate the clinical manifestations caused by the genetic deficiency.

In a further embodiment of the invention, diseases or disorders caused by deficiencies in PMMM are treated by constructing mammalian expression vectors encoding PMMM and introducing these vectors by mechanical means into PMMM-deficient cells. Mechanical transfer technologies for use with cells in vivo or ex vitro include (i) direct DNA microinjection into individual cells, (ii) ballistic gold particle delivery, (iii) liposome-mediated transfection, (iv) receptor-mediated gene transfer, and (v) the use of DNA transposons (Morgan, R. A. and W. F. Anderson (1993) Annu. Rev. Biochem.

62: 191-217; Ivics, Z. (1997) Cell 91: 501-510; Boulay, J. -L. and H. Récipon (1998) Curr. Opin.

Biotechnol. 9: 445-450).

Expression vectors that may be effective for the expression of PMMM include, but are not limited to, the PCDNA 3.1, EPITAG, PRCCMV2, PREP, PVAX, PCR2-TOPOTA vectors (Invitrogen, Carlsbad CA), PCMV-SCRIPT, PCMV-TAG, PEGSH/PERV (Stratagene, La Jolla CA), and PTET-OFF, PTET-ON, PTRE2, PTRE2-LUC, PTK-HYG (Clontech, Palo Alto CA). PMMM may be expressed using (i) a constitutively active promoter, (e. g. , from cytomegalovirus (CMV), Rous sarcoma virus (RSV), SV40 virus, thymidine kinase (TK), or p-actin genes), (ii) an inducible promoter (e. g. , the tetracycline-regulated promoter (Gossen, M. and H. Bujard (1992) Proc. Natl. Acad. Sci.

USA 89: 5547-5551; Gossen, M. et al. (1995) Science 268: 1766-1769; Rossi, F. M. V. and H. M. Blau (1998) Curr. Opin. Biotechnol. 9: 451-456), commercially available in the T-REX plasmid (Invitrogen) ) ; the ecdysone-inducible promoter (available in the plasmids PVGRXR and PIND ; Invitrogen); the FK506/rapamycin inducible promoter; or the RU486/mifepristone inducible promoter (Rossi, F. M. V. and H. M. Blau, supra)), or (iii) a tissue-specific promoter or the native promoter of the endogenous gene encoding PMMM from a normal individual.

Commercially available liposome transformation kits (e. g. , the PERFECT LIPID TRANSFECTION KIT, available from Invitrogen) allow one with ordinary skill in the art to deliver polynucleotides to target cells in culture and require minimal effort to optimize experimental parameters. In the alternative, transformation is performed using the calcium phosphate method (Graham, F. L. and A. J. Eb (1973) Virology 52: 456-467), or by electroporation (Neumann, E. et al.

(1982) EMBO J. 1: 841-845). The introduction of DNA to primary cells requires modification of these standardized mammalian transfection protocols.

In another embodiment of the invention, diseases or disorders caused by genetic defects with respect to PMMM expression are treated by constructing a retrovirus vector consisting of (i) the polynucleotide encoding PMMM under the control of an independent promoter or the retrovirus long terminal repeat (LTR) promoter, (ii) appropriate RNA packaging signals, and (iii) a Rev-responsive element (RRE) along with additional retrovirus cis-acting RNA sequences and coding sequences required for efficient vector propagation. Retrovirus vectors (e. g. , PFB and PFBNEO) are

commercially available (Stratagene) and are based on published data (Riviere, I. et al. (1995) Proc.

Natl. Acad. Sci. USA 92: 6733-6737), incorporated by reference herein. The vector is propagated in an appropriate vector producing cell line (VPCL) that expresses an envelope gene with a tropism for receptors on the target cells or a promiscuous envelope protein such as VSVg (Armentano, D. et al.

(1987) J. Virol. 61: 1647-1650; Bender, M. A. et al. (1987) J. Virol. 61: 1639-1646; Adam, M. A. and A. D. Miller (1988) J. Virol. 62: 3802-3806; Dull, T. et al. (1998) J. Virol. 72: 8463-8471; Zufferey, R. et al. (1998) J. Virol. 72: 9873-9880). U. S. Patent No. 5,910, 434 to Rigg ("Method for obtaining retrovirus packaging cell lines producing high transducing efficiency retroviral supernatant") discloses a method for obtaining retrovirus packaging cell lines and is hereby incorporated by reference.

Propagation of retrovirus vectors, transduction of a population of cells (e. g., CD4+ T-cells), and the return of transduced cells to a patient are procedures well known to persons skilled in the art of gene therapy and have been well documented (Ranga, U. et al. (1997) J. Virol. 71: 7020-7029; Bauer, G. et al. (1997) Blood 89: 2259-2267; Bonyhadi, M. L. (1997) J. Virol. 71: 4707-4716; Ranga, U. et al. (1998) Proc. Natl. Acad. Sci. USA 95: 1201-1206; Su, L. (1997) Blood 89: 2283-2290).

In an embodiment, an adenovirus-based gene therapy delivery system is used to deliver polynucleotides encoding PMMM to cells which have one or more genetic abnormalities with respect to the expression of PMMM. The construction and packaging of adenovirus-based vectors are well known to those with ordinary skill in the art. Replication defective adenovirus vectors have proven to be versatile for importing genes encoding immunoregulatory proteins into intact islets in the pancreas (Csete, M. E. et al. (1995) Transplantation 27: 263-268). Potentially useful adenoviral vectors are described in U. S. Patent No. 5,707, 618 to Armentano ("Adenovirus vectors for gene therapy"), hereby incorporated by reference. For adenoviral vectors, see also Antinozzi, P. A. et al. (1999; Annu.

Rev. Nutr. 19: 511-544) and Verma, I. M. and N. Somia (1997; Nature 18: 389: 239-242).

In another embodiment, a herpes-based, gene therapy delivery system is used to deliver polynucleotides encoding PMMM to target cells which have one or more genetic abnormalities with respect to the expression of PMMM. The use of herpes simplex virus (HSV) -based vectors may be especially valuable for introducing PMMM to cells of the central nervous system, for which HSV has a tropism. The construction and packaging of herpes-based vectors are well known to those with ordinary skill in the art. A replication-competent herpes simplex virus (HSV) type 1-based vector has been used to deliver a reporter gene to the eyes of primates (Liu, X. et al. (1999) Exp. Eye Res.

169: 385-395). The construction of a HSV-1 virus vector has also been disclosed in detail in U. S.

Patent No. 5,804, 413 to DeLuca ("Herpes simplex virus strains for gene transfer"), which is hereby incorporated by reference. U. S. Patent No. 5,804, 413 teaches the use of recombinant HSV d92 which consists of a genome containing at least one exogenous gene to be transferred to a cell under

the control of the appropriate promoter for purposes including human gene therapy. Also taught by this patent are the construction and use of recombinant HSV strains deleted for ICP4, ICP27 and ICP22. For HSV vectors, see also Goins, W. F. et al. (1999 ; J. Virol. 73: 519-532) and Xu, H. et al.

(1994; Dev. Biol. 163: 152-161). The manipulation of cloned herpesvirus sequences, the generation of recombinant virus following the transfection of multiple plasmids containing different segments of the large herpesvirus genomes, the growth and propagation of herpesvirus, and the infection of cells with herpesvirus are techniques well known to those of ordinary skill in the art.

In another embodiment, an alphavirus (positive, single-stranded RNA virus) vector is used to deliver polynucleotides encoding PMMM to target cells. The biology of the prototypic alphavirus, Semliki Forest Virus (SFV), has been studied extensively and gene transfer vectors have been based on the SFV genome (Garoff, H. and K. -J. Li (1998) Curr. Opin. Biotechnol. 9: 464-469). During alphavirus RNA replication, a subgenomic RNA is generated that normally encodes the viral capsid proteins. This subgenomic RNA replicates to higher levels than the full length genomic RNA, resulting in the overproduction of capsid proteins relative to the viral proteins with enzymatic activity (e. g. , protease and polymerase). Similarly, inserting the coding sequence for PMMM into the alphavirus genome in place of the capsid-coding region results in the production of a large number of PMMM-coding RNAs and the synthesis of high levels of PMMM in vector transduced cells. While alphavirus infection is typically associated with cell lysis within a few days, the ability to establish a persistent infection in hamster normal kidney cells (BHK-21) with a variant of Sindbis virus (SIN) indicates that the lytic replication of alphaviruses can be altered to suit the needs of the gene therapy application (Dryga, S. A. et al. (1997) Virology 228: 74-83). The wide host range of alphaviruses will allow the introduction of PMMM into a variety of cell types. The specific transduction of a subset of cells in a population may require the sorting of cells prior to transduction. The methods of manipulating infectious cDNA clones of alphaviruses, performing alphavirus cDNA and RNA transfections, and performing alphavirus infections, are well known to those with ordinary skill in the art.

Oligonucleotides derived from the transcription initiation site, e. g. , between about positions-10 and +10 from the start site, may also be employed to inhibit gene expression. Similarly, inhibition can be achieved using triple helix base-pairing methodology. Triple helix pairing is useful because it causes inhibition of the ability of the double helix to open sufficiently for the binding of polymerases, transcription factors, or regulatory molecules. Recent therapeutic advances using triplex DNA have been described in the literature (Gee, J. E. et al. (1994) in Huber, B. E. and B. I. Carr, Molecular and Immunologic Approaches, Futura Publishing, Mt. Kisco NY, pp. 163-177). A complementary

sequence or antisense molecule may also be designed to block translation of mRNA by preventing the transcript from binding to ribosomes.

Ribozymes, enzymatic RNA molecules, may also be used to catalyze the specific cleavage of RNA. The mechanism of ribozyme action involves sequence-specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage. For example, engineered hammerhead motif ribozyme molecules may specifically and efficiently catalyze endonucleolytic cleavage of RNA molecules encoding PMMM.

Specific ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites, including the following sequences: GUA, GUU, and GUC. Once identified, short RNA sequences of between 15 and 20 ribonucleotides, corresponding to the region of the target gene containing the cleavage site, may be evaluated for secondary structural features which may render the oligonucleotide inoperable. The suitability of candidate targets may also be evaluated by testing accessibility to hybridization with complementary oligonucleotides using ribonuclease protection assays.

Complementary ribonucleic acid molecules and ribozymes may be prepared by any method known in the art for the synthesis of nucleic acid molecules. These include techniques for chemically synthesizing oligonucleotides such as solid phase phosphoramidite chemical synthesis. Alternatively, RNA molecules may be generated by in vitro and in vivo transcription of DNA molecules encoding PMMM. Such DNA sequences may be incorporated into a wide variety of vectors with suitable RNA polymerase promoters such as T7 or SP6. Alternatively, these cDNA constructs that synthesize complementary RNA, constitutively or inducibly, can be introduced into cell lines, cells, or tissues.

RNA molecules may be modified to increase intracellular stability and half-life. Possible modifications include, but are not limited to, the addition of flanking sequences at the 5'and/or 3'ends of the molecule, or the use of phosphorothioate or 2'O-methyl rather than phosphodiesterase linkages within the backbone of the molecule. This concept is inherent in the production of PNAs and can be extended in all of these molecules by the inclusion of nontraditional bases such as inosine, queosine, and wybutosine, as well as acetyl-, methyl-, thio-, and similarly modified forms of adenine, cytidine, guanine, thymine, and uridine which are not as easily recognized by endogenous endonucleases.

In other embodiments of the invention, the expression of one or more selected polynucleotides of the present invention can be altered, inhibited, decreased, or silenced using RNA interference (RNAi) or post-transcriptional gene silencing (PTGS) methods known in the art. RNAi is a post- transcriptional mode of gene silencing in which double-stranded RNA (dsRNA) introduced into a targeted cell specifically suppresses the expression of the homologous gene (i. e. , the gene bearing the

sequence complementary to the dsRNA). This effectively knocks out or substantially reduces the expression of the targeted gene. PTGS can also be accomplished by use of DNA or DNA fragments as well. RNAi methods are described by Fire, A. et al. (1998; Nature 391: 806-811) and Gura, T.

(2000; Nature 404: 804-808). PTGS can also be initiated by introduction of a complementary segment of DNA into the selected tissue using gene delivery and/or viral vector delivery methods described herein or known in the art.

RNAi can be induced in mammalian cells by the use of small interfering RNA also known as siRNA. SiRNA are shorter segments of dsRNA (typically about 21 to 23 nucleotides in length) that result in vivo from cleavage of introduced dsRNA by the action of an endogenous ribonuclease.

SiRNA appear to be the mediators of the RNAi effect in mammals. The most effective siRNAs appear to be 21 nucleotide dsRNAs with 2 nucleotide 3'overhangs. The use of siRNA for inducing RNAi in mammalian cells is described by Elbashir, S. M. et al. (2001; Nature 411: 494-498).

SiRNA can either be generated indirectly by introduction of dsRNA into the targeted cell, or directly by mammalian transfection methods and agents described herein or known in the art (such as liposome-mediated transfection, viral vector methods, or other polynucleotide delivery/introductory methods). Suitable SiRNAs can be selected by examining a transcript of the target polynucleotide (e. g., mRNA) for nucleotide sequences downstream from the AUG start codon and recording the occurrence of each nucleotide and the 3'adjacent 19 to 23 nucleotides as potential siRNA target sites, with sequences having a 21 nucleotide length being preferred. Regions to be avoided for target siRNA sites include the 5'and 3'untranslated regions (UTRs) and regions near the start codon (within 75 bases), as these may be richer in regulatory protein binding sites. UTR-binding proteins and/or translation initiation complexes may interfere with binding of the siRNP endonuclease complex. The selected target sites for siRNA can then be compared to the appropriate genome database (e. g., human, etc. ) using BLAST or other sequence comparison algorithms known in the art. Target sequences with significant homology to other coding sequences can be eliminated from consideration.

The selected SiRNAs can be produced by chemical synthesis methods known in the art or by in vitro transcription using commercially available methods and kits such as the SILENCER siRNA construction kit (Ambion, Austin TX).

In alternative embodiments, long-term gene silencing and/or RNAi effects can be induced in selected tissue using expression vectors that continuously express siRNA. This can be accomplished using expression vectors that are engineered to express hairpin RNAs (shRNAs) using methods known in the art (see, e. g. , Brummelkamp, T. R. et al. (2002) Science 296: 550-553; and Paddison, P. J. et al. (2002) Genes Dev. 16: 948-958). In these and related embodiments, shRNAs can be delivered to target cells using expression vectors known in the art. An example of a suitable expression vector for

delivery of siRNA is the PSILENCER1. 0-U6 (circular) plasmid (Ambion). Once delivered to the target tissue, shRNAs are processed in vivo into siRNA-like molecules capable of carrying out gene- specific silencing.

In various embodiments, the expression levels of genes targeted by RNAi or PTGS methods can be determined by assays for mRNA and/or protein analysis. Expression levels of the mRNA of a targeted gene, can be determined by northern analysis methods using, for example, the NORTHERNMAX-GLY kit (Ambion); by microarray methods; by PCR methods; by real time PCR methods; and by other RNA/polynucleotide assays known in the art or described herein. Expression levels of the protein encoded by the targeted gene can be determined by Western analysis using standard techniques known in the art.

An additional embodiment of the invention encompasses a method for screening for a compound which is effective in altering expression of a polynucleotide encoding PMMM. Compounds which may be effective in altering expression of a specific polynucleotide may include, but are not limited to, oligonucleotides, antisense oligonucleotides, triple helix-forming oligonucleotides, transcription factors and other polypeptide transcriptional regulators, and non-macromolecular chemical entities which are capable of interacting with specific polynucleotide sequences. Effective compounds may alter polynucleotide expression by acting as either inhibitors or promoters of polynucleotide expression. Thus, in the treatment of disorders associated with increased PMMM expression or activity, a compound which specifically inhibits expression of the polynucleotide encoding PMMM may be therapeutically useful, and in the treatment of disorders associated with decreased PMMM expression or activity, a compound which specifically promotes expression of the polynucleotide encoding PMMM may be therapeutically useful.

In various embodiments, one or more test compounds may be screened for effectiveness in altering expression of a specific polynucleotide. A test compound may be obtained by any method commonly known in the art, including chemical modification of a compound known to be effective in altering polynucleotide expression; selection from an existing, commercially-available or proprietary library of naturally-occurring or non-natural chemical compounds; rational design of a compound based on chemical and/or structural properties of the target polynucleotide; and selection from a library of chemical compounds created combinatorially or randomly. A sample comprising a polynucleotide encoding PMMM is exposed to at least one test compound thus obtained. The sample may comprise, for example, an intact or permeabilized cell, or an in vitro cell-free or reconstituted biochemical system. Alterations in the expression of a polynucleotide encoding PMMM are assayed by any method commonly known in the art. Typically, the expression of a specific nucleotide is detected by hybridization with a probe having a nucleotide sequence complementary to the sequence

of the polynucleotide encoding PMMM. The amount of hybridization may be quantified, thus forming the basis for a comparison of the expression of the polynucleotide both with and without exposure to one or more test compounds. Detection of a change in the expression of a polynucleotide exposed to a test compound indicates that the test compound is effective in altering the expression of the polynucleotide. A screen for a compound effective in altering expression of a specific polynucleotide can be carried out, for example, using a Schizosaccharomyces pombe gene expression system (Atkins, D. et al. (1999) U. S. Patent No. 5,932, 435; Arndt, G. M. et al. (2000) Nucleic Acids Res.

28: E15) or a human cell line such as HeLa cell (Clarke, M. L. et al. (2000) Biochem. Biophys. Res.

Commun. 268: 8-13). A particular embodiment of the present invention involves screening a combinatorial library of oligonucleotides (such as deoxyribonucleotides, ribonucleotides, peptide nucleic acids, and modified oligonucleotides) for antisense activity against a specific polynucleotide sequence (Bruice, T. W. et al. (1997) U. S. Patent No. 5,686, 242; Bruice, T. W. et al. (2000) U. S. Patent No.

6,022, 691).

Many methods for introducing vectors into cells or tissues are available and equally suitable for use in vivo, in vitro, and ex vivo. For ex vivo therapy, vectors may be introduced into stem cells taken from the patient and clonally propagated for autologous transplant back into that same patient.

Delivery by transfection, by liposome injections, or by polycationic amino polymers may be achieved using methods which are well known in the art (Goldman, C. K. et al. (1997) Nat. Biotechnol. 15: 462- 466).

Any of the therapeutic methods described above may be applied to any subject in need of such therapy, including, for example, mammals such as humans, dogs, cats, cows, horses, rabbits, and monkeys.

An additional embodiment of the invention relates to the administration of a composition which generally comprises an active ingredient formulated with a pharmaceutically acceptable excipient.

Excipients may include, for example, sugars, starches, celluloses, gums, and proteins. Various formulations are commonly known and are thoroughly discussed in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing, Easton PA). Such compositions may consist of PMMM, antibodies to PMMM, and mimetics, agonists, antagonists, or inhibitors of PMMM.

In various embodiments, the compositions described herein, such as pharmaceutical compositions, may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, pulmonary, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal means.

Compositions for pulmonary administration may be prepared in liquid or dry powder form.

These compositions are generally aerosolized immediately prior to inhalation by the patient. In the

case of small molecules (e. g. traditional low molecular weight organic drugs), aerosol delivery of fast- acting formulations is well-known in the art. In the case of macromolecules (e. g. larger peptides and proteins), recent developments in the field of pulmonary delivery via the alveolar region of the lung have enabled the practical delivery of drugs such as insulin to blood circulation (see, e. g., Patton, J. S. et al., U. S. Patent No. 5,997, 848). Pulmonary delivery allows administration without needle injection, and obviates the need for potentially toxic penetration enhancers.

Compositions suitable for use in the invention include compositions wherein the active ingredients are contained in an effective amount to achieve the intended purpose. The determination of an effective dose is well within the capability of those skilled in the art.

Specialized forms of compositions may be prepared for direct intracellular delivery of macromolecules comprising PMMM or fragments thereof. For example, liposome preparations containing a cell-impermeable macromolecule may promote cell fusion and intracellular delivery of the macromolecule. Alternatively, PMMM or a fragment thereof may be joined to a short cationic N- terminal portion from the HIV Tat-1 protein. Fusion proteins thus generated have been found to transduce into the cells of all tissues, including the brain, in a mouse model system (Schwarze, S. R. et al. (1999) Science 285: 1569-1572).

For any compound, the therapeutically effective dose can be estimated initially either in cell culture assays, e. g., of neoplastic cells, or in animal models such as mice, rats, rabbits, dogs, monkeys, or pigs. An animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.

A therapeutically effective dose refers to that amount of active ingredient, for example PMMM or fragments thereof, antibodies of PMMM, and agonists, antagonists or inhibitors of PMMM, which ameliorates the symptoms or condition. Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or with experimental animals, such as by calculating the ED50 (the dose therapeutically effective in 50% of the population) or LD50 (the dose lethal to 50% of the population) statistics. The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the LD50/ED50 ratio. Compositions which exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies are used to formulate a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that includes the ED50 with little or no toxicity.

The dosage varies within this range depending upon the dosage form employed, the sensitivity of the patient, and the route of administration.

The exact dosage will be determined by the practitioner, in light of factors related to the subject requiring treatment. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, the general health of the subject, the age, weight, and gender of the subject, time and frequency of administration, drug combination (s), reaction sensitivities, and response to therapy. Long-acting compositions may be administered every 3 to 4 days, every week, or biweekly depending on the half-life and clearance rate of the particular formulation.

Normal dosage amounts may vary from about 0. 1, ug to 100, 000, ug, up to a total dose of about 1 gram, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art.

Those skilled in the art will employ different formulations for nucleotides than for proteins or their inhibitors. Similarly, delivery of polynucleotides or polypeptides will be specific to particular cells, conditions, locations, etc.

DIAGNOSTICS In another embodiment, antibodies which specifically bind PMMM may be used for the diagnosis of disorders characterized by expression of PMMM, or in assays to monitor patients being treated with PMMM or agonists, antagonists, or inhibitors of PMMM. Antibodies useful for diagnostic purposes may be prepared in the same manner as described above for therapeutics. Diagnostic assays for PMMM include methods which utilize the antibody and a label to detect PMMM in human body fluids or in extracts of cells or tissues. The antibodies may be used with or without modification, and may be labeled by covalent or non-covalent attachment of a reporter molecule. A wide variety of reporter molecules, several of which are described above, are known in the art and may be used.

A variety of protocols for measuring PMMM, including ELISAs, RIAs, and FACS, are known in the art and provide a basis for diagnosing altered or abnormal levels of PMMM expression. Normal or standard values for PMMM expression are established by combining body fluids or cell extracts taken from normal mammalian subjects, for example, human subjects, with antibodies to PMMM under conditions suitable for complex formation. The amount of standard complex formation may be quantitated by various methods, such as photometric means. Quantities of PMMM expressed in subject, control, and disease samples from biopsied tissues are compared with the standard values.

Deviation between standard and subject values establishes the parameters for diagnosing disease.

In another embodiment of the invention, polynucleotides encoding PMMM may be used for diagnostic purposes. The polynucleotides which may be used include oligonucleotides, complementary RNA and DNA molecules, and PNAs. The polynucleotides may be used to detect and quantify gene expression in biopsied tissues in which expression of PMMM may be correlated with disease. The

diagnostic assay may be used to determine absence, presence, and excess expression of PMMM, and to monitor regulation of PMMM levels during therapeutic intervention.

In one aspect, hybridization with PCR probes which are capable of detecting polynucleotides, including genomic sequences, encoding PMMM or closely related molecules may be used to identify nucleic acid sequences which encode PMMM. The specificity of the probe, whether it is made from a highly specific region, e. g. , the 5'regulatory region, or from a less specific region, e. g. , a conserved motif, and the stringency of the hybridization or amplification will determine whether the probe identifies only naturally occurring sequences encoding PMMM, allelic variants, or related sequences.

Probes may also be used for the detection of related sequences, and may have at least 50% sequence identity to any of the PMMM encoding sequences. The hybridization probes of the subject invention may be DNA or RNA and may be derived from the sequence of SEQ ID NO : 72-142 or from genomic sequences including promoters, enhancers, and introns of the PMMM gene.

Means for producing specific hybridization probes for polynucleotides encoding PMMM include the cloning of polynucleotides encoding PMMM or PMMM derivatives into vectors for the production of mRNA probes. Such vectors are known in the art, are commercially available, and may be used to synthesize RNA probes in vitro by means of the addition of the appropriate RNA polymerases and the appropriate labeled nucleotides. Hybridization probes may be labeled by a variety of reporter groups, for example, by radionuclides such as 32p or 35S, or by enzymatic labels, such as alkaline phosphatase coupled to the probe via avidin/biotin coupling systems, and the like.

Polynucleotides encoding PMMM may be used for the diagnosis of disorders associated with expression of PMMM. Examples of such disorders include, but are not limited to, a gastrointestinal disorder, such as dysphagia, peptic esophagitis, esophageal spasm, esophageal stricture, esophageal carcinoma, dyspepsia, indigestion, gastritis, gastric carcinoma, anorexia, nausea, emesis, gastroparesis, antral or pyloric edema, abdominal angina, pyrosis, gastroenteritis, intestinal obstruction, infections of the intestinal tract, peptic ulcer, cholelithiasis, cholecystitis, cholestasis, pancreatitis, pancreatic carcinoma, biliary tract disease, hepatitis, hyperbilirubinemia, cirrhosis, passive congestion of the liver, hepatoma, infectious colitis, ulcerative colitis, ulcerative proctitis, Crohn's disease, Whipple's disease, Mallory-Weiss syndrome, colonic carcinoma, colonic obstruction, irritable bowel syndrome, short bowel syndrome, diarrhea, constipation, gastrointestinal hemorrhage, acquired immunodeficiency syndrome (AIDS) enteropathy, jaundice, hepatic encephalopathy, hepatorenal syndrome, hepatic steatosis, hemochromatosis, Wilson's disease, alpha, -antitrypsin deficiency, Reye's syndrome, primary sclerosing cholangitis, liver infarction, portal vein obstruction and thrombosis, centrilobular necrosis, peliosis hepatis, hepatic vein thrombosis, veno-occlusive disease, preeclampsia, eclampsia, acute fatty liver of pregnancy, intrahepatic cholestasis of pregnancy, and hepatic tumors including nodular

hyperplasias, adenomas, and carcinomas; a cardiovascular disorder, such as arteriovenous fistula, atherosclerosis, hypertension, vasculitis, Raynaud's disease, aneurysms, arterial dissections, varicose veins, thrombophlebitis and phlebothrombosis, vascular tumors, and complications of thrombolysis, balloon angioplasty, vascular replacement, and coronary artery bypass graft surgery, congestive heart failure, ischemic heart disease, angina pectoris, myocardial infarction, hypertensive heart disease, degenerative valvular heart disease, calcific aortic valve stenosis, congenitally bicuspid aortic valve, mitral annular calcification, mitral valve prolapse, rheumatic fever and rheumatic heart disease, infective endocarditis, nonbacterial thrombotic endocarditis, endocarditis of systemic lupus erythematosus, carcinoid heart disease, cardiomyopathy, myocarditis, pericarditis, neoplastic heart disease, congenital heart disease, and complications of cardiac transplantation; an autoimmune/inflammatory disease, such as acquired immunodeficiency syndrome (AIDS), Addison's disease, adult respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis, anemia, asthma, atherosclerosis, atherosclerotic plaque rupture, autoimmune hemolytic anemia, autoimmune thyroiditis, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), bronchitis, cholecystitis, contact dermatitis, Crohn's disease, atopic dermatitis, dermatomyositis, diabetes mellitus, emphysema, episodic lymphopenia with lymphocytotoxins, erythroblastosis fetalis, erythema nodosum, atrophic gastritis, glomerulonephritis, Goodpasture's syndrome, gout, Graves'disease, Hashimoto's thyroiditis, hypereosinophilia, irritable bowel syndrome, multiple sclerosis, myasthenia gravis, myocardial or pericardial inflammation, osteoarthritis, degradation of articular cartilage, osteoporosis, pancreatitis, polymyositis, psoriasis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic anaphylaxis, systemic lupus erythematosus, systemic sclerosis, thrombocytopenic purpura, ulcerative colitis, uveitis, Werner syndrome, complications of cancer, hemodialysis, and extracorporeal circulation, viral, bacterial, fungal, parasitic, protozoal, and helminthic infections, and trauma; a cell proliferative disorder such as actinic keratosis, arteriosclerosis, atherosclerosis, bursitis, cirrhosis, hepatitis, mixed connective tissue disease (MCTD), myelofibrosis, paroxysmal nocturnal hemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia, and cancers including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, cancers of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, colon, gall bladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, and uterus; a developmental disorder, such as renal tubular acidosis, anemia, Cushing's syndrome, achondroplastic dwarfism, Duchenne and Becker muscular dystrophy, bone resorption, epilepsy, gonadal dysgenesis, WAGR syndrome (Wilms'tumor, aniridia, genitourinary abnormalities, and mental retardation), Smith-Magenis syndrome, myelodysplastic syndrome, hereditary mucoepithelial dysplasia, hereditary keratodermas,

hereditary neuropathies such as Charcot-Marie-Tooth disease and neurofibromatosis, hypothyroidism, hydrocephalus, seizure disorders such as Syndenham's chorea and cerebral palsy, spina bifida, anencephaly, craniorachischisis, congenital glaucoma, cataract, age-related macular degeneration, and sensorineural hearing loss ; an epithelial disorder, such as dyshidrotic eczema, allergic contact dermatitis, keratosis pilaris, melasma, vitiligo, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, seborrheic keratosis, folliculitis, herpes simplex, herpes zoster, varicella, candidiasis, dermatophytosis, scabies, insect bites, cherry angioma, keloid, dermatofibroma, acrochordons, urticaria, transient acantholytic dermatosis, xerosis, eczema, atopic dermatitis, contact dermatitis, hand eczema, nummular eczema, lichen simplex chronicus, asteatotic eczema, stasis dermatitis and stasis ulceration, seborrheic dermatitis, psoriasis, lichen planus, pityriasis rosea, impetigo, ecthyma, dermatophytosis, tinea versicolor, warts, acne vulgaris, acne rosacea, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, bullous pemphigoid, herpes gestationis, dermatitis herpetiformis, linear IgA disease, epidermolysis bullosa acquisita, dermatomyositis, lupus erythematosus, scleroderma and morphea, erythroderma, alopecia, figurate skin lesions, telangiectasias, hypopigmentation, hyperpigmentation, vesicles/bullae, exanthems, cutaneous drug reactions, papulonodular skin lesions, chronic non-healing wounds, photosensitivity diseases, epidermolysis bullosa simplex, epidermolytic hyperkeratosis, epidermolytic and nonepidermolytic palmoplantar keratoderma, ichthyosis bullosa of Siemens, ichthyosis exfoliativa, keratosis palmaris et plantaris, keratosis palmoplantaris, palmoplantar keratoderma, keratosis punctata, Meesmann's corneal dystrophy, pachyonychia congenita, white sponge nevus, steatocystoma multiplex, epidermal nevi/epidermolytic hyperkeratosis type, monilethrix, trichothiodystrophy, chronic hepatitis/cryptogenic cirrhosis, and colorectal hyperplasia; a neurological disorder, such as epilepsy, ischemic cerebrovascular disease, stroke, cerebral neoplasms, Alzheimer's disease, Pick's disease, Huntington's disease, dementia, Parkinson's disease and other extrapyramidal disorders, amyotrophic lateral sclerosis and other motor neuron disorders, progressive neural muscular atrophy, retinitis pigmentosa, hereditary ataxias, multiple sclerosis and other demyelinating diseases, bacterial and viral meningitis, brain abscess, subdural empyema, epidural abscess, suppurative intracranial thrombophlebitis, myelitis and radiculitis, viral central nervous system disease, prion diseases including kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, nutritional and metabolic diseases of the nervous system, neurofibromatosis, tuberous sclerosis, cerebelloretinal hemangioblastomatosis, encephalotrigeminal syndrome, mental retardation and other developmental disorders of the central nervous system including Down syndrome, cerebral palsy, neuroskeletal disorders, autonomic nervous system disorders, cranial nerve disorders, spinal cord diseases, muscular dystrophy and other neuromuscular disorders, peripheral nervous system disorders, dermatomyositis and polymyositis, inherited, metabolic, endocrine, and toxic

myopathies, myasthenia gravis, periodic paralysis, mental disorders including mood, anxiety, and schizophrenic disorders, seasonal affective disorder (SAD), akathesia, amnesia, catatonia, diabetic neuropathy, tardive dyskinesia, dystonias, paranoid psychoses, postherpetic neuralgia, Tourette's disorder, progressive supranuclear palsy, corticobasal degeneration, and familial frontotemporal dementia; and a reproductive disorder, such as infertility, including tubal disease, ovulatory defects, and endometriosis, a disorder of prolactin production, a disruption of the estrous cycle, a disruption of the menstrual cycle, polycystic ovary syndrome, ovarian hyperstimulation syndrome, an endometrial or ovarian tumor, a uterine fibroid, autoimmune disorders, an ectopic pregnancy, and teratogenesis; cancer of the breast, fibrocystic breast disease, and galactorrhea ; a disruption of spermatogenesis, abnormal sperm physiology, cancer of the testis, cancer of the prostate, benign prostatic hyperplasia, prostatitis, Peyronie's disease, impotence, carcinoma of the male breast, and gynecomastia.

Polynucleotides encoding PMMM may be used in Southern or northern analysis, dot blot, or other membrane-based technologies; in PCR technologies; in dipstick, pin, and multiformat ELISA-like assays; and in microarrays utilizing fluids or tissues from patients to detect altered PMMM expression.

Such qualitative or quantitative methods are well known in the art.

In a particular embodiment, polynucleotides encoding PMMM may be used in assays that detect the presence of associated disorders, particularly those mentioned above. Polynucleotides complementary to sequences encoding PMMM may be labeled by standard methods and added to a fluid or tissue sample from a patient under conditions suitable for the formation of hybridization complexes. After a suitable incubation period, the sample is washed and the signal is quantified and compared with a standard value. If the amount of signal in the patient sample is significantly altered in comparison to a control sample then the presence of altered levels of polynucleotides encoding PMMM in the sample indicates the presence of the associated disorder. Such assays may also be used to evaluate the efficacy of a particular therapeutic treatment regimen in animal studies, in clinical trials, or to monitor the treatment of an individual patient.

In order to provide a basis for the diagnosis of a disorder associated with expression of PMMM, a normal or standard profile for expression is established. This may be accomplished by combining body fluids or cell extracts taken from normal subjects, either animal or human, with a sequence, or a fragment thereof, encoding PMMM, under conditions suitable for hybridization or amplification. Standard hybridization may be quantified by comparing the values obtained from normal subjects with values from an experiment in which a known amount of a substantially purified polynucleotide is used. Standard values obtained in this manner may be compared with values obtained from samples from patients who are symptomatic for a disorder. Deviation from standard values is used to establish the presence of a disorder.

Once the presence of a disorder is established and a treatment protocol is initiated, hybridization assays may be repeated on a regular basis to determine if the level of expression in the patient begins to approximate that which is observed in the normal subject. The results obtained from successive assays may be used to show the efficacy of treatment over a period ranging from several days to months.

With respect to cancer, the presence of an abnormal amount of transcript (either under-or overexpressed) in biopsied tissue from an individual may indicate a predisposition for the development of the disease, or may provide a means for detecting the disease prior to the appearance of actual clinical symptoms. A more definitive diagnosis of this type may allow health professionals to employ preventative measures or aggressive treatment earlier, thereby preventing the development or further progression of the cancer.

Additional diagnostic uses for oligonucleotides designed from the sequences encoding PMMM may involve the use of PCR. These oligomers may be chemically synthesized, generated enzymatically, or produced in vitro. Oligomers will preferably contain a fragment of a polynucleotide encoding PMMM, or a fragment of a polynucleotide complementary to the polynucleotide encoding PMMM, and will be employed under optimized conditions for identification of a specific gene or condition. Oligomers may also be employed under less stringent conditions for detection or quantification of closely related DNA or RNA sequences.

In a particular aspect, oligonucleotide primers derived from polynucleotides encoding PMMM may be used to detect single nucleotide polymorphisms (SNPs). SNPs are substitutions, insertions and deletions that are a frequent cause of inherited or acquired genetic disease in humans. Methods of SNP detection include, but are not limited to, single-stranded conformation polymorphism (SSCP) and fluorescent SSCP (fSSCP) methods. In SSCP, oligonucleotide primers derived from polynucleotides encoding PMMM are used to amplify DNA using the polymerase chain reaction (PCR). The DNA may be derived, for example, from diseased or normal tissue, biopsy samples, bodily fluids, and the like. SNPs in the DNA cause differences in the secondary and tertiary structures of PCR products in single-stranded form, and these differences are detectable using gel electrophoresis in non-denaturing gels. In fSCCP, the oligonucleotide primers are fluorescently labeled, which allows detection of the amplimers in high-throughput equipment such as DNA sequencing machines. Additionally, sequence database analysis methods, termed in silico SNP (isSNP), are capable of identifying polymorphisms by comparing the sequence of individual overlapping DNA fragments which assemble into a common consensus sequence. These computer-based methods filter out sequence variations due to laboratory preparation of DNA and sequencing errors using statistical models and automated analyses of DNA sequence chromatograms. In the alternative, SNPs may be detected and characterized by mass

spectrometry using, for example, the high throughput MASSARRAY system (Sequenom, Inc. , San Diego CA).

SNPs may be used to study the genetic basis of human disease. For example, at least 16 common SNPs have been associated with non-insulin-dependent diabetes mellitus. SNPs are also useful for examining differences in disease outcomes in monogenic disorders, such as cystic fibrosis, sickle cell anemia, or chronic granulomatous disease. For example, variants in the mannose-binding lectin, MBL2, have been shown to be correlated with deleterious pulmonary outcomes in cystic fibrosis. SNPs also have utility in pharmacogenomics, the identification of genetic variants that influence a patient's response to a drug, such as life-threatening toxicity. For example, a variation in N-acetyl transferase is associated with a high incidence of peripheral neuropathy in response to the anti-tuberculosis drug isoniazid, while a variation in the core promoter of the ALOX5 gene results in diminished clinical response to treatment with an anti-asthma drug that targets the 5-lipoxygenase pathway. Analysis of the distribution of SNPs in different populations is useful for investigating genetic drift, mutation, recombination, and selection, as well as for tracing the origins of populations and their migrations (Taylor, J. G. et al. (2001) Trends Mol. Med. 7: 507-512; Kwok, P. -Y. and Z. Gu (1999) Mol. Med. Today 5: 538-543; Nowotny, P. et al. (2001) Curr. Opin. Neurobiol. 11: 637-641).

Methods which may also be used to quantify the expression of PMMM include radiolabeling or biotinylating nucleotides, coamplification of a control nucleic acid, and interpolating results from standard curves (Melby, P. C. et al. (1993) J. Immunol. Methods 159: 235-244; Duplaa, C. et al. (1993) Anal. Biochem. 212: 229-236). The speed of quantitation of multiple samples may be accelerated by running the assay in a high-throughput format where the oligomer or polynucleotide of interest is presented in various dilutions and a spectrophotometric or colorimetric response gives rapid quantitation.

In further embodiments, oligonucleotides or longer fragments derived from any of the polynucleotides described herein may be used as elements on a microarray. The microarray can be used in transcript imaging techniques which monitor the relative expression levels of large numbers of genes simultaneously as described below. The microarray may also be used to identify genetic variants, mutations, and polymorphisms. This information may be used to determine gene function, to understand the genetic basis of a disorder, to diagnose a disorder, to monitor progression/regression of disease as a function of gene expression, and to develop and monitor the activities of therapeutic agents in the treatment of disease. In particular, this information may be used to develop a pharmacogenomic profile of a patient in order to select the most appropriate and effective treatment regimen for that patient. For example, therapeutic agents which are highly effective and display the fewest side effects may be selected for a patient based on his/her pharmacogenomic profile.

In another embodiment, PMMM, fragments of PMMM, or antibodies specific for PMMM may be used as elements on a microarray. The microarray may be used to monitor or measure protein-protein interactions, drug-target interactions, and gerie expression profiles, as described above.

A particular embodiment relates to the use of the polynucleotides of the present invention to generate a transcript image of a tissue or cell type. A transcript image represents the global pattern of gene expression by a particular tissue or cell type. Global gene expression patterns are analyzed by quantifying the number of expressed genes and their relative abundance under given conditions and at a given time (Seilhamer et al. ,"Comparative Gene Transcript Analysis, "U. S. Patent No. 5,840, 484; hereby expressly incorporated by reference herein). Thus a transcript image may be generated by hybridizing the polynucleotides of the present invention or their complements to the totality of transcripts or reverse transcripts of a particular tissue or cell type. In one embodiment, the hybridization takes place in high-throughput format, wherein the polynucleotides of the present invention or their complements comprise a subset of a plurality of elements on a microarray. The resultant transcript image would provide a profile of gene activity.

Transcript images may be generated using transcripts isolated from tissues, cell lines, biopsies, or other biological samples. The transcript image may thus reflect gene expression in vivo, as in the case of a tissue or biopsy sample, or in vitro, as in the case of a cell line.

Transcript images which profile the expression of the polynucleotides of the present invention may also be used in conjunction with in vitro model systems and preclinical evaluation of pharmaceuticals, as well as toxicological testing of industrial and naturally-occurring environmental compounds. All compounds induce characteristic gene expression patterns, frequently termed molecular fingerprints or toxicant signatures, which are indicative of mechanisms of action and toxicity (Nuwaysir, E. F. et al. (1999) Mol. Carcinog. 24: 153-159; Steiner, S. and N. L. Anderson (2000) Toxicol. Lett. 112-113: 467-471). If a test compound has a signature similar to that of a compound with known toxicity, it is likely to share those toxic properties. These fingerprints or signatures are most useful and refined when they contain expression information from a large number of genes and gene families. Ideally, a genome-wide measurement of expression provides the highest quality signature. Even genes whose expression is not altered by any tested compounds are important as well, as the levels of expression of these genes are used to normalize the rest of the expression data.

The normalization procedure is useful for comparison of expression data after treatment with different compounds. While the assignment of gene function to elements of a toxicant signature aids in interpretation of toxicity mechanisms, knowledge of gene function is not necessary for the statistical matching of signatures which leads to prediction of toxicity (see, for example, Press Release 00-02 from the National Institute of Environmental Health Sciences, released February 29,2000, available at

http ://www. niehs. nih. gov/oc/news/toxchip. htm). Therefore, it is important and desirable in toxicological screening using toxicant signatures to include all expressed gene sequences.

In an embodiment, the toxicity of a test compound can be assessed by treating a biological sample containing nucleic acids with the test compound. Nucleic acids that are expressed in the treated biological sample are hybridized with one or more probes specific to the polynucleotides of the present invention, so that transcript levels corresponding to the polynucleotides of the present invention may be quantified. The transcript levels in the treated biological sample are compared with levels in an untreated biological sample. Differences in the transcript levels between the two samples are indicative of a toxic response caused by the test compound in the treated sample.

Another embodiment relates to the use of the polypeptides disclosed herein to analyze the proteome of a tissue or cell type. The term proteome refers to the global pattern of protein expression in a particular tissue or cell type. Each protein component of a proteome can be subjected individually to further analysis. Proteome expression patterns, or profiles, are analyzed by quantifying the number of expressed proteins and their relative abundance under given conditions and at a given time. A profile of a cell's proteome may thus be generated by separating and analyzing the polypeptides of a particular tissue or cell type. In one embodiment, the separation is achieved using two-dimensional gel electrophoresis, in which proteins from a sample are separated by isoelectric focusing in the first dimension, and then according to molecular weight by sodium dodecyl sulfate slab gel electrophoresis in the second dimension (Steiner and Anderson, supra). The proteins are visualized in the gel as discrete and uniquely positioned spots, typically by staining the gel with an agent such as Coomassie Blue or silver or fluorescent stains. The optical density of each protein spot is generally proportional to the level of the protein in the sample. The optical densities of equivalently positioned protein spots from different samples, for example, from biological samples either treated or untreated with a test compound or therapeutic agent, are compared to identify any changes in protein spot density related to the treatment. The proteins in the spots are partially sequenced using, for example, standard methods employing chemical or enzymatic cleavage followed by mass spectrometry. The identity of the protein in a spot may be determined by comparing its partial sequence, preferably of at least 5 contiguous amino acid residues, to the polypeptide sequences of interest. In some cases, further sequence data may be obtained for definitive protein identification.

A proteomic profile may also be generated using antibodies specific for PMMM to quantify the levels of PMMM expression. In one embodiment, the antibodies are used as elements on a microarray, and protein expression levels are quantified by exposing the microarray to the sample and detecting the levels of protein bound to each array element (Lueking, A. et al. (1999) Anal. Biochem.

270: 103-111 ; Mendoze, L. G. et al. (1999) Biotechniques 27: 778-788). Detection may be performed by

a variety of methods known in the art, for example, by reacting the proteins in the sample with a thiol- or amino-reactive fluorescent compound and detecting the amount of fluorescence bound at each array element.

Toxicant signatures at the proteome level are also useful for toxicological screening, and should be analyzed in parallel with toxicant signatures at the transcript level. There is a poor correlation between transcript and protein abundances for some proteins in some tissues (Anderson, N. L. and J. Seilhamer (1997) Electrophoresis 18: 533-537), so proteome toxicant signatures may be useful in the analysis of compounds which do not significantly affect the transcript image, but which alter the proteomic profile. In addition, the analysis of transcripts in body fluids is difficult, due to rapid degradation of mRNA, so proteomic profiling may be more reliable and informative in such cases.

In another embodiment, the toxicity of a test compound is assessed by treating a biological sample containing proteins with the test compound. Proteins that are expressed in the treated biological sample are separated so that the amount of each protein can be quantified. The amount of each protein is compared to the amount of the corresponding protein in an untreated biological sample.

A difference in the amount of protein between the two samples is indicative of a toxic response to the test compound in the treated sample. Individual proteins are identified by sequencing the amino acid residues of the individual proteins and comparing these partial sequences to the polypeptides of the present invention.

In another embodiment, the toxicity of a test compound is assessed by treating a biological sample containing proteins with the test compound. Proteins from the biological sample are incubated with antibodies specific to the polypeptides of the present invention. The amount of protein recognized by the antibodies is quantified. The amount of protein in the treated biological sample is compared with the amount in an untreated biological sample. A difference in the amount of protein between the two samples is indicative of a toxic response to the test compound in the treated sample.

Microarrays may be prepared, used, and analyzed using methods known in the art (Brennan, T. M. et al. (1995) U. S. Patent No. 5,474, 796; Schena, M. et al. (1996) Proc. Natl. Acad. Sci. USA 93: 10614-10619; Baldeschweiler et al. (1995) PCT application W095/25116 ; Shalon, D. et al. (1995) PCT application W095/35505 ; Heller, R. A. et al. (1997) Proc. Natl. Acad. Sci. USA 94: 2150-2155; Heller, M. J. et al. (1997) U. S. Patent No. 5,605, 662). Various types of microarrays are well known and thoroughly described in Schena, M. , ed. (1999 ; DNA Microarrays: A Practical Approach, Oxford University Press, London).

In another embodiment of the invention, nucleic acid sequences encoding PMMM may be used to generate hybridization probes useful in mapping the naturally occurring genomic sequence.

Either coding or noncoding sequences may be used, and in some instances, noncoding sequences may

be preferable over coding sequences. For example, conservation of a coding sequence among members of a multi-gene family may potentially cause undesired cross hybridization during chromosomal mapping. The sequences may be mapped to a particular chromosome, to a specific region of a chromosome, or to artificial chromosome constructions, e. g. , human artificial chromosomes (HACs), yeast artificial chromosomes (YACs), bacterial artificial chromosomes (BACs), bacterial PI constructions, or single chromosome cDNA libraries (Harrington, J. J. et al. (1997) Nat. Genet. 15: 345- 355; Price, C. M. (1993) Blood Rev. 7: 127-134; Trask, B. J. (1991) Trends Genet. 7: 149-154). Once mapped, the nucleic acid sequences may be used to develop genetic linkage maps, for example, which correlate the inheritance of a disease state with the inheritance of a particular chromosome region or restriction fragment length polymorphism (RFLP) (Lander, E. S. and D. Botstein (1986) Proc. Natl.

Acad. Sci. USA 83: 7353-7357).

Fluorescent in situ hybridization (FISH) may be correlated with other physical and genetic map data (Heinz-Ulrich, et al. (1995) in Meyers, supra, pp. 965-968). Examples of genetic map data can be found in various scientific journals or at the Online Mendelian Inheritance in Man (OMIM) World Wide Web site. Correlation between the location of the gene encoding PMMM on a physical map and a specific disorder, or a predisposition to a specific disorder, may help define the region of DNA associated with that disorder and thus may further positional cloning efforts.

In situ hybridization of chromosomal preparations and physical mapping techniques, such as linkage analysis using established chromosomal markers, may be used for extending genetic maps.

Often the placement of a gene on the chromosome of another mammalian species, such as mouse, may reveal associated markers even if the exact chromosomal locus is not known. This information is valuable to investigators searching for disease genes using positional cloning or other gene discovery techniques. Once the gene or genes responsible for a disease or syndrome have been crudely localized by genetic linkage to a particular genomic region, e. g. , ataxia-telangiectasia to l lq22-23, any sequences mapping to that area may represent associated or regulatory genes for further investigation (Gatti, R. A. et al. (1988) Nature 336: 577-580). The nucleotide sequence of the instant invention may also be used to detect differences in the chromosomal location due to translocation, inversion, etc., among normal, carrier, or affected individuals.

In another embodiment of the invention, PMMM, its catalytic or immunogenic fragments, or oligopeptides thereof can be used for screening libraries of compounds in any of a variety of drug screening techniques. The fragment employed in such screening may be free in solution, affixed to a solid support, borne on a cell surface, or located intracellularly. The formation of binding complexes between PMMM and the agent being tested may be measured.

Another technique for drug screening provides for high throughput screening of compounds having suitable binding affinity to the protein of interest (Geysen, et al. (1984) PCT application W084/03564). In this method, large numbers of different small test compounds are synthesized on a solid substrate. The test compounds are reacted with PMMM, or fragments thereof, and washed.

Bound PMMM is then detected by methods well known in the art. Purified PMMM can also be coated directly onto plates for use in the aforementioned drug screening techniques. Alternatively, non-neutralizing antibodies can be used to capture the peptide and immobilize it on a solid support.

In another embodiment, one may use competitive drug screening assays in which neutralizing antibodies capable of binding PMMM specifically compete with a test compound for binding PMMM.

In this manner, antibodies can be used to detect the presence of any peptide which shares one or more antigenic determinants with PMMM.

In additional embodiments, the nucleotide sequences which encode PMMM may be used in any molecular biology techniques that have yet to be developed, provided the new techniques rely on properties of nucleotide sequences that are currently known, including, but not limited to, such properties as the triplet genetic code and specific base pair interactions.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

The disclosures of all patents, applications, and publications mentioned above and below, including U. S. Ser. No. 60/368,686, U. S. Ser. No. 60/378,205, and U. S. Ser. No. 60/377,489, are hereby expressly incorporated by reference.

EXAMPLES 1. Construction of cDNA Libraries Incyte cDNAs were derived from cDNA libraries described in the LIFESEQ GOLD database (Incyte, Palo Alto CA). Some tissues were homogenized and lysed in guanidinium isothiocyanate, while others were homogenized and lysed in phenol or in a suitable mixture of denaturants, such as TRIZOL (Invitrogen), a monophasic solution of phenol and guanidine isothiocyanate. The resulting lysates were centrifuged over CsCI cushions or extracted with chloroform. RNA was precipitated from the lysates with either isopropanol or sodium acetate and ethanol, or by other routine methods.

Phenol extraction and precipitation of RNA were repeated as necessary to increase RNA purity. In some cases, RNA was treated with DNase. For most libraries, poly (A) + RNA was

isolated using oligo d (T)-coupled paramagnetic particles (Promega), OLIGOTEX latex particles (QIAGEN, Chatsworth CA), or an OLIGOTEX mRNA purification kit (QIAGEN). Alternatively, RNA was isolated directly from tissue lysates using other RNA isolation kits, e. g. , the POLY (A) PURE mRNA purification kit (Ambion, Austin TX).

In some cases, Stratagene was provided with RNA and constructed the corresponding cDNA libraries. Otherwise, cDNA was synthesized and cDNA libraries were constructed with the UNIZAP vector system (Stratagene) or SUPERSCRIPT plasmid system (Invitrogen), using the recommended procedures or similar methods known in the art (Ausubel et al., supra, ch. 5). Reverse transcription was initiated using oligo d (T) or random primers. Synthetic oligonucleotide adapters were ligated to double stranded cDNA, and the cDNA was digested with the appropriate restriction enzyme or enzymes. For most libraries, the cDNA was size-selected (300-1000 bp) using SEPHACRYL S1000, SEPHAROSE CL2B, or SEPHAROSE CL4B column chromatography (Amersham Biosciences) or preparative agarose gel electrophoresis. cDNAs were ligated into compatible restriction enzyme sites of the polylinker of a suitable plasmid, e. g. , PBLUESCRIPT plasmid (Stratagene), PSPORT1 plasmid (Invitrogen, Carlsbad CA), PCDNA2.1 plasmid (Invitrogen), PBK- CMV plasmid (Stratagene), PCR2-TOPOTA plasmid (Invitrogen), PCMV-ICIS plasmid (Stratagene), pIGEN (Incyte, Palo Alto CA), pRARE (Incyte), or pINCY (Incyte), or derivatives thereof.

Recombinant plasmids were transformed into competent E. coli cells including XL1-Blue, XL1- BlueMRF, or SOLR from Stratagene or DHSa, DH10B, or ElectroMAX DH10B from Invitrogen.

II. Isolation of cDNA Clones Plasmids obtained as described in Example I were recovered from host cells by in vivo excision using the UNIZAP vector system (Stratagene) or by cell lysis. Plasmids were purified using at least one of the following: a Magic or WIZARD Minipreps DNA purification system (Promega); an AGTC Miniprep purification kit (Edge Biosystems, Gaithersburg MD); and QIAWELL 8 Plasmid, QIAWELL 8 Plus Plasmid, QIAWELL 8 Ultra Plasmid purification systems or the R. E. A. L. PREP 96 plasmid purification kit from QIAGEN. Following precipitation, plasmids were resuspended in 0.1 ml of distilled water and stored, with or without lyophilization, at 4°C.

Alternatively, plasmid DNA was amplified from host cell lysates using direct link PCR in a high-throughput format (Rao, V. B. (1994) Anal. Biochem. 216: 1-14). Host cell lysis and thermal cycling steps were carried out in a single reaction mixture. Samples were processed and stored in 384-well plates, and the concentration of amplified plasmid DNA was quantified fluorometrically using PICOGREEN dye (Molecular Probes, Eugene OR) and a FLUOROSKAN II fluorescence scanner (Labsystems Oy, Helsinki, Finland).

III. Sequencing and Analysis

Incyte cDNA recovered in plasmids as described in Example II were sequenced as follows.

Sequencing reactions were processed using standard methods or high-throughput instrumentation such as the ABI CATALYST 800 (Applied Biosystems) thermal cycler or the PTC-200 thermal cycler (MJ Research) in conjunction with the HYDRA microdispenser (Robbins Scientific) or the MICROLAB 2200 (Hamilton) liquid transfer system. cDNA sequencing reactions were prepared using reagents provided by Amersham Biosciences or supplied in ABI sequencing kits such as the ABI PRISM BIGDYE Terminator cycle sequencing ready reaction kit (Applied Biosystems).

Electrophoretic separation of cDNA sequencing reactions and detection of labeled polynucleotides were carried out using the MEGABACE 1000 DNA sequencing system (Amersham Biosciences); the ABI PRISM 373 or 377 sequencing system (Applied Biosystems) in conjunction with standard ABI protocols and base calling software; or other sequence analysis systems known in the art.

Reading frames within the cDNA sequences were identified using standard methods (Ausubel et al., supra, ch. 7). Some of the cDNA sequences were selected for extension using the techniques disclosed in Example VIII.

The polynucleotide sequences derived from Incyte cDNAs were validated by removing vector, linker, and poly (A) sequences and by masking ambiguous bases, using algorithms and programs based on BLAST, dynamic programming, and dinucleotide nearest neighbor analysis. The Incyte cDNA sequences or translations thereof were then queried against a selection of public databases such as the GenBank primate, rodent, mammalian, vertebrate, and eukaryote databases, and BLOCKS, PRINTS, DOMO, PRODOM; PROTEOME databases with sequences from Homo sapiens, Rattus norvegicus, Mus musculus, Caenorhabditis elegans, Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Candida albicans (Incyte, Palo Alto CA); hidden Markov model (HMM) -based protein family databases such as PFAM, INCY, and TIGRFAM (Haft, D. H. et al.

(2001) Nucleic Acids Res. 29: 41-43); and HMM-based protein domain databases such as SMART (Schultz, J. et al. (1998) Proc. Natl. Acad. Sci. USA 95: 5857-5864; Letunic, I. et al. (2002) Nucleic Acids Res. 30: 242-244). (HMM is a probabilistic approach which analyzes consensus primary structures of gene families; see, for example, Eddy, S. R. (1996) Curr. Opin. Struct. Biol. 6: 361-365. ) The queries were performed using programs based on BLAST, FASTA, BLIMPS, and HMMER.

The Incyte cDNA sequences were assembled to produce full length polynucleotide sequences.

Alternatively, GenBank cDNAs, GenBank ESTs, stitched sequences, stretched sequences, or Genscan-predicted coding sequences (see Examples IV and V) were used to extend Incyte cDNA assemblages to full length. Assembly was performed using programs based on Phred, Phrap, and Consed, and cDNA assemblages were screened for open reading frames using programs based on GeneMark, BLAST, and FASTA. The full length polynucleotide sequences were translated to derive

the corresponding full length polypeptide sequences. Alternatively, a polypeptide may begin at any of the methionine residues of the full length translated polypeptide. Full length polypeptide sequences were subsequently analyzed by querying against databases such as the GenBank protein databases (genpept), SwissProt, the PROTEOME databases, BLOCKS, PRINTS, DOMO, PRODOM, Prosite, hidden Markov model (HMM) -based protein family databases such as PFAM, INCY, and TIGRFAM; and HMM-based protein domain databases such as SMART. Full length polynucleotide sequences are also analyzed using MACDNASIS PRO software (MiraiBio, Alameda CA) and LASERGENE software (DNASTAR). Polynucleotide and polypeptide sequence alignments are generated using default parameters specified by the CLUSTAL algorithm as incorporated into the MEGALIGN multisequence alignment program (DNASTAR), which also calculates the percent identity between aligned sequences.

Table 7 summarizes the tools, programs, and algorithms used for the analysis and assembly of Incyte cDNA and full length sequences and provides applicable descriptions, references, and threshold parameters. The first column of Table 7 shows the tools, programs, and algorithms used, the second column provides brief descriptions thereof, the third column presents appropriate references, all of which are incorporated by reference herein in their entirety, and the fourth column presents, where applicable, the scores, probability values, and other parameters used to evaluate the strength of a match between two sequences (the higher the score or the lower the probability value, the greater the identity between two sequences).

The programs described above for the assembly and analysis of full length polynucleotide and polypeptide sequences were also used to identify polynucleotide sequence fragments from SEQ ID NO : 72-142. Fragments from about 20 to about 4000 nucleotides which are useful in hybridization and amplification technologies are described in Table 4, column 2.

IV. Identification and Editing of Coding Sequences from Genomic DNA Putative protein modification and maintenance molecules were initially identified by running the Genscan gene identification program against public genomic sequence databases (e. g. , gbpri and gbhtg). Genscan is a general-purpose gene identification program which analyzes genomic DNA sequences from a variety of organisms (Burge, C. and S. Karlin (1997) J. Mol. Biol. 268: 78-94; Burge, C. and S. Karlin (1998) Curr. Opin. Struct. Biol. 8: 346-354). The program concatenates predicted exons to form an assembled cDNA sequence extending from a methionine to a stop codon. The output of Genscan is a FASTA database of polynucleotide and polypeptide sequences. The maximum range of sequence for Genscan to analyze at once was set to 30 kb. To determine which of these Genscan predicted cDNA sequences encode protein modification and maintenance molecules, the encoded polypeptides were analyzed by querying against PFAM models for protein modification and

maintenance molecules. Potential protein modification and maintenance molecules were also identified by homology to Incyte cDNA sequences that had been annotated as protein modification and maintenance molecules. These selected Genscan-predicted sequences were then compared by BLAST analysis to the genpept and gbpri public databases. Where necessary, the Genscan-predicted sequences were then edited by comparison to the top BLAST hit from genpept to correct errors in the sequence predicted by Genscan, such as extra or omitted exons. BLAST analysis was also used to find any Incyte cDNA or public cDNA coverage of the Genscan-predicted sequences, thus providing evidence for transcription. When Incyte cDNA coverage was available, this information was used to correct or confirm the Genscan predicted sequence. Full length polynucleotide sequences were obtained by assembling Genscan-predicted coding sequences with Incyte cDNA sequences and/or public cDNA sequences using the assembly process described in Example III. Alternatively, full length polynucleotide sequences were derived entirely from edited or unedited Genscan-predicted coding sequences.

V. Assembly of Genomic Sequence Data with cDNA Sequence Data "Stitched"Sequences Partial cDNA sequences were extended with exons predicted by the Genscan gene identification program described in Example IV. Partial cDNAs assembled as described in Example III were mapped to genomic DNA and parsed into clusters containing related cDNAs and Genscan exon predictions from one or more genomic sequences. Each cluster was analyzed using an algorithm based on graph theory and dynamic programming to integrate cDNA and genomic information, generating possible splice variants that were subsequently confirmed, edited, or extended to create a full length sequence. Sequence intervals in which the entire length of the interval was present on more than one sequence in the cluster were identified, and intervals thus identified were considered to be equivalent by transitivity. For example, if an interval was present on a cDNA and two genomic sequences, then all three intervals were considered to be equivalent. This process allows unrelated but consecutive genomic sequences to be brought together, bridged by cDNA sequence. Intervals thus identified were then"stitched"together by the stitching algorithm in the order that they appear along their parent sequences to generate the longest possible sequence, as well as sequence variants.

Linkages between intervals which proceed along one type of parent sequence (cDNA to cDNA or genomic sequence to genomic sequence) were given preference over linkages which change parent type (cDNA to genomic sequence). The resultant stitched sequences were translated and compared by BLAST analysis to the genpept and gbpri public databases. Incorrect exons predicted by Genscan were corrected by comparison to the top BLAST hit from genpept. Sequences were further extended with additional cDNA sequences, or by inspection of genomic DNA, when necessary.

"Stretched"Sequences Partial DNA sequences were extended to full length with an algorithm based on BLAST analysis. First, partial cDNAs assembled as described in Example III were queried against public databases such as the GenBank primate, rodent, mammalian, vertebrate, and eukaryote databases using the BLAST program. The nearest GenBank protein homolog was then compared by BLAST analysis to either Incyte cDNA sequences or GenScan exon predicted sequences described in Example IV. A chimeric protein was generated by using the resultant high-scoring segment pairs (HSPs) to map the translated sequences onto the GenBank protein homolog. Insertions or deletions may occur in the chimeric protein with respect to the original GenBank protein homolog. The GenBank protein homolog, the chimeric protein, or both were used as probes to search for homologous genomic sequences from the public human genome databases. Partial DNA sequences were therefore"stretched"or extended by the addition of homologous genomic sequences. The resultant stretched sequences were examined to determine whether it contained a complete gene.

VI. Chromosomal Mapping of PMMM Encoding Polynucleotides The sequences which were used to assemble SEQ ID NO : 72-142 were compared with sequences from the Incyte LIFESEQ database and public domain databases using BLAST and other implementations of the Smith-Waterman algorithm. Sequences from these databases that matched SEQ ID NO : 72-142 were assembled into clusters of contiguous and overlapping sequences using assembly algorithms such as Phrap (Table 7). Radiation hybrid and genetic mapping data available from public resources such as the Stanford Human Genome Center (SHGC), Whitehead Institute for Genome Research (WIGR), and Généthon were used to determine if any of the clustered sequences had been previously mapped. Inclusion of a mapped sequence in a cluster resulted in the assignment of all sequences of that cluster, including its particular SEQ ID NO:, to that map location.

Map locations are represented by ranges, or intervals, of human chromosomes. The map position of an interval, in centiMorgans, is measured relative to the terminus of the chromosome's p- arm. (The centiMorgan (cM) is a unit of measurement based on recombination frequencies between chromosomal markers. On average, 1 cM is roughly equivalent to 1 megabase (Mb) of DNA in humans, although this can vary widely due to hot and cold spots of recombination. ) The cM distances are based on genetic markers mapped by Généthon which provide boundaries for radiation hybrid markers whose sequences were included in each of the clusters. Human genome maps and other resources available to the public, such as the NCBI"GeneMap'99"World Wide Web site (http ://www. ncbi. nlm. nih. gov/genemap/), can be employed to determine if previously identified disease genes map within or in proximity to the intervals indicated above.

Association of PMMM polynucleotides with Lung Cancer

Heritable forms of lung carcinoma have not been reported and thus, identification of relevant disease-associated genes through conventional linkage analysis is not possible. However, several studies of sporadic nonsmall cell lung carcinoma (NSCLC) tumors have reported loss of heterozygosity (LOH) in regions of chromosome 11 suggesting the presence of one or more tumor suppressor genes (Bepler, G. and Garcia-Blanco, M. A. (1994) Proc. Natl. Acad. Sci. 91: 5513-5517; Iizuka, M. (1995) Genes, Chromosomes & Cancer 13: 40-46; Rasio, D. (1995) Cancer Research 55: 3988-3991). In a study of 79 patients with lung cancer, Iizuka and coworkers found that 1 lql4- 1 lq24. 2 was deleted in many of the lung tumors studied. Mapping of this region with additional markers showed that the region of chromosome 1 Iq bounded by markers Dl 1S939 and Dl 1S938 was commonly deleted (Iizuka, et al., supra). In another study it was shown that human A549 NSCLC cells transformed with a human-derived YAC clone containing a region of chromosome 1 lq within the region bounded by Dl 1S939 and Dl 1S938, exhibited little or no increase in cell number (versus control cells whose number increased 5-10-fold in the same 5 day period). Further studies of these hybrid cells showed a decrease in tumorigenicity and an increase in latency following injection into athymic, nude mice, as compared with mice injected with control A549 cells. These studies suggest the presence of a tumor suppressor gene within this region of chromosome 1 Iq and support the association of LOH in this region with NSCLC.

Restriction fragment length polymorphism (RFLP) markers shown to be near regions of DNA known as sequence-tagged sites (STS), have been mapped to NT Contigs generated by the Human Genome Project using ePCR (Schuler, G. D. (1997) Genome Research 7: 541-550, and (1998) Trends Biotechnol. 16 (11): 456-459). Contigs containing regions of DNA with known disease-associated markers are therefore used to identify PMMM sequences that map to disease-associated regions of the genome.

Polynucleotides encoding PMMM were mapped to NT Contigs. Contigs longer than 1Mb were broken into subcontigs of 1Mb length with overlapping sections of 100kb. A preliminary step used an algorithm, similar to MEGABLAST, to define the mRNA sequence/masked genomic DNA contig pairings. The cDNA/genomic pairings identified by the first algorithm were confirmed, and the PMMM polynucleotides mapped to DNA contigs, using SIM4 (Florea, L. et al. (1998) Genome Res.

8: 967-974, version May 2000) which had been optimized for high throughput processing and strand assignment confidence). The SIM4 output of the mRNA sequence/genomic contig pairs was further processed to determine the correct location of the PMMM polynucleotides on the genomic contig, as well as their strand identity.

SEQ ID NO : 72 and SEQ ID NO : 75 were mapped to GBI: NT_009151_020. 8; and SEQ ID NO : 140 was mapped to GBI: NT_009151_019. 8 from Genbank, version 128, covering a 5.5 Mb region

of the genome that also contains lung cancer-associated genetic markers D1 lS939 and D11S938.

The maximum distance between SEQ ID NO : 72, SEQ ID NO : 75, and SEQ ID NO : 140 and markers Dl 1S939 and Dl lS938, therefore, is 5.5 Mb. Thus, SEQ ID NO : 72, SEQ ID NO : 75, and SEQ ID NO : 140 are in proximity with genetic markers shown to consistently associate with lung cancer.

Therefore, in various embodiments, SEQ ID NO : 72, SEQ ID NO : 75, and SEQ ID NO : 140 can be used for one or more of the following: i) determination of LOH in persons with lung cancer in the lung cancer disease region at 1 lql2-24. 2, ii) diagnostic assays for lung cancer, and iii) developing therapeutics and/or other treatments for lung cancer.

VII. Analysis of Polynucleotide Expression Northern analysis is a laboratory technique used to detect the presence of a transcript of a gene and involves the hybridization of a labeled nucleotide sequence to a membrane on which RNAs from a particular cell type or tissue have been bound (Sambrook and Russell, supra, ch. 7; Ausubel et al., supra, ch. 4).

Analogous computer techniques applying BLAST were used to search for identical or related molecules in databases such as GenBank or LIFESEQ (Incyte). This analysis is much faster than multiple membrane-based hybridizations. In addition, the sensitivity of the computer search can be modified to determine whether any particular match is categorized as exact or similar. The basis of the search is the product score, which is defined as: BLAST Score x Percent Identity 5 x minimum {length (Seq. 1), length (Seq. 2)} The product score takes into account both the degree of similarity between two sequences and the length of the sequence match. The product score is a normalized value between 0 and 100, and is calculated as follows : the BLAST score is multiplied by the percent nucleotide identity and the product is divided by (5 times the length of the shorter of the two sequences). The BLAST score is calculated by assigning a score of +5 for every base that matches in a high-scoring segment pair (HSP), and-4 for every mismatch. Two sequences may share more than one HSP (separated by gaps). If there is more than one HSP, then the pair with the highest BLAST score is used to calculate the product score. The product score represents a balance between fractional overlap and quality in a BLAST alignment. For example, a product score of 100 is produced only for 100% identity over the entire length of the shorter of the two sequences being compared. A product score of 70 is produced either by 100% identity and 70% overlap at one end, or by 88% identity and 100% overlap at the

other. A product score of 50 is produced either by 100% identity and 50% overlap at one end, or 79% identity and 100% overlap.

Alternatively, polynucleotides encoding PMMM are analyzed with respect to the tissue sources from which they were derived. For example, some full length sequences are assembled, at least in part, with overlapping Incyte cDNA sequences (see Example III). Each cDNA sequence is derived from a cDNA library constructed from a human tissue. Each human tissue is classified into one of the following organ/tissue categories: cardiovascular system; connective tissue; digestive system; embryonic structures; endocrine system; exocrine glands ; genitalia, female; genitalia, male ; germ cells; hemic and immune system; liver; musculoskeletal system; nervous system; pancreas; respiratory system; sense organs; skin; stomatognathic system; unclassified/mixed; or urinary tract.

The number of libraries in each category is counted and divided by the total number of libraries across all categories. Similarly, each human tissue is classified into one of the following disease/condition categories: cancer, cell line, developmental, inflammation, neurological, trauma, cardiovascular, pooled, and other, and the number of libraries in each category is counted and divided by the total number of libraries across all categories. The resulting percentages reflect the tissue-and disease-specific expression of cDNA encoding PMMM. cDNA sequences and cDNA library/tissue information are found in the LIFESEQ GOLD database (Incyte, Palo Alto CA).

VIII. Extension of PMMM Encoding Polynucleotides Full length polynucleotides are produced by extension of an appropriate fragment of the full length molecule using oligonucleotide primers designed from this fragment. One primer was synthesized to initiate 5'extension of the known fragment, and the other primer was synthesized to initiate 3'extension of the known fragment. The initial primers were designed using OLIGO 4.06 software (National Biosciences), or another appropriate program, to be about 22 to 30 nucleotides in length, to have a GC content of about 50% or more, and to anneal to the target sequence at temperatures of about 68°C to about 72°C. Any stretch of nucleotides which would result in hairpin structures and primer-primer dimerizations was avoided.

Selected human cDNA libraries were used to extend the sequence. If more than one extension was necessary or desired, additional or nested sets of primers were designed.

High fidelity amplification was obtained by PCR using methods well known in the art. PCR was performed in 96-well plates using the PTC-200 thermal cycler (MJ Research, Inc. ). The reaction mix contained DNA template, 200 nmol of each primer, reaction buffer containing Mg2+, (NH4) 2SO4, and 2-mercaptoethanol, Taq DNA polymerase (Amersham Biosciences), ELONGASE enzyme (Invitrogen), and Pfu DNA polymerase (Stratagene), with the following parameters for primer pair PCI A and PCI B: Step 1 : 94°C, 3 min; Step 2: 94°C, 15 sec; Step 3: 60°C, 1 min; Step 4: 68°C, 2

min; Step 5: Steps 2,3, and 4 repeated 20 times; Step 6: 68°C, 5 min; Step 7: storage at 4°C. In the alternative, the parameters for primer pair T7 and SK+ were as follows: Step 1: 94°C, 3 min; Step 2: 94°C, 15 sec; Step 3: 57°C, 1 min; Step 4: 68°C, 2 min; Step 5: Steps 2,3, and 4 repeated 20 times; Step 6: 68°C, 5 min; Step 7: storage at 4°C.

The concentration of DNA in each well was determined by dispensing 100 itl PICOGREEN quantitation reagent (0.25% (v/v) PICOGREEN; Molecular Probes, Eugene OR) dissolved in 1X TE and 0.5 yl of undiluted PCR product into each well of an opaque fluorimeter plate (Corning Costar, Acton MA), allowing the DNA to bind to the reagent. The plate was scanned in a Fluoroskan 11 (Labsystems Oy, Helsinki, Finland) to measure the fluorescence of the sample and to quantify the concentration of DNA. A 5 tl to 10, ul aliquot of the reaction mixture was analyzed by electrophoresis on a 1 % agarose gel to determine which reactions were successful in extending the sequence.

The extended nucleotides were desalted and concentrated, transferred to 384-well plates, digested with CviJI cholera virus endonuclease (Molecular Biology Research, Madison WI), and sonicated or sheared prior to religation into pUC 18 vector (Amersham Biosciences). For shotgun sequencing, the digested nucleotides were separated on low concentration (0.6 to 0.8%) agarose gels, fragments were excised, and agar digested with Agar ACE (Promega). Extended clones were religated using T4 ligase (New England Biolabs, Beverly MA) into pUC 18 vector (Amersham Biosciences), treated with Pfu DNA polymerase (Stratagene) to fill-in restriction site overhangs, and transfected into competent E. coli cells. Transformed cells were selected on antibiotic-containing media, and individual colonies were picked and cultured overnight at 37°C in 384-well plates in LB/2x carb liquid media.

The cells were lysed, and DNA was amplified by PCR using Taq DNA polymerase (Amersham Biosciences) and Pfu DNA polymerase (Stratagene) with the following parameters: Step 1: 94°C, 3 min; Step 2: 94°C, 15 sec; Step 3: 60°C, 1 min; Step 4: 72°C, 2 min; Step 5: steps 2,3, and 4 repeated 29 times; Step 6: 72°C, 5 min; Step 7: storage at 4°C. DNA was quantified by PICOGREEN reagent (Molecular Probes) as described above. Samples with low DNA recoveries were reamplified using the same conditions as described above. Samples were diluted with 20% dimethysulfoxide (1: 2, v/v), and sequenced using DYENAMIC energy transfer sequencing primers and the DYENAMIC DIRECT kit (Amersham Biosciences) or the ABI PRISM BIGDYE Terminator cycle sequencing ready reaction kit (Applied Biosystems).

In like manner, full length polynucleotides are verified using the above procedure or are used to obtain 5'regulatory sequences using the above procedure along with oligonucleotides designed for such extension, and an appropriate genomic library.

IX. Identification of Single Nucleotide Polymorphisms in PMMM Encoding Polynucleotides Common DNA sequence variants known as single nucleotide polymorphisms (SNPs) were identified in SEQ ID NO : 72-142 using the LIFESEQ database (Incyte). Sequences from the same gene were clustered together and assembled as described in Example III, allowing the identification of all sequence variants in the gene. An algorithm consisting of a series of filters was used to distinguish SNPs from other sequence variants. Preliminary filters removed the majority of basecall errors by requiring a minimum Phred quality score of 15, and removed sequence alignment errors and errors resulting from improper trimming of vector sequences, chimeras, and splice variants. An automated procedure of advanced chromosome analysis analysed the original chromatogram files in the vicinity of the putative SNP. Clone error filters used statistically generated algorithms to identify errors introduced during laboratory processing, such as those caused by reverse transcriptase, polymerase, or somatic mutation. Clustering error filters used statistically generated algorithms to identify errors resulting from clustering of close homologs or pseudogenes, or due to contamination by non-human sequences. A final set of filters removed duplicates and SNPs found in immunoglobulins or T-cell receptors.

Certain SNPs were selected for further characterization by mass spectrometry using the high throughput MASSARRAY system (Sequenom, Inc. ) to analyze allele frequencies at the SNP sites in four different human populations. The Caucasian population comprised 92 individuals (46 male, 46 female), including 83 from Utah, four French, three Venezualan, and two Amish individuals. The African population comprised 194 individuals (97 male, 97 female), all African Americans. The Hispanic population comprised 324 individuals (162 male, 162 female), all Mexican Hispanic. The Asian population comprised 126 individuals (64 male, 62 female) with a reported parental breakdown of 43% Chinese, 31% Japanese, 13% Korean, 5% Vietnamese, and 8% other Asian. Allele frequencies were first analyzed in the Caucasian population; in some cases those SNPs which showed no allelic variance in this population were not further tested in the other three populations.

X. Labeling and Use of Individual Hybridization Probes Hybridization probes derived from SEQ ID NO : 72-142 are employed to screen cDNAs, genomic DNAs, or mRNAs. Although the labeling of oligonucleotides, consisting of about 20 base pairs, is specifically described, essentially the same procedure is used with larger nucleotide fragments. Oligonucleotides are designed using state-of-the-art software such as OLIGO 4.06 software (National Biosciences) and labeled by combining 50 pmol of each oligomer, 250 iCi of [y 32p] adenosine triphosphate (Amersham Biosciences), and T4 polynucleotide kinase (DuPont NEN, Boston MA). The labeled oligonucleotides are substantially purified using a SEPHADEX G-25

superfine size exclusion dextran bead column (Amersham Biosciences). An aliquot containing 10' counts per minute of the labeled probe is used in a typical membrane-based hybridization analysis of human genomic DNA digested with one of the following endonucleases : Ase I, Bgl II, Eco RI, Pst I, Xba I, or Pvu II (DuPont NEN).

The DNA from each digest is fractionated on a 0.7% agarose gel and transferred to nylon membranes (Nytran Plus, Schleicher & Schuell, Durham NH). Hybridization is carried out for 16 hours at 40°C. To remove nonspecific signals, blots are sequentially washed at room temperature under conditions of up to, for example, 0.1 x saline sodium citrate and 0.5% sodium dodecyl sulfate.

Hybridization patterns are visualized using autoradiography or an alternative imaging means and compared.

XI. Microarrays The linkage or synthesis of array elements upon a microarray can be achieved utilizing photolithography, piezoelectric printing (ink-jet printing; see, e. g. , Baldeschweiler et al., supra), mechanical microspotting technologies, and derivatives thereof. The substrate in each of the aforementioned technologies should be uniform and solid with a non-porous surface (Schena, M. , ed.

(1999) DNA Microarrays : A Practical Approach, Oxford University Press, London). Suggested substrates include silicon, silica, glass slides, glass chips, and silicon wafers. Alternatively, a procedure analogous to a dot or slot blot may also be used to arrange and link elements to the surface of a substrate using thermal, UV, chemical, or mechanical bonding procedures. A typical array may be produced using available methods and machines well known to those of ordinary skill in the art and may contain any appropriate number of elements (Schena, M. et al. (1995) Science 270: 467-470; Shalon, D. et al. (1996) Genome Res. 6: 639-645; Marshal, A. and J. Hodgson (1998) Nat. Biotechnol.

16: 27-31).

Full length cDNAs, Expressed Sequence Tags (ESTs), or fragments or oligomers thereof may comprise the elements of the microarray. Fragments or oligomers suitable for hybridization can be selected using software well known in the art such as LASERGENE software (DNASTAR). The array elements are hybridized with polynucleotides in a biological sample. The polynucleotides in the biological sample are conjugated to a fluorescent label or other molecular tag for ease of detection.

After hybridization, nonhybridized nucleotides from the biological sample are removed, and a fluorescence scanner is used to detect hybridization at each array element. Alternatively, laser desorbtion and mass spectrometry may be used for detection of hybridization. The degree of complementarity and the relative abundance of each polynucleotide which hybridizes to an element on the microarray may be assessed. In one embodiment, microarray preparation and usage is described in detail below.

Tissue or Cell Sample Preparation Total RNA is isolated from tissue samples using the guanidinium thiocyanate method and poly (A) + RNA is purified using the oligo- (dT) cellulose method. Each poly (A) + RNA sample is reverse transcribed using MMLV reverse-transcriptase, 0.05 pg/8l oligo-(dT) primer (21mer), 1X first strand buffer, 0.03 units/lil RNase inhibitor, 500, uM dATP, 500 yM dGTP, 500, uM dTTP, 40, uM dCTP, 40 AM dCTP-Cy3 (BDS) or dCTP-Cy5 (Amersham Biosciences). The reverse transcription reaction is performed in a 25 ml volume containing 200 ng poly (A) + RNA with GEMBRIGHT kits (Incyte). Specific control poly (A) + RNAs are synthesized by in vitro transcription from non-coding yeast genomic DNA. After incubation at 37° C for 2 hr, each reaction sample (one with Cy3 and another with Cy5 labeling) is treated with 2.5 ml of 0. 5M sodium hydroxide and incubated for 20 minutes at 85° C to the stop the reaction and degrade the RNA. Samples are purified using two successive CHROMA SPIN 30 gel filtration spin columns (Clontech, Palo Alto CA) and after combining, both reaction samples are ethanol precipitated using 1 ml of glycogen (1 mg/ml), 60 ml sodium acetate, and 300 ml of 100% ethanol. The sample is then dried to completion using a SpeedVAC (Savant Instruments Inc. , Holbrook NY) and resuspended in 14 yI SX SSC/0.2% SDS.

Microarray Preparation Sequences of the present invention are used to generate array elements. Each array element is amplified from bacterial cells containing vectors with cloned cDNA inserts. PCR amplification uses primers complementary to the vector sequences flanking the cDNA insert. Array elements are amplified in thirty cycles of PCR from an initial quantity of 1-2 ng to a final quantity greater than 5 itg.

Amplified array elements are then purified using SEPHACRYL-400 (Amersham Biosciences).

Purified array elements are immobilized on polymer-coated glass slides. Glass microscope slides (Corning) are cleaned by ultrasound in 0. 1% SDS and acetone, with extensive distilled water washes between and after treatments. Glass slides are etched in 4% hydrofluoric acid (VWR Scientific Products Corporation (VWR), West Chester PA), washed extensively in distilled water, and coated with 0.05% aminopropyl silane (Sigma-Aldrich, St. Louis MO) in 95% ethanol. Coated slides are cured in a 110°C oven.

Array elements are applied to the coated glass substrate using a procedure described in U. S.

Patent No. 5,807, 522, incorporated herein by reference. 1 Al of the array element DNA, at an average concentration of 100 ng/1, is loaded into the open capillary printing element by a high-speed robotic apparatus. The apparatus then deposits about 5 nl of array element sample per slide.

Microarrays are UV-crosslinked using a STRATALINKER UV-crosslinker (Stratagene).

Microarrays are washed at room temperature once in 0.2% SDS and three times in distilled water.

Non-specific binding sites are blocked by incubation of microarrays in 0.2% casein in phosphate

buffered saline (PBS) (Tropix, Inc. , Bedford MA) for 30 minutes at 60°C followed by washes in 0.2% SDS and distilled water as before.

Hybridization Hybridization reactions contain 9 Ill of sample mixture consisting of 0.2 ttg each of Cy3 and Cy5 labeled cDNA synthesis products in 5X SSC, 0.2% SDS hybridization buffer. The sample mixture is heated to 65° C for 5 minutes and is aliquoted onto the microarray surface and covered with an 1.8 cm'coverslip. The arrays are transferred to a waterproof chamber having a cavity just slightly larger than a microscope slide. The chamber is kept at 100% humidity internally by the addition of 140 lil of 5X SSC in a corner of the chamber. The chamber containing the arrays is incubated for about 6. 5 hours at 60°C. The arrays are washed for 10 min at 45°C in a first wash buffer (1X SSC, 0.1% SDS), three times for 10 minutes each at 45°C in a second wash buffer (0. 1X SSC), and dried.

Detection Reporter-labeled hybridization complexes are detected with a microscope equipped with an Innova 70 mixed gas 10 W laser (Coherent, Inc. , Santa Clara CA) capable of generating spectral lines at 488 nm for excitation of Cy3 and at 632 nm for excitation of Cy5. The excitation laser light is focused on the array using a 20X microscope objective (Nikon, Inc. , Melville NY). The slide containing the array is placed on a computer-controlled X-Y stage on the microscope and raster- scanned past the objective. The 1.8 cm x 1.8 cm array used in the present example is scanned with a resolution of 20 micrometers.

In two separate scans, a mixed gas multiline laser excites the two fluorophores sequentially.

Emitted light is split, based on wavelength, into two photomultiplier tube detectors (PMT R1477, Hamamatsu Photonics Systems, Bridgewater NJ) corresponding to the two fluorophores. Appropriate filters positioned between the array and the photomultiplier tubes are used to filter the signals. The emission maxima of the fluorophores used are 565 nm for Cy3 and 650 nm for Cy5. Each array is typically scanned twice, one scan per fluorophore using the appropriate filters at the laser source, although the apparatus is capable of recording the spectra from both fluorophores simultaneously.

The sensitivity of the scans is typically calibrated using the signal intensity generated by a cDNA control species added to the sample mixture at a known concentration. A specific location on the array contains a complementary DNA sequence, allowing the intensity of the signal at that location to be correlated with a weight ratio of hybridizing species of 1: 100,000. When two samples from different sources (e. g. , representing test and control cells), each labeled with a different fluorophore, are hybridized to a single array for the purpose of identifying genes that are differentially expressed, the calibration is done by labeling samples of the calibrating cDNA with the two fluorophores and adding identical amounts of each to the hybridization mixture.

The output of the photomultiplier tube is digitized using a 12-bit RTI-835H analog-to-digital (A/D) conversion board (Analog Devices, Inc. , Norwood MA) installed in an IBM-compatible PC computer. The digitized data are displayed as an image where the signal intensity is mapped using a linear 20-color transformation to a pseudocolor scale ranging from blue (low signal) to red (high signal). The data is also analyzed quantitatively. Where two different fluorophores are excited and measured simultaneously, the data are first corrected for optical crosstalk (due to overlapping emission spectra) between the fluorophores using each fluorophore's emission spectrum.

A grid is superimposed over the fluorescence signal image such that the signal from each spot is centered in each element of the grid. The fluorescence signal within each element is then integrated to obtain a numerical value corresponding to the average intensity of the signal. The software used for signal analysis is the GEMTOOLS gene expression analysis program (Incyte). Array elements that exhibit at least about a two-fold change in expression, a signal-to-background ratio of at least about 2.5, and an element spot size of at least about 40%, are considered to be differentially expressed.

Expression For example, SEQ ID NO : 74, SEQ ID NO : 83, and SEQ ID NO : 91 showed differential expression in breast tumor cell lines versus normal mammary epithelial cell lines as determined by microarray analysis. The gene expression profile of a nonmalignant mammary epithelial cell line was compared to the gene expression profiles of breast carcinoma lines at different stages of tumor progression. Cell lines compared included: a) BT-20, a breast carcinoma cell line derived in vitro from the cells emigrating out of thin slices of tumor mass isolated from a 74-year-old female, b) BT- 474, a breast ductal carcinoma cell line that was isolated from a solid, invasive ductal carcinoma of the breast obtained from a 60-year-old woman, c) BT-483, a breast ductal carcinoma cell line that was isolated from a papillary invasive ductal tumor obtained from a 23-year-old normal, menstruating, parous female with a family history of breast cancer, d) Hs 578T, a breast ductal carcinoma cell line isolated from a 74-year-old female with breast carcinoma, e) MCF7, a nonmalignant breast adenocarcinoma cell line isolated from the pleural effusion of a 69-year-old female, f) MCF-10A, a breast mammary gland (luminal ductal characteristics) cell line isolated from a 36-year-old woman with fibrocystic breast disease, g) MDA-MB-468, a breast adenocarcinoma cell line isolated from the pleural effusion of a 51-year-old female with metastatic adenocarcinoma of the breast, and h) HMEC, a primary breast epithelial cell line isolated from a normal donor. The expression of SEQ ID NO : 74 was increased by at least two-fold in the MDA-MB-468 cell line as compared to the HMEC cell line.

The expression of SEQ ID NO : 83 was decreased by at least two-fold in the MCF7 cell line as compared to the HMEC cell line. The expression of SEQ ID NO : 91 was increased by at least two-

fold in the Hs 578T cell line as compared to the HMEC cell line. Therefore, SEQ ID NO : 74, SEQ ID NO : 83, and SEQ ID NO : 91 are useful in monitoring treatment of, and diagnostic assays for, breast cancer.

In an alternative example, SEQ ID NO : 75 showed differential expression in ovary tumors versus normal ovary tissue as determined by microarray analysis. A normal ovary from a 79 year-old female donor was compared to an ovarian tumor from the same donor (Huntsman Cancer Institute, Salt Lake City, UT). The expression of SEQ ID NO : 75 was decreased by at least two-fold in the ovarian tumor tissue as compared to the matched normal tissue. Therefore, SEQ ID NO : 75 is useful in monitoring treatment of, and diagnostic assays for, ovarian cancer.

In an alternative example, SEQ ID NO : 76 showed differential expression in colon tumor tissue versus normal colon tissue as determined by microarray analysis. Gene expression profiles were obtained by comparing normal sigmoid colon tissue from a 48-year-old female to a sigmoid colon tumor originating from a metastatic gastric sarcoma (stromal tumor) from the same donor (Huntsman Cancer Institute, Salt Lake City, UT). The expression of SEQ ID NO : 76 was increased by at least two-fold in the lung tumor tissue as compared to the matched normal tissue. Therefore, SEQ ID NO : 76 is useful in monitoring treatment of, and diagnostic assays for, colon cancer.

In an alternative example, SEQ ID NO : 79 and SEQ ID NO : 85 showed differential expression in lung tumor tissue versus normal lung as determined by microarray analysis. Normal lung was compared to lung tumor tissue from the same donor (Roy Castle International Centre for Lung Cancer Research, Liverpool, UK). The expression of SEQ ID NO : 79 and SEQ ID NO : 85 were increased by at least two-fold in the lung tumor tissue as compared to the matched normal tissue. Therefore, SEQ ID NO : 79 and SEQ ID NO : 85 are useful in monitoring treatment of, and diagnostic assays for, lung cancer.

In an alternative example, SEQ ID NO : 77 showed differential expression in a prostate tumor cell line versus a normal primary prostate epithelial cell line as determined by microarray analysis.

Primary prostate epithelial cells were compared with prostate carcinomas representative of the different stages of tumor progression. Cell lines compared included: a) PrEC, a primary prostate epithelial cell line isolated from a normal donor, b) DU 145, a prostate carcinoma cell line isolated from a metastatic site in the brain of 69-year old male with widespread metastatic prostate carcinoma, c) LNCaP, a prostate carcinoma cell line isolated from a lymph node biopsy of a 50-year-old male with metastatic prostate carcinoma, and d) PC-3, a prostate adenocarcinoma cell line isolated from a metastatic site in the bone of a 62-year-old male with grade IV prostate adenocarcinoma. Cells grown under in basal media in the absence of growth factors and hormones, or under optimal growth conditions in the presence of growth factors and nutrients, were compared to normal PrECs grown

under restrictive conditions. In both cases, the expression of SEQ ID NO : 77 was increased by at least two-fold in the LNCaP prostate carcinoma cell line as compared to PrEC cells. Therefore, SEQ ID NO : 77 is useful in monitoring treatment of, and diagnostic assays for, prostate cancer.

In an alternative example, PBMCs were stimulated in vitro with soluble PMA and ionomycin for 1,2, 4,8, and 20 hours. These treated cells were compared to untreated PBMCs kept in culture in the absence of stimuli. Jurkat cells were stimulated in vitro with soluble PMA and ionomycin for 0.5, 1,2, and 4 hours. These treated cells were compared to untreated Jurkat cells kept in culture in the absence of stimuli. In both cases, the expression of SEQ ID NO : 86 was increased at least two-fold in the treated cells as compared to the untreated cells at later timepoints. Therefore, SEQ ID NO : 86 is useful in monitoring treatment of, and diagnostic assays for, autoimmune and inflammatory disorders.

In an alternative example, SEQ ID NO : 94 is downregulated in endothelial umbilical vein (ECV) cells treated with phorbol myristate acetate (PMA) versus untreated ECV cells as determined by microarray analysis. ECV304 (endothelial umbilical vein) cells were stimulated in vitro with soluble PMA and ionomycin for 0.5, 1,2, 4, and 8 hours. The treated cells were compared to untreated ECV304 cells kept in culture in the absence of stimuli. Array elements that exhibited about at least a two-fold change in expression and a signal intensity over 250 units, a signal-to-background ratio of a least 2.5, and an element spot size of at least 40% were identified as differentially expressed using the GEMTOOLS program (Incyte Genomics). Therefore, SEQ ID NO : 94 is useful in monitoring treatment of, and diagnostic assays for, autoimmune/inflammatory disorders.

In an alternative example, SEQ ID NO : 96 and SEQ ID NO : 120 are downregulated in colon cancer versus normal sigmoid colon tissue as determined by microarray analysis. Gene expression profiles were obtained by comparing normal sigmoid colon tissue from a 48-year-old female to a sigmoid colon tumor originating from a metastatic gastric sarcoma (stromal tumor) from the same donor (Huntsman Cancer Institute, Salt Lake City, UT). Therefore, SEQ ID NO : 96 and SEQ ID NO : 120 are useful in monitoring treatment of, and diagnostic assays for, colon cancer.

In an alternative example, SEQ ID NO : 96 is upregulated in human umbilical vascular endothelium cells (HUVEC) treated with interferon-gamma (IFN-Y) and tumor necrosis factor-alpha (TNF-a) versus untreated HUVECs as determined by microarray analysis. HUVECs were pretreated with IFN-y at 10 ng/ml and 200 ng/ml for 24 hours, washed, and then stimulated with TNF-a for an additional 1, 4, and 24 hours. The effect of IFN-y pretreatment was assessed on HUVECs incubated with this factor for 24 hours at 10 ng/ml and 200 ng/ml. In addition, HUVECs were stimulated with TNF-a for 1, 4, and 24 hours, in the absence of any pretreatment. Treated HUVECs were compared to HUVECs maintained in culture in the absence of stimuli for 24 hours.

Therefore, SEQ ID NO : 96 is useful in monitoring treatment of, and diagnostic assays for, autoimmune/inflammatory and cell proliferative disorders.

In an alternative example, SEQ ID NO : 97 is downregulated in lung cancer versus grossly uninvolved lung tissue as determined by microarray analysis. In one experiment, grossly uninvolved lung tissue from a 66 year-old male was compared to lung squamous cell carcinoma tissue from the same donor (Roy Castle International Centre for Lung Cancer Research, Liverpool, UK). In a second experiment, grossly uninvolved lung tissue with no visible abnormalities, from a 73 year-old male, was compared to lung squamous cell adenocarcinoma tissue from the same donor (Roy Castle International Centre for Lung Cancer Research, Liverpool, UK). Therefore, SEQ ID NO : 97 is useful in monitoring treatment of, and diagnostic assays for, lung cancer.

In an alternative example, SEQ ID NO : 102, SEQ ID NO : 108, and SEQ ID NO : 114 are downregulated in osteosarcoma versus normal human osteoblasts as determined by microarray analysis. Messenger RNA from normal human osteoblasts was compared with mRNA from biopsy specimens, osteosarcoma tissues, or primary cultures or metastasized tissues. A normal osteoblast primary culture, NHOst 5488, was chosen as the reference in the initial experiments. One basic set of experiments is defined as the comparison of mRNA from biopsy specimen with that of definitive surgical specimen from the same patient. Extended study of this basic set includes mRNA from primary cell cultures of the definitive surgical specimen, muscle, or cartilage tissue from the same patient. Biopsy specimens, definitive surgical specimens, or lung metastatic tissues from different individuals were also included to reveal individual variability. Therefore, SEQ ID NO : 102, SEQ ID NO : 108, and SEQ ID NO : 114 are useful in monitoring treatment of, and diagnostic assays for, bone cancer.

In an alternative example, SEQ ID NO : 108 is downregulated in THP-1 cells treated with PMA and ionomycin versus untreated THP-1 cells. THP-1 is a promonocyte cell line that was isolated from the peripheral blood of a 1-year-old male with acute monocytic leukemia. PMA is a broad activator of the protein kinase C-dependent pathways. Upon stimulation with PMA, THP-1 differentiates into a macrophagelike cell that displays many characteristics of peripheral human macrophages. THP-1 cells were stimulated in vitro with soluble PMA and ionomycin for 0.5, 1,2, 4, and 8 hours. These treated cells were compared to untreated THP-1 cells kept in culture in the absence of stimuli. Therefore, SEQ ID N0 : 108 is useful in monitoring treatment of, and diagnostic assays for, autoimmune/inflammatory and cell proliferative disorders.

In an alternative example, SEQ ID NO : 108 is upregulated in lung adenocarcinoma versus normal lung tissue, as determined by microarray analysis. In one experiment, grossly uninvolved lung tissue from a 66 year-old female was compared to lung adenocarcinoma tissue from the same donor

(Roy Castle International Centre for Lung Cancer Research, Liverpool, UK). In a second experiment, grossly uninvolved lung tissue from a 73 year-old male was compared to lung squamous cell carcinoma tissue from the same donor (Roy Castle International Centre for Lung Cancer Research, Liverpool, UK). Therefore, SEQ ID NO : 108 is useful in monitoring treatment of, and diagnostic assays for, lung cancer.

In an alternative example, SEQ ID NO : 108 is upregulated in human umbilical vascular endothelium cells (HUVEC) treated with interferon-gamma (IFN-y) and tumor necrosis factor-alpha (TNF-a) versus untreated HUVECs as determined by microarray analysis. In one experiment, HUVECs were pretreated with the PKC-agonist PMA at 10 nM and 100 nM for 24 hours, washed, and then stimulated with TNF-a for an additional 1,4, and 24 hours. The effect of PMA pretreatment was assessed on HUVECs incubated with this factor for 24 hours at 10 nM and 100 nM. In addition, HUVECs were stimulated with TNF-a for 1,4, and 24 hours, in the absence of any pretreatment.

PMA-pretreated HUVECs were compared to HUVECs maintained in culture in the absence of stimuli for 24 hours. TNF-a-treated control HUVECs were compared to untreated cells. In a second experiment, HUVECs were pretreated with IFN-y at 10 ng/ml and 200 ng/ml for 24 hours, washed, and then stimulated with TNF-a for an additional 1,4, and 24 hours. The effect of IFN-y pretreatment was assessed on HUVECs incubated with this factor for 24 hours at 10 ng/ml and 200 ng/ml. In addition, HUVECs were stimulated with TNF-a for 1, 4, and 24 hours, in the absence of any pretreatment. Treated HUVECs were compared to HUVECs maintained in culture in the absence of stimuli for 24 hours. Therefore, SEQ ID NO: 108 is useful in monitoring treatment of, and diagnostic assays for, cell proliferative disorders.

In an alternative example, SEQ ID NO : 108 is downregulated in specific brain regions including dentate, neocortex, and spinal cord cervical neurons versus pooled brain tissue, as determined by microarray analysis. Specific brain regions from 4 individual male donors (47,48, 59, and 60 years old) were compared to a pooled brain control. The pooled brain control was reconstituted from the purified mRNA isolated from the major regions of the brain from two male brains (the 47-year-old male and the 48-year-old male). Therefore, SEQ ID NO : 108 is useful in monitoring treatment of, and diagnostic assays for, neurological disorders.

In an alternative example, SEQ ID NO : 108 and SEQ ID NO : 114 are downregulated in preadipocytes treated with differentiation medium versus untreated preadipocytes, as determined by microarray analysis. In one experiment, primary subcutaneous preadipocytes were isolated from adipose tissue of a 28-year-old healthy female with body mass index (BMI) of 23.59. The preadipocytes were cultured and induced to differentiate into adipocytes by culturing them in the differentiation medium containing active components PPAR-y agonist and human insulin (Zen-Bio).

Thiazolidinediones or PPAR-y agonists can bind and activate an orphan nuclear receptor, PPAR-y, and some of them have been proven to be able to induce human adipocyte differentiation. The preadipocytes were treated with human insulin and PPAR-y agonist for 3 days and subsequently were switched to medium containing insulin for a variety of time periods ranging from one to 20 days before the cells were collected for analysis. Differentiated adipocytes were compared to untreated preadipocytes maintained in culture in the absence of inducing agents. Between 80% and 90% of the preadipocytes finally differentiated to adipocytes observed under phase contrast microscope. In a second experiment, primary subcutaneous preadipocytes were isolated from adipose tissue of a 40- year-old healthy female with a body mass index (BMI) of 32.47. The preadipocytes were cultured and induced to differentiate into adipocytes by culturing them in the differentiation medium containing active components PPAR-y agonist and human insulin (Zen-Bio). The preadipocytes were treated with human insulin and PPAR-y agonist for 3 days and subsequently were switched to medium containing insulin alone for a variety of time periods ranging from one to 20 days before the cells were collected for analysis. Differentiated adipocytes were compared to untreated preadipocytes maintained in culture in the absence of inducing agents. Between 80% and 90% of the preadipocytes finally differentiated to adipocytes observed under phase contrast microscope. Thus, SEQ ID NO : 108 and SEQ ID NO: 114 are useful for the diagnosis, prognosis, or treatment of diabetes mellitus and other disorders, such as obesity, hypertension, atherosclerosis, polycystic ovarian syndrome, and cancers including breast, prostate, and colon.

In an alternative example, SEQ ID NO : 109 is downregulated, and SEQ ID NO : 113 is upregulated, in ovarian cancer versus normal ovarian tissue, as determined by microarray analysis. A normal ovary from a 79 year-old female donor was compared to an ovarian tumor from the same donor (Huntsman Cancer Institute, Salt Lake City, UT). Therefore, SEQ ID NO : 109 and SEQ ID NO : 113 are useful in monitoring treatment of, and diagnostic assays for, ovarian cancer.

In an alternative example, SEQ ID NO: 111 is upregulated in PBMCs treated with cytokines versus untreated PBMCs, as determined by microarray analysis. Peripheral blood mononuclear cells (PBMCs) were collected from the blood of 6 healthy volunteer donors using standard gradient separation. The PBMCs from each donor were placed in culture for 2 and 4 hours in the presence of one or more cytokines selected from one of the two following cytokine groups: a) Cytokines associated positively with the inflammatory response ("pro-inflammatory") such as IL-1 ß, IL-2, IL-6, IL-8, IL-12, IL-18, IFN-y, and TNF-a ; or b) Cytokines negatively or neutrally associated with the inflammatory response ("anti-inflammatory") such as IL-3, IL-4, IL-5, IL-7, IL-10, G-CSF, GM-CSF, Leptin, LIF, and TGF-p. Cytokine-treated PBMCs and untreated control-PBMCs from the different donors were pooled according to their respective treatments. Therefore, SEQ ID NO : 111 is useful in

monitoring treatment of, and diagnostic assays for, autoimmune/inflammatory and cell proliferative disorders.

In an alternative example, SEQ ID NO : 111, SEQ ID NO : 112, and SEQ ID NO : 119 are downregulated in breast cancer cell lines versus nonmalignant mammary epithelial cells, as determined by microarray analysis. In one experiment, gene expression profiles of nonmalignant mammary epithelial cells were compared to gene expression profiles of various breast carcinoma lines at different stages of tumor progression. The cells were grown in defined serum-free H14 medium to 70- 80% confluence prior to RNA harvest. Cell lines compared included: a) HMEC, a primary breast epithelial cell line isolated from a normal donor, b) MCF-10A, a breast mammary gland cell line isolated from a 36-year-old woman with fibrocystic breast disease, c) MCF7, a nonmalignant breast adenocarcinoma cell line isolated from the pleural effusion of a 69-year-old female, d) T-47D, a breast carcinoma cell line isolated from a pleural effusion obtained from a 54-year-old female with an infiltrating ductal carcinoma of the breast, e) Sk-BR-3, a breast adenocarcinoma cell line isolated from a malignant pleural effusion of a 43-year-old female, f) BT-20, a breast carcinoma cell line derived in vitro from cells emigrating out of thin slices of the tumor mass isolated from a 74-year-old female, g) MDA-mb-231, a breast tumor cell line isolated from the pleural effusion of a 51-year-old female, and h) MDA-mb-435S, a spindle-shaped strain that evolved from the parent line (435) isolated by R.

Cailleau from pleural effusion of a 31-year-old female with metastatic, ductal adenocarcinoma of the breast. Therefore, SEQ ID NO : 111, SEQ ID NO : 112, and SEQ ID NO : 119 are useful in monitoring treatment of, and diagnostic assays for, breast cancer.

In an alternative example, SEQ ID NO : 111 and SEQ ID NO : 127 are downregulated in prostate carcinomas versus primary prostate epithelial cells, as determined by microarray analysis.

Primary prostate epithelial cells were compared with prostate carcinomas representative of the different stages of tumor progression. Cell lines compared included: a) PrEC, a primary prostate epithelial cell line isolated from a normal donor, b) DU 145, a prostate carcinoma cell line isolated from a metastatic site in the brain of 69-year old male with widespread metastatic prostate carcinoma, c) LNCaP, a prostate carcinoma cell line isolated from a lymph node biopsy of a 50-year-old male with metastatic prostate carcinoma, and d) PC-3, a prostate adenocarcinoma cell line isolated from a metastatic site in the bone of a 62-year-old male with grade IV prostate adenocarcinoma. In one experiment, cells were grown in basal media in the absence of growth factors and hormones. In a second experiment, cells were grown under optimal growth conditions, in the presence of growth factors and nutrients. Cells grown under restrictive conditions were compared to normal PrECs grown under restrictive conditions. Therefore, SEQ ID NO: 111 and SEQ ID NO : 127 are useful in monitoring treatment of, and diagnostic assays for, prostate cancer.

In an alternative example, SEQ ID NO : 112 is downregulated in Tangier disease derived fibroblasts versus normal fibroblasts. Human fibroblasts were obtained from skin explants from both normal subjects and two patients with homozygous Tangier disease. Cell lines were immortalized by transfection with human papillomavirus 16 genes E6 and E7 and a neomycin resistance selectable marker. In addition, both types of cells were cultured in the presence of cholesterol and compared with the same cell type cultured in the absence of cholesterol (TD derived cells are shown to be deficient in an assay of apoA-I mediated tritiated cholesterol efflux). Therefore, SEQ ID NO : 112 is useful in diagnostic assays for Tangier disease.

In an alternative example, SEQ ID NO : 114 is downregulated in Jurkat (acute T cell leukemia cell line) cells treated with anti-human CD3 versus untreated Jurkat cells, as determined by microarray analysis. Jurkat cells were stimulated in vitro with lyg soluble mouse anti-human CD3 for 0.5, 1,2, 4, and 8 hours. These treated cells were compared to untreated Jurkat cells kept in culture in the absence of stimuli. Therefore, SEQ ID NO : 114 is useful in monitoring treatment of, and diagnostic assays for, cell proliferative disorders.

In an alternative example, SEQ ID NO : 114 is downregulated in breast cancer versus normal breast tissue, as determined by microarray analysis. A tumor from the right breast of a 43-year-old female diagnosed with invasive lobular carcinoma was compared to grossly uninvolved breast tissue from the same donor (Huntsman Cancer Institute, Salt Lake City, UT). The tumor is described as well differentiated and metastatic to 2 of 13 lymph nodes. Therefore, SEQ ID NO : 114 is useful in monitoring treatment of, and diagnostic assays for, breast cancer.

In an alternative example, SEQ ID NO : 114 is downregulated in lung cancer versus normal lung tissue, as determined by microarray analysis. In one experiment, moderately differentiated adenocarcinoma of the right lung was compared to grossly uninvolved lung tissue from a 60 year-old donor (Huntsman Cancer Institute). In a second experiment, normal lung tissue from a 68 year-old female was compared to lung tumor from the same donor (Roy Castle International Centre for Lung Cancer Research, Liverpool, UK). In a third experiment, lung squamous cell carcinoma tissue was compared to grossly uninvolved lung tissue from the same donor, a 75 year-old female (Roy Castle International Centre for Lung Cancer Research, Liverpool, UK). Therefore, SEQ ID NO: 114 is useful in monitoring treatment of, and diagnostic assays for, lung cancer.

In an alternative example, SEQ ID NO : 119 is downregulated in colon cancer versus normal colon tissue as determined by microarray analysis. Gene expression profiles were obtained by comparing tumorous rectal tissue from a 38-year-old male with invasive, poorly differentiated adenocarcinoma with metastases to 2 out of 13 lymph nodes surveyed (Huntsman Cancer Institute, Salt Lake City, UT; TNM classification: T3, N1, Mx), to normal colon tissue from the same donor.

Different pieces of normal tissue were also compared against a pool of normal tissue from the same donor to determine gene expression variation in normal colon tissue. Therefore, SEQ ID NO : 119 is useful in monitoring treatment of, and diagnostic assays for, colon cancer.

In an alternative example, SEQ ID NO : 121 is downregulated in lung cancer versus grossly uninvolved lung tissue as determined by microarray analysis. Grossly uninvolved lung tissue from a 66 year-old male was compared to lung squamous cell carcinoma tissue from the same donor (Roy Castle International Centre for Lung Cancer Research, Liverpool, UK). Therefore, SEQ ID NO: 121 is useful in monitoring treatment of, and diagnostic assays for, lung cancer.

In an alternative example, SEQ ID NO : 130 was found to be upregulated by at least two-fold in matched bone tumor versus normal bone tissues in one out of seven donors tested. Therefore, SEQ ID NO : 130, encoding SEQ ID NO : 59 can be used for monitoring treatment of, diagnostic assays for, and developing therapeutics for osteosarcomas.

In an alternative example, gene expression profiles of nonmalignant mammary epithelial cells were compared to gene expression profiles of various breast carcinoma lines at different stages of tumor progression. The cells were grown in defined serum-free H14 medium to 70-80% confluence prior to RNA harvest. Cell lines compared included: a) HMEC, a primary breast epithelial cell line isolated from a normal donor, b) MCF-10A, a breast mammary gland cell line isolated from a 36-year- old woman with fibrocystic breast disease, c) MCF7, a nonmalignant breast adenocarcinoma cell line isolated from the pleural effusion of a 69-year-old female, d) T-47D, a breast carcinoma cell line isolated from a pleural effusion obtained from a 54-year-old female with an infiltrating ductal carcinoma of the breast, e) Sk-BR-3, a breast adenocarcinoma cell line isolated from a malignant pleural effusion of a 43-year-old female, f) BT-20, a breast carcinoma cell line derived in vitro from cells emigrating out of thin slices of the tumor mass isolated from a 74-year-old female, g) MDA-mb- 231, a breast tumor cell line isolated from the pleural effusion of a 51-year-old female, and h) MDA- mb-435S, a spindle-shaped strain that evolved from the parent line (435) isolated by R. Cailleau from pleural effusion of a 31-year-old female with metastatic, ductal adenocarcinoma of the breast. SEQ ID NO : 131 was found to be upregulated by at least two-fold in MDA-mb-435S and Sk-BR-3 cell lines when compared to HMEC cells. Therefore, SEQ ID NO : 131, encoding SEQ ID NO : 60 can be used for monitoring treatment of, diagnostic assays for, and developing therapeutics for breast cancer.

In an alternative example, SEQ ID NO : 131 was found to be downregulated by at least two- fold in matched colon cancer versus normal colon tissues in one out of six donors tested. Therefore, SEQ ID NO : 131, encoding SEQ ID NO : 60 can be used for monitoring treatment of, diagnostic assays for, and developing therapeutics for colon cancer.

In an alternative example, THP-1 is promonocyte cell line that was isolated from the peripheral blood of a 1-year-old male with acute monocytic leukemia. PMA is a broad activator of the protein kinase C-dependent pathways. Upon stimulation with PMA, THP-1 differentiates into a macrophagelike cell that displays many characteristics of peripheral human macrophages. THP-1 cells were stimulated in vitro with soluble PMA and ionomycin for 0.5, 1,2, 4, and 8 hours. These treated cells were compared to untreated THP-1 cells kept in culture in the absence of stimuli. SEQ ID NO : 132 was upregulated in THP-1 cells after a minimum of 2 hours and a maximum of 4 hours of stimulation with PMA and ionomycin as compared to untreated THP-1 cells. Therefore, SEQ ID NO : 132, encoding SEQ ID N0 : 61 can be used to monitor the immune response.

In an alternative example, SEQ ID N0 : 133 was upregulated by at least two-fold in matched lung tumor versus normal lung tissues from one donor and downregulated by at least two-fold in matched lung tumor versus normal lung tissue from another donor tested. Therefore, SEQ ID NO: 133, encoding SEQ ID N0 : 62 can be used for monitoring treatment of and developing therapeutics for lung cancer. Since the regulation of its expression was different in lung tumors from two different donors, SEQ ID N0 : 133, encoding SEQ ID NO : 62 could prove to be a valuable indicator of the nature of the primary lesion, which is very likely to have been different in the two donors.

In an alternative example, SEQ ID N0 : 133 was upregulated by at least two-fold in matched ovarian tumor versus normal ovarian tissues in one donor. This result was reproduced consistently.

Therefore, SEQ ID N0 : 133, encoding SEQ ID N0 : 62 can be used for monitoring treatment of, diagnostic assays for, and developing therapeutics for ovarian cancer.

In an alternative example, SEQ ID N0 : 135 was downregulated in matched lung tumor versus normal lung tissues in two out of six donors tested. Therefore, SEQ ID N0 : 135, encoding SEQ ID NO : 64 can be used for monitoring treatment of, diagnostic assays for, and developing therapeutics for lung cancer.

In an alternative example, early confluent C3A cells were treated with various amounts of Gemfibrozil (120,600, 800, and 1200, ug/ml) dissolved CMC, for 1, 3, and 6 hours. Parallel samples of C3A cells were treated with 1% CMC only, as a control. SEQ ID N0 : 135 was found to be consistently downregulated by at least two-fold in C3A cells treated with a minimum concentration of 120 yg/ml and a maximum concentration of 800 yg/ml of Gemfibrozil for 3 hours as compared to the control cells which were treated with CMC alone. Therefore, SEQ ID N0 : 135, encoding SEQ ID NO : 64 can be used for monitoring treatment of, diagnostic assays for, and developing therapeutics for hepatomas.

In an alternative example, SEQ ID N0 : 138 was downregulated in matched lung tumor versus normal lung tissues in seven out of seven donors tested. Therefore, SEQ ID N0 : 138, encoding SEQ

ID NO : 67 can be used for monitoring treatment of, diagnostic assays for, and developing therapeutics for lung cancer.

XII. Complementary Polynucleotides Sequences complementary to the PMMM-encoding sequences, or any parts thereof, are used to detect, decrease, or inhibit expression of naturally occurring PMMM. Although use of oligonucleotides comprising from about 15 to 30 base pairs is described, essentially the same procedure is used with smaller or with larger sequence fragments. Appropriate oligonucleotides are designed using OLIGO 4.06 software (National Biosciences) and the coding sequence of PMMM.

To inhibit transcription, a complementary oligonucleotide is designed from the most unique 5'sequence and used to prevent promoter binding to the coding sequence. To inhibit translation, a complementary oligonucleotide is designed to prevent ribosomal binding to the PMMM-encoding transcript.

XIII. Expression of PMMM Expression and purification of PMMM is achieved using bacterial or virus-based expression systems. For expression of PMMM in bacteria, cDNA is subcloned into an appropriate vector containing an antibiotic resistance gene and an inducible promoter that directs high levels of cDNA transcription. Examples of such promoters include, but are not limited to, the trp-lac (tac) hybrid promoter and the T5 or T7 bacteriophage promoter in conjunction with the lac operator regulatory element. Recombinant vectors are transformed into suitable bacterial hosts, e. g. , BL21 (DE3).

Antibiotic resistant bacteria express PMMM upon induction with isopropyl beta-D- thiogalactopyranoside (IPTG). Expression of PMMM in eukaryotic cells is achieved by infecting insect or mammalian cell lines with recombinant Autographica californica nuclear polyhedrosis virus (AcMNPV), commonly known as baculovirus. The nonessential polyhedrin gene of baculovirus is replaced with cDNA encoding PMMM by either homologous recombination or bacterial-mediated transposition involving transfer plasmid intermediates. Viral infectivity is maintained and the strong polyhedrin promoter drives high levels of cDNA transcription. Recombinant baculovirus is used to infect Spodopterafrugiperda (Sf9) insect cells in most cases, or human hepatocytes, in some cases.

Infection of the latter requires additional genetic modifications to baculovirus (Engelhard, E. K. et al.

(1994) Proc. Natl. Acad. Sci. USA 91: 3224-3227; Sandig, V. et al. (1996) Hum. Gene Ther. 7: 1937- 1945).

In most expression systems, PMMM is synthesized as a fusion protein with, e. g. , glutathione S-transferase (GST) or a peptide epitope tag, such as FLAG or 6-His, permitting rapid, single-step, affinity-based purification of recombinant fusion protein from crude cell lysats. GST, a 26-kilodalton enzyme from Schistosoma japonicum, enables the purification of fusion proteins on immobilized glutathione under conditions that maintain protein activity and antigenicity (Amersham Biosciences).

Following purification, the GST moiety can be proteolytically cleaved from PMMM at specifically engineered sites. FLAG, an 8-amino acid peptide, enables immunoaffinity purification using commercially available monoclonal and polyclonal anti-FLAG antibodies (Eastman Kodak). 6-His, a stretch of six consecutive histidine residues, enables purification on metal-chelate resins (QIAGEN).

Methods for protein expression and purification are discussed in Ausubel et al. (supra, ch. 10 and 16).

Purified PMMM obtained by these methods can be used directly in the assays shown in Examples XVII, XVIII, XIX, and XX, where applicable.

XIV. Functional Assays PMMM function is assessed by expressing the sequences encoding PMMM at physiologically elevated levels in mammalian cell culture systems. cDNA is subcloned into a mammalian expression vector containing a strong promoter that drives high levels of cDNA expression. Vectors of choice include PCMV SPORT plasmid (Invitrogen, Carlsbad CA) and PCR3.1 plasmid (Invitrogen), both of which contain the cytomegalovirus promoter. 5-10, ug of recombinant vector are transiently transfected into a human cell line, for example, an endothelial or hematopoietic cell line, using either liposome formulations or electroporation. 1-2, ug of an additional plasmid containing sequences encoding a marker protein are co-transfected. Expression of a marker protein provides a means to distinguish transfected cells from nontransfected cells and is a reliable predictor of cDNA expression from the recombinant vector. Marker proteins of choice include, e. g. , Green Fluorescent Protein (GFP; Clontech), CD64, or a CD64-GFP fusion protein. Flow cytometry (FCM), an automated, laser optics-based technique, is used to identify transfected cells expressing GFP or CD64-GFP and to evaluate the apoptotic state of the cells and other cellular properties. FCM detects and quantifies the uptake of fluorescent molecules that diagnose events preceding or coincident with cell death. These events include changes in nuclear DNA content as measured by staining of DNA with propidium iodide; changes in cell size and granularity as measured by forward light scatter and 90 degree side light scatter; down-regulation of DNA synthesis as measured by decrease in bromodeoxyuridine uptake; alterations in expression of cell surface and intracellular proteins as measured by reactivity with specific antibodies; and alterations in plasma membrane composition as measured by the binding of fluorescein-conjugated Annexin V protein to the cell surface. Methods in flow cytometry are discussed in Ormerod, M. G. (1994; Flow Cytometry, Oxford, New York NY).

The influence of PMMM on gene expression can be assessed using highly purified populations of cells transfected with sequences encoding PMMM and either CD64 or CD64-GFP. CD64 and CD64-GFP are expressed on the surface of transfected cells and bind to conserved regions of human immunoglobulin G (IgG). Transfected cells are efficiently separated from nontransfected cells using magnetic beads coated with either human IgG or antibody against CD64 (DYNAL, Lake Success

NY). mRNA can be purified from the cells using methods well known by those of skill in the art.

Expression of mRNA encoding PMMM and other genes of interest can be analyzed by northern analysis or microarray techniques.

XV. Production of PMMM Specific Antibodies PMMM substantially purified using polyacrylamide gel electrophoresis (PAGE; see, e. g., Harrington, M. G. (1990) Methods Enzymol. 182: 488-495), or other purification techniques, is used to immunize animals (e. g. , rabbits, mice, etc. ) and to produce antibodies using standard protocols.

Alternatively, the PMMM amino acid sequence is analyzed using LASERGENE software (DNASTAR) to determine regions of high immunogenicity, and a corresponding oligopeptide is synthesized and used to raise antibodies by means known to those of skill in the art. Methods for selection of appropriate epitopes, such as those near the C-terminus or in hydrophilic regions are well described in the art (Ausubel et al., supra, ch. 11).

Typically, oligopeptides of about 15 residues in length are synthesized using an ABI 431A peptide synthesizer (Applied Biosystems) using FMOC chemistry and coupled to KLH (Sigma- Aldrich, St. Louis MO) by reaction with N-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS) to increase immunogenicity (Ausubel et al., supra). Rabbits are immunized with the oligopeptide-KLH complex in complete Freund's adjuvant. Resulting antisera are tested for antipeptide and anti-PMMM activity by, for example, binding the peptide or PMMM to a substrate, blocking with 1% BSA, reacting with rabbit antisera, washing, and reacting with radio-iodinated goat anti-rabbit IgG.

XVI. Purification of Naturally Occurring PMMM Using Specific Antibodies Naturally occurring or recombinant PMMM is substantially purified by immunoaffinity chromatography using antibodies specific for PMMM. An immunoaffinity column is constructed by covalent coupling anti-PMMM antibody to an activated chromatographic resin, such as CNBr-activated SEPHAROSE (Amersham Biosciences). After the coupling, the resin is blocked and washed according to the manufacturer's instructions.

Media containing PMMM are passed over the immunoaffinity column, and the column is washed under conditions that allow the preferential absorbance of PMMM (e. g. , high ionic strength buffers in the presence of detergent). The column is eluted under conditions that disrupt antibody/PMMM binding (e. g. , a buffer of pH 2 to pH 3, or a high concentration of a chaotrope, such as urea or thiocyanate ion), and PMMM is collected.

XVII. Identification of Molecules Which Interact with PMMM PMMM, or biologically active fragments thereof, are labeled with'25I Bolton-Hunter reagent (Bolton, A. E. and W. M. Hunter (1973) Biochem. J. 133: 529-539). Candidate molecules previously arrayed in the wells of a multi-well plate are incubated with the labeled PMMM, washed, and any

wells with labeled PMMM complex are assayed. Data obtained using different concentrations of PMMM are used to calculate values for the number, affinity, and association of PMMM with the candidate molecules.

Alternatively, molecules interacting with PMMM are analyzed using the yeast two-hybrid system as described in Fields, S. and O. Song (1989; Nature 340: 245-246), or using commercially available kits based on the two-hybrid system, such as the MATCHMAKER system (Clontech).

PMMM may also be used in the PATHCALLING process (CuraGen Corp. , New Haven CT) which employs the yeast two-hybrid system in a high-throughput manner to determine all interactions between the proteins encoded by two large libraries of genes (Nandabalan, K. et al.

(2000) U. S. Patent No. 6,057, 101).

XVIII. Demonstration of PMMM Activity PMMM activity can be demonstrated using a generic immunoblotting strategy or through a variety of specific activity assays, some of which are outlined below. As a general approach, cell lines or tissues transformed with a vector containing PMMM coding sequences can be assayed for PMMM activity by immunoblotting. Transformed cells are denatured in SDS in the presence of b- mercaptoethanol, nucleic acids are removed by ethanol precipitation, and proteins are purified by acetone precipitation. Pellets are resuspended in 20 mM Tris buffer at pH 7.5 and incubated with Protein G-Sepharose pre-coated with an antibody specific for PMMM. After washing, the Sepharose beads are boiled in electrophoresis sample buffer, and the eluted proteins subjected to SDS-PAGE.

The SDS-PAGE is transferred to a membrane for immunoblotting, and the PMMM activity is assessed by visualizing and quantifying bands on the blot using the antibody specific for PMMM as the primary antibody and 1211_labeled IgG specific for the primary antibody as the secondary antibody.

PMMM kinase activity is measured by quantifying the phosphorylation of a protein substrate by PMMM in the presence of gamma-labeled 32P-ATP. PMMM is incubated with the protein substrate, 32P-ATP, and an appropriate kinase buffer. The 32p incorporated into the substrate is separated from free 32P-ATP by electrophoresis and the incorporated 32p is counted using a radioisotope counter. The amount of incorporated 32p is proportional to the activity of PMMM. A determination of the specific amino acid residue phosphorylated is made by phosphoamino acid analysis of the hydrolyzed protein.

PMMM phosphatase activity is measured by the hydrolysis of p-nitrophenyl phosphate (PNPP). PMMM is incubated together with PNPP in HEPES buffer, pH 7.5, in the presence of 0. 1% p-mercaptoethanol at 37°C for 60 min. The reaction is stopped by the addition of 6 ml of 10 N NaOH and the increase in light absorbance at 410 nm resulting from the hydrolysis of PNPP is

measured using a spectrophotometer. The increase in light absorbance is proportional to the activity of PMMM in the assay (Diamond, R. H. et al. (1994) Mol. Cell. Biol. 14: 3752-3762).

In the alternative, PMMM phosphatase activity is determined by measuring the amount of phosphate removed from a phosphorylated protein substrate. Reactions are performed with 2 or 4 nM enzyme in a final volume of 30 1 containing 60 mM Tris, pH 7.6, 1 mM EDTA, 1 mM EGTA, 0. 1 % 2-mercaptoethanol and 10 uM substrate, 32P-labeled on serine/threonine or tyrosine, as appropriate.

Reactions are initiated with substrate and incubated at 30° C for 10-15 min. Reactions are quenched with 450 tel of 4% (w/v) activated charcoal in 0.6 M HCI, 90 mM Na4P2O"and 2 mM NaH2PO4, then centrifuged at 12,000 x g for 5 min. Acid-soluble 32Pi is quantified by liquid scintillation counting (Sinclair, C. et al. (1999) J. Biol. Chem. 274: 23666-23672).

PMMM protease activity is measured by the hydrolysis of appropriate synthetic peptide substrates conjugated with various chromogenic molecules in which the degree of hydrolysis is quantified by spectrophotometric (or fluorometric) absorption of the released chromophore (Beynon, R. J. and J. S. Bond (1994) Proteolytic Enzymes: A Practical Approach, Oxford University Press, New York, NY, pp. 25-55). Peptide substrates are designed according to the category of protease activity as endopeptidase (serine, cysteine, aspartic proteases, or metalloproteases), aminopeptidase (leucine aminopeptidase), or carboxypeptidase (carboxypeptidases A and B, procollagen C-proteinase).

Commonly used chromogens are 2-naphthylamine, 4-nitroaniline, and furylacrylic acid. Assays are performed at ambient temperature and contain an aliquot of the enzyme and the appropriate substrate in a suitable buffer. Reactions are carried out in an optical cuvette, and the increase/decrease in absorbance of the chromogen released during hydrolysis of the peptide substrate is measured. The change in absorbance is proportional to the enzyme activity in the assay.

In the alternative, an assay for PMMM protease activity takes advantage of fluorescence resonance energy transfer (FRET) that occurs when one donor and one acceptor fluorophore with an appropriate spectral overlap are in close proximity. A flexible peptide linker containing a cleavage site specific for PMMM is fused between a red-shifted variant (RSGFP4) and a blue variant (BFP5) of Green Fluorescent Protein. This fusion protein has spectral properties that suggest energy transfer is occurring from BFP5 to RSGFP4. When the fusion protein is incubated with PMMM, the substrate is cleaved, and the two fluorescent proteins dissociate. This is accompanied by a marked decrease in energy transfer which is quantified by comparing the emission spectra before and after the addition of PMMM (Mitra, R. D. et al (1996) Gene 173: 13-17). This assay can also be performed in living cells.

In this case the fluorescent substrate protein is expressed constitutively in cells and PMMM is introduced on an inducible vector so that FRET can be monitored in the presence and absence of PMMM (Sagot, I. et al (1999) FEBS Letters 447: 53-57).

An assay for ubiquitin hydrolase activity measures the hydrolysis of a ubiquitin precursor. The assay is performed at ambient temperature and contains an aliquot of PMMM and the appropriate substrate in a suitable buffer. Chemically synthesized human ubiquitin-valine may be used as substrate. Cleavage of the C-terminal valine residue from the substrate is monitored by capillary electrophoresis (Franklin, K. et al. (1997) Anal. Biochem. 247: 305-309).

PMMM protease inhibitor activity for alpha 2-HS-glycoprotein (AHSG) can be measured as a decrease in osteogenic activity in dexamethasone-treated rat bone marrow cell cultures (dex-RBMC).

Assays are carried out in 96-well culture plates containing minimal essential medium supplemented with 15% fetal bovine serum, ascorbic acid (50 mg/ml), antibiotics (100 mg/ml penicillin G, 50 mg/ml gentamicin, 0.3 mg/ml fungizone), 10 mM B-glycerophosphate, dexamethasone (10-8 M) and various concentrations of PMMM for 12-14 days. Mineralized tissue formation in the cultures is quantified by measuring the absorbance at 525 nm using a 96-well plate reader (Binkert, C. et al. (1999) J. Biol.

Chem. 274: 28514-28520).

PMMM protease inhibitor activity for inter-alpha-trypsin inhibitor (ITI) can be measured by a continuous spectrophotometric rate determination of trypsin activity. The assay is performed at ambient temperature in a quartz cuvette in pH 7.6 assay buffer containing 63 mM sodium phosphate, 0.23 mM N a-benzoyle-L-arginine ethyl ester, 0.06 mM hydrochloric acid, 100 units trypsin, and various concentrations of PMMM. Immediately after mixing by inversion, the increase in A253 nm is recorded for approximately 5 minutes and the enzyme activity is calculated (Bergmeyer, H. U. et al.

(1974) Meth. Enzym. Anal. 1: 515-516).

PMMM isomerase activity such as peptidyl prolyl cisltrans isomerase activity can be assayed by an enzyme assay described by Rahfeld, J. U. , et al. (1994; FEBS Lett. 352: 180-184). The assay is performed at 10°C in 35 mM HEPES buffer, pH 7.8, containing chymotrypsin (0.5 mg/ml) and PMMM at a variety of concentrations. Under these assay conditions, the substrate, Suc-Ala-Xaa- Pro-Phe-4-NA, is in equilibrium with respect to the prolyl bond, with 80-95% in trans and 5-20% in cis conformation. An aliquot (2 ml) of the substrate dissolved in dimethyl sulfoxide (10 mg/ml) is added to the reaction mixture described above. Only the cis isomer of the substrate is a substrate for cleavage by chymotrypsin. Thus, as the substrate is isomerized by PMMM, the product is cleaved by chymotrypsin to produce 4-nitroanilide, which is detected by it's absorbance at 390 nm. 4-nitroanilide appears in a time-dependent and a PMMM concentration-dependent manner.

PMMM galactosyltransferase activity can be determined by measuring the transfer of radiolabeled galactose from UDP-galactose to a GIcNAc-terminated oligosaccharide chain (Kolbinger, F. et al. (1998) J. Biol. Chem. 273: 58-65). The sample is incubated with 14, ul of assay stock solution (180 mM sodium cacodylate, pH 6.5, 1 mg/ml bovine serum albumin, 0.26 mM UDP-

galactose, 2 , 1 of UDP- ['H] galactose), 1 , 1 of MnCl2 (500 mM), and 2.5 ofG) cNAcpO- (CHJ,- CO2Me (37 mg/ml in dimethyl sulfoxide) for 60 minutes at 37°C. The reaction is quenched by the addition of 1 ml of water and loaded on a C18 Sep-Pak cartridge (Waters), and the column is washed twice with 5 ml of water to remove unreacted UDP-[3H] galactose. The ['H] galactosylated GlcNAcßO-(CH2)8-CO2Me remains bound to the column during the water washes and is eluted with 5 ml of methanol. Radioactivity in the eluted material is measured by liquid scintillation counting and is proportional to galactosyltransferase activity in the starting sample.

PMMM induction by heat or toxins may be demonstrated using primary cultures of human fibroblasts or human cell lines such as CCL-13, HEK293, or HEP G2 (ATCC). To heat induce PMMM expression, aliquots of cells are incubated at 42°C for 15,30, or 60 minutes. Control aliquots are incubated at 37°C for the same time periods. To induce PMMM expression by toxins, aliquots of cells are treated with 100 µM arsenite or 20 mM azetidine-2-carboxylic acid for 0,3, 6, or 12 hours.

After exposure to heat, arsenite, or the amino acid analogue, samples of the treated cells are harvested and cell lysates prepared for analysis by western blot. Cells are lysed in lysis buffer containing 1% Nonidet P-40,0. 15 M NaCl, 50 mM Tris-HCl, 5 mM EDTA, 2 mM N-ethylmaleimide, 2 mM phenylmethylsulfonyl fluoride, 1 mg/ml leupeptin, and 1 mg/ml pepstatin. Twenty micrograms of the cell lysate is separated on an 8% SDS-PAGE gel and transferred to a membrane. After blocking with 5% nonfat dry milk/phosphate-buffered saline for 1 h, the membrane is incubated overnight at 4°C or at room temperature for 2-4 hours with an appropriate dilution of anti-PMMM serum in 2% nonfat dry milk/phosphate-buffered saline. The membrane is then washed and incubated with a 1: 1000 dilution of horseradish peroxidase-conjugated goat anti-rabbit IgG in 2% dry milk/phosphate-buffered saline. After washing with 0.1% Tween 20 in phosphate-buffered saline, the PMMM protein is detected and compared to controls using chemiluminescence.

PMMM lysyl hydroxylase activity is determined by measuring the production of hydroxy ['4C] lysine from ['4C] lysine. Radiolabeled protocollagen is incubated with PMMM in buffer containing ascorbic acid, iron sulfate, dithiothreitol, bovine serum albumin, and catalase. Following a 30 minute incubation, the reaction is stopped by the addition of acetone, and centrifuged. The sedimented material is dried, and the hydroxy ['4C] lysine is converted to ['4C] formaldehyde by oxidation with periodate, and then extracted into toluene. The amount of'4C extracted into toluene is quantified by scintillation counting, and is proportional to the activity of PMMM in the sample (Kivirikko, K. , and R. Myllyla (1982) Methods Enzymol. 82: 245-304).

XIX. Identification of PMMM Substrates Phage display libraries can be used to identify optimal substrate sequences for PMMM. A random hexamer followed by a linker and a known antibody epitope is cloned as an N-terminal

extension of gene III in a filamentous phage library. Gene III codes for a coat protein, and the epitope will be displayed on the surface of each phage particle. The library is incubated with PMMM under proteolytic conditions so that the epitope will be removed if the hexamer codes for a PMMM cleavage site. An antibody that recognizes the epitope is added along with immobilized protein A. Uncleaved phage, which still bear the epitope, are removed by centrifugation. Phage in the supernatant are then amplified and undergo several more rounds of screening. Individual phage clones are then isolated and sequenced. Reaction kinetics for these peptide substrates can be studied using an assay in Example XVIII, and an optimal cleavage sequence can be derived (Ke, S. H. et al. (1997) J. Biol.

Chem. 272: 16603-16609).

To screen for in vivo PMMM substrates, this method can be expanded to screen a cDNA expression library displayed on the surface of phage particles (T7SELECT10-3 Phage display vector, Novagen, Madison, WI) or yeast cells (pYDl yeast display vector kit, Invitrogen, Carlsbad, CA). In this case, entire cDNAs are fused between Gene III and the appropriate epitope.

XX. Identification of PMMM Inhibitors Compounds to be tested are arrayed in the wells of a multi-well plate in varying concentrations along with an appropriate buffer and substrate, as described in the assays in Example XVIII. PMMM activity is measured for each well and the ability of each compound to inhibit PMMM activity can be determined, as well as the dose-response kinetics. This assay could also be used to identify molecules which enhance PMMM activity.

In the alternative, phage display libraries can be used to screen for peptide PMMM inhibitors.

Candidates are found among peptides which bind tightly to a protease. In this case, multi-well plate wells are coated with PMMM and incubated with a random peptide phage display library or a cyclic peptide library (Koivunen, E. et al. (1999) Nature Biotech 17: 768-774). Unbound phage are washed away and selected phage amplified and rescreened for several more rounds. Candidates are tested for PMMM inhibitory activity using an assay described in Example XVIII.

Various modifications and variations of the described compositions, methods, and systems of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. It will be appreciated that the invention provides novel and useful proteins, and their encoding polynucleotides, which can be used in the drug discovery process, as well as methods for using these compositions for the detection, diagnosis, and treatment of diseases and conditions.

Although the invention has been described in connection with certain embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments.

Nor should the description of such embodiments be considered exhaustive or limit the invention to the precise forms disclosed. Furthermore, elements from one embodiment can be readily recombined with elements from one or more other embodiments. Such combinations can form a number of embodiments within the scope of the invention. It is intended that the scope of the invention be defined by the following claims and their equivalents.

Table 1 Incyte Project ID Polypeptide Incyte Polynucleotide Incyte SEQ ID NO : Polypeptide ID SEQ ID NO : Polynucleotide ID Incyte Full Length Clones 2828629LJ2828629CD1 722828629CB1 7185349CA2 7509905 2 7509905CD 1 73 7509905CB 1 l 7502048 3 7502048CD1 74 7502048CB1 95168269CA2 7510031 4 751003 lCD1 75 7510031CB 1 7510116 5 7510116CD1 76 7510116CB1 7500548 16 7500548CD1 77 7500548CB 1 750480777504807CD1 787504807CB1 750498887504988CD1 797504988CB1 7505051 9 7505051CD1 80 7505051CB1 7505079 10 7505079CD 1 81 7505079CB 1 7505159 11 7505159CD1 82 7505159CB 1 7510086 12 7510086CD1 83 7510086CB1 7510131 13 7510131CD1 84 7510131CB1 90042674CA2 s 7510137 14 7510137CD1 85 7510137CB1 7510690 15 7510690CD1 86 7510690CB 1 7510695 16 7510695CD1 187 7510695CB1 l 7504781 17 17504781CDI 88 7504781CBI 90017915CA2, 90017947CA2 7504798 18 7504798CD1 89 7504798CB1 90080516CA2 7504800 19 7504800CD1 90 7504800CB 1 2211441CA2 7504902 20 7504902CD 1 1 7504902CB 1 7510792 21 7510792CD1 92 7510792CB 1 7510557 22 7510557CD1 93 7510557CB 1 7510649 23 7510649CD 1 94 7510649CB 1 7510264 24 7510264CD 1 95 7510264CB 1 7506464 25 7506464CDI 196 7506464CB 1 7510101 26 7510101CD1 97 7510101CB1 2445190CA2 7510845 27 7510845CD 1 98 7510845CB 1 7510846 28 l7510846CD1 99 |7510846CB1 7510921 29 7510921CD1 100, 7510921CB1 Table 1 Incyte Project ID Polypeptide Incyte Polynucleotide Incyte SEQ ID NO : Polypeptide ID SEQ ID NO : Polynucleotide ID Incyte Full Length Clones 7505097 30 7505097CD1 101 7505097CB1 7506527 31 7506527CD 1 102 7506527CB 1 7504894 32 7504894CD1 103 7504894CB1 7510529 33 7510529CD1 104 7510529CB 1 I 7510581 34 7510581CD1 105 7510581CB1 7510582 35 7510582CD1 106 7510582CB1 7510583367510583CD1 1077510583CB1 7510596 37 7510596CD1 108 7510596CB 1 7510643 38 7510643CD1 109 7510643CB1 7506671 39 750667 lCD1 110 7506671CB 1 7510518 40 7510518CD1 |111 7510518CB1 7510585 41 7510585CD1 112 7510585CB1 7510590 42 7510590CD1 113 7510590CB1 7510617 43 7510617CD1 114 7510617CB1 95105420CA2 8669577CA2, 90041252CA2, 90215143CA2, 90215259CA2, 7510618 44 7510618CD1 115 7510618CB 1 90217459CA2 7510620 45 7510620CD1 116 7510620CB1 7510628 46 7510628CD1 117 7510628CB1 2651143CA2 7510650 47 7510650CD1 118 7510650CB1 7506644 48 7506644CD 1 119 7506644CB 1 90005372CA2 7506692 49 7506692CD 1 120 7506692CB 1 7504938 50 7504938CD1 121 7504938CB1 7505625 51 7505625CD 1 122 7505625CB 1 7506468 52 7506468CD1 | 123 7506468CB1 90019716CA2 7510682 53 7510682CD1 124 7510682CB1 7505420 1 S4 7505420CD 1 125 7505420CB 1 95153854CA2 7505604 55 7505604CD1 126 7505604CB1 7505606 56 7505606CD1 127 7505606CB1 I 7511044J577511044CD1 1287511044CB1 Table 1 Incyte Project ID Polypeptide Incyte Polynucleotide Incyte SEQ ID NO : Polypeptide ID SEQ ID NO : Polynucleotide ID Incyte Full Length Clones 2579533 58 2579533CDI 129 2579533CB1 90213919CA2 7511097 59 7511097CD1 130 7511097CB1 2320222CA2, 95203034CA2 7510842 60 7510842CD1 131 7510842CB 1 7511249 61 7511249CD1 132 7511249CB 1 7511254 62 7511254CD1 133 7511254CB 1 4567020CA2 7511274 63 7511274CD 1 134 7511274CB 1 7511303 64 7511303CD 1 135 7511303CB 1 7511309 65 7511309CD 1 136 7511309CB 1 7511314 66 7511314CD1 137 7511314CB1 7511316 67 7511316CD1 138 7511316CB1 7511391 68 7511391CD1 139 7511391CB1 90130113CA2, 90130336CA2 7510144 69 7510144CD 1 140 7510144CB 1 7510810 70 7510810CD1 141 7510810CB1 7511241 71 7511241CD1 142 7511241CB1 Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 1 2828629CDI gl4715064 4. 3E-141 [Homo sapiens] proprotein convertase subtilisin/kexin type 7 1 2828629CD1 341028PCSK7 8. 2E-141 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] [Unspecified membrane] Lymphoma proprotein convertase, a member of the proprotein convertase family, a Ca2+- dependent serine protease prohormone convertase that may be involved in cell-cell signaling Cheng, M. et al. Int J Cancer 71, 966-971 (1997) 1 2828629CD1 582383|Pcsk7 1. lE-120 [Mus musculus] [Hydrolase ; Protease (other than proteasomal)] [Unspecified membrane] Lymphoma proprotein convertase, a subtilisin-like proprotein convertase, possibly regulates growth factor activation during embryonic development Constam, D. B. et al. J. Cell Biol. 134, 181-191 (1996). ! 2'7509905CD1 gl8088520 1. 5E-138 [Homo sapiens] (BC020507) aminopeptidase-like 1 l 2 7509905CD1 691122FLJ1158 1. 8E-138 [Homo sapiens] Protein containing a cytosol aminopeptidase family catalytic domain, has 3 high similarity to uncharacterized C. elegans ZK353. 6 2 7509905CD1 276703|ZK353. 6 6. 8E-66 [Caenorhabditis elegans] [Unknown] Member of the cytosol aminopeptidase protein family Joshua, G. W. Mol. Biochem. Parasitol. 113, 223-232 (2001) 3 7502048CD 1 g994715 1. 5E-138 [Homo sapiens] deoxyhypusine synthase Joe, Y. A. et al. J. Biol. Chem. 270, 22386-22392 (1995) 3 7502048CD 1 568722DHPS 2. 8E-140 [Homo sapiens] [Oxidoreductase] Deoxyhypusine synthase, catalyzes NAD-dependent transfer of an aminobutyl moiety from spermidine to a specific lysine residue of initiation factor 5A (EIF5A), the first step in the formation of a deoxyhypusine residue Joe, Y. A. et al. (supra) 3 7502048CD1 10247pYSl 5. 2E-68 [Saccharomyces cerevisiae] [Oxidoreductase] Deoxyhypusine synthase, catalyzes the first step in hypusine biosynthesis, the conversion of lysine plus spermidine into deoxyhypusine Park, M. H. et al. J. Biol. Chem. 273, 1677-1683 (1998) Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 4 7510031CD1 gl276912 0. 0 [Homo sapiens] UHX1 protein Swanson, D. A. et al. Hum. Mol. Genet. 5, 533-538 (1996) 4 7510031CD1 341412USP11 0. 0 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Ubiquitin specific protease 11, a member of the ubiquitin-specific cysteine (thiol) protease family which removes ubiquitin from ubiquitin-conjugated protein substrates ; may play a role in oncogenesis Swanson, D. A. et al. (supra) ; D'Andrea, A. et al. Crit. Rev. Biochem. Mol. Biol. 33, 337- 352 (1998) 4 7510031CD1 586113lUsp4 1. 4E-197 [Mus musculus] [Hydrolase ; Protease (other than proteasomal) ; Small molecule-binding protein] [Nuclear] Ubiquitin specific protease 4 (ubiquitous nuclear protein), efficiently cleaves ubiquitin-proline bonds, transforms cells when overexpressed, may bind to the retinoblastoma gene product ; expression of human USP4 is elevated in small cell lung carcinomas Frederick, A. et al. Oncogene 10, 2179-2183 (1995) 5 7510116CD1 gl402590 0. 0 [Homo sapiens] PK-120 precursor Nishimura, H. et al. FEBS Lett. 357, 207-211 (1995) 5 7510116CDI 336080|ITIH4 0. 0 [Homo sapiens] [Regulatory subunit ; Structural protein ; Inhibitor or repressor] [Extracellular matrix (cuticle and basement membrane)] Inter-alpha (globulin) inhibitor H4 (plasma Kallikrein-sensitive glycoprotein), non-catalytic subunit of protease inhibitor complex which stabilizes the extracellular matrix, sensitive to plasma kallikrein ; increases in serum during acute phase response Pineiro, M. et al. Biochem. Biophys. Res. Commun. 263, 224-229 (1999) 5 7510116CD 1 608150lItih4 1. 6E-247 [Mus musculus] [Regulatory subunit ; Structural protein ; Inhibitor or repressor] [Extracellular matrix (cuticle and basement membrane)] Inter alpha-trypsin inhibitor (heavy chain 4), inter alpha-trypsin inhibitor proteoglycan family member, noncatalytic subunits of a protease inhibitor complex that stabilizes the extracellular matrix, may play a role in liver development Cai, T. et al. Biochim. Biophys. Acta 1398, 32-37 (1998) Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 6 7500548CD1 g2897946 0. 0 [Homo sapiens] prostate-specific membrane antigen O'Keefe, D. S. et al. Biochim. Biophys. Acta 1443, 113-127 (1998) 6 7500548CD1 340582lFOLHl 0. 0 [Homo sapiens] [Hydrolase] [Unspecified membrane ; Plasma membrane] Folate hydrolase 1, has folate hydrolase and N-acetylated alpha-linked acidic dipeptidase activity, highly expressed in prostate cancer, cytosolic form is found mostly in normal cells while membrane form predominates in prostate cancer cells Carter, R. E. et al. Proc. Natl. Acad. Sc. U S A 93, 749-753 (1996) ; Lapidus, R. G. et al. Prostate 45, 350-354 (2000) 6 7500548CD1 760206jFolhl 0. 0 [Rattus norvegicus] [Hydrolase ; Protease (other than proteasomal)] [Unspecified membrane ; Plasma membrane] Folate hydrolase 1, has folate hydrolase and N-acetylated alpha-linked acidic dipeptidase activity, possibly influences glutaminergic signaling processes and CPP response to cocaine ; human FOLH1 is highly expressed in prostate cancer Carter, R. E. et al. (supra) I 7 7504807CD1 gl5778988 2. 2E-213 [Homo sapiens] Similar to carboxypeptidase A2 (pancreatic) 7 7504807CD1 342306|CPA2 7. 6E-214 [Homo sapiens] (hydrolase ; Protease (other than proteasomal)] Carboxypeptidase A2, a monomeric pancreatic metalloprotease that has a substrate preference for large hydrophobic C-terminal residues and is involved in vacuolar protein degradation Reverter, D. et al. FEBS Lett. 420, 7-10 (1997) 7 7504807CD1 332330lRn. 17687 1. 6E-189 [Rattus norvegicus] (hydrolase ; Protease (other than proteasomal)] Carboxypeptidase A2, a monomeric pancreatic metalloprotease that has a substrate preference for large hydrophobic C-terminal residues Normant, E. et al. Proc. Nat. Acad. Sci. U S A 92, 12225-12229 (1995) 8 7504988CD1 g521218 1. 3E-113 [Homo sapiens] trypsinogen Emi, M. et al. Gene 41, 305-310 (1986) Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 8 7504988CD1 337264lPRSS2 l. lE-114 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Trypsinogen-2 (pancreatic trypsin II, anionic trypsinogen), a serine protease produced mainly in the pancreas, presence in serum or urine is used as a marker for pancreatitis Kemppainen, E. et al. Gut 41, 690-695. (1997) ; Williams, S. J. et al. Int. J. Cancer 93, 67- 73. (2001) 8 7504988CD1 435023PRSS4 5. 6E-99 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Protease serine 4 (trypsin 4, trypsinogen 4, mesotrypsin, mesotrypsinogen), an inhibitor-resistant trypsin that plays a role in digestion ; mutations cause hereditary pancreatitis and elevated levels are associated with chronic alcoholism Ferec, C. et al. J. Med. Genet. 36, 228-232. (1999) 9 7505051CD1 g3510663 7. 4E-222 [Homo sapiens] thymus specific serine peptidase Bowlus, C. L. et al. Cell. Immunol. 196, 80-86 (1999) 7505051CD1 342704lPRSSl6 6. 1E-223 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Putative serine peptidase, contains an alpha/beta hydrolase fold 9 7505051CD1 608498|Prssl6 9. 1E-174 [Mus musculus] [Hydrolase ; Protease (other than proteasomal)] Thymic-specific serine peptidase, a putative serine protease potentially involved in thymocyte development and function 10 7505079CD1 g2393947 0. 0 [Homo sapiens] ADAM10 Rosendahl, M. S. et al. J. Biol. Chem. 272, 24588-24593 (1997) 10 7505079CD1 339050|ADAM1 0. 0 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] [Plasma membrane] A 0 disintegrin and metalloproteinase domain 10, an ADAM family disintegrin domain- containing zinc metalloprotease, acts in ectodomain proteolysis of membrane proteins, cleaves cellular prion protein (PRNP), acts as an alpha secretase on APP Kojro, E. et al. Proc. Natl. Acad. Sci. U S A 98, 5815-5820. (2001) Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 10 7505079CD1 583547lAdaml0 0. 0 [Mus musculus] [Hydrolase ; Protease (other than proteasomal)] A disintegrin and metalloproteinase domain 10, an ADAM family disintegrin domain-containing zinc metalloprotease, acts in membrane protein ectodomain proteolysis Marcinkiewicz, M., and Seidah, N. G. J. Neurochem. 75, 2133-2143 (2000) 11 7505159CD 1 g7008025 5. 2E-121 [Callithrix jacchus] prochymosin Kageyama, T. J. Biochem. (Tokyo) 127, 761-770 (2000) 11 7505159CD 1 610015lLOC5682 4. 7E-110 [Rattus norvegicus] [Hydrolase ; Protease (other than proteasomal)] [Extracellular (excluding 5 cell wall)] Prochymosin, a major neonatal pepsinogen, expressed only at neonatal-infant stages Kageyama, T. et al. Biochem. Biophys. Res. Commun. 267, 806-812 (2000) 11 7505159CD1 435127lPGA5 2. 5E-76 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Pepsinogen 5, a member of the pepsinogen I family of aspartic proteinases that is activated upon secretion and functions as a gastric enzyme, serum levels serve as a biomarker for drug therapies and gastritis Gritti, I. et al. Pharmacol. Res. 41, 265-281. (2000) 12 7510086CD1 gl945609 1. OE-213 [Homo sapiens] 26S proteasome subunit p44. 5 Saito, A. et al. Gene 203, 241-250 (1997) 12 7510086CD1 337332PSMD11 9. 8E-214 [Homo sapiens] [Proteasome subunit] [Cytoplasmic] Subunit 9 of the 26S proteasome (proteasome 26S subunit non-ATPase 11), a non-ATPase subunit of the 19S regulatory unit of the 26S proteasome complex, confers ATP dependency to the 26S proteasome, which mediates ubiquitin-dependent protein degradation Ferrell, K. et al. Trends Biochem. Sci. 25, 83-88. (2000) 12 7510086CD1 6389RPN6 7. 7E-85 [Saccharomyces cerevisiae] [Regulatory subunit ; Proteasome subunit] [Nuclear ; Endoplasmic reticulum] Non-ATPase subunit of the 26S proteasome complex that also functions in RNA polymerase II transcription elongation Tanaka, K. et al. Biochem Biophys Res Commun 247, 537-541 (1998) 113 17510131CDI igl4715064 10. 0 [Homo sapiens] proprotein convertase subtilisin/kexin type 7 Table 2 m 7 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 13 7510131CD1 341028lPCSK7 0. 0 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] [Unspecified membrane] Lymphoma proprotein convertase, a member of the proprotein convertase family, a Ca2+- dependent serine protease prohormone convertase that may be involved in cell-cell signaling Cheng, M. et al. Int. J. Cancer 71, 966-71 (1997) 13 7510131CD1 582383lPcsk7 0. 0 [Mus musculus] [Hydrolase ; Protease (other than proteasomal)] [Unspecified membrane] Lymphoma proprotein convertase, a subtilisin-like proprotein convertase, possibly regulates growth factor activation during embryonic development Constam, D. B. et al. J. Cell Biol. 134, 181-191 (1996) 14 |7510137CD1 g2791680 6. 2E-188 [Homo sapiens] 26S proteasome ATPase subunit Zhang, Q. H. et al. Genome Res. 10, 1546-1560 (2000) 14 7510137CD 1 432406|PSMC4 5. 1E-189 [Homo sapiens] [Proteasome subunit ; Hydrolase ; ATPase] [Cytoplasmic] Proteasome (prosome, macropain) 26S subunit ATPase 4, a component of the 26S proteasome complex that specifically degrades ubiquitinated proteins ; interacts with an orphan nuclear hormone receptor and with HIV tat protein Choi, H. S. et al. J. Steroid Biochem. Mol. Biol. 56, 23-30 (1996) ; Makino, Y. et al. Genes Cells 4, 529-539. (1999) 14 7510137CDI 586749IPsmc4 1. 4E-186 [Mus musculus] [Proteasome subunit ; Hydrolase ; ATPase] [Nuclear ; Cytoplasmic] Proteasome 26S subunit ATPase 4, a component of the 26S proteasome complex that specifically degrades ubiquitinated proteins ; interacts with some members of the nuclear hormone receptor superfamily, plays a critical role during embryogenesis Sakao, Y. et al. Genomics 67, 1-7 (2000) 15 17510690CD1 g181186 2. SE-33 [Homo sapiens] granzyme B Haddad, P. et al. Gene 87, 265-271 (1990) Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 15 7510690CD1 340668lGZMB 2. 1E-34 [Homo sapiens] [Ligand ; Activator Hydrolase ; Protease (other than proteasomal)] [Cytoplasmic] Granzyme B (cytotoxic T-lymphocyte-associated serine esterase 1), a serine protease that is released by cytotoxic T-cells and induces apoptosis in target cells, plays a role in the immune response and in the host response to bacteria Lauw, F. N. et al. J. Infect. Di. s 182, 206-213. (2000) Igarashi, T., Konno, R., Okamoto, S., Moriya, T., Satoh, S., and Yajima, A. Tohoku J. Exp. Med. 193, 13-25. (2001) 15 7510690CD1 329514|Rn. 9837 5. 8E-23 [Rattus norvegicus] [Hydrolase ; Protease (other than proteasomal)] Natural killer-associated serine protease Zunino, S. J. et al. J. Immunol. 144, 2001-2009 (1990) 16 7510695CD1 glO503942 1. 0E-242 [Homo sapiens] calpain-like protease CAPNIOc Horikawa, Y. et al. Nat. Genet. 26, 163-175 (2000) 16 7510695CD1 690578CAPN10 4. 2E-246 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Calpain 10, a member of the cysteine protease calpain superfamily, may play a role in lens development ; mutations are associated with non-insulin-dependent diabetes mellitus Ma, H. et al. J. Biol. Chem. 276, 28525-28531 (2001) 16 7510695CD1 429686lCapnl0 5. 6E-198 [Mus musculus] [Hydrolase ; Protease (other than proteasomal) ; Small molecule-binding protein] [Cytoplasmic] Calpain 10, a member of the cysteine protease calpain superfamily, may play a role in lens development, signal transduction, inflammation and apoptosis ; human CAPN10 mutations are associated with non-insulin-dependent diabetes mellitus Horikawa, Y. et al. (supra) t 17 7504781CD1 lgl3097684 1. 9E-19 [Homo sapiens] calnexin Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 17 7504781CD 1 613519lCANX 4. 8E-20 [Homo sapiens] [Chaperones ; Small molecule-binding protein] [Endoplasmic reticulum ; Cytoplasmic ; Plasma membrane ; Unspecified membrane] Calnexin, a calcium and lectin binding protein that functions as a chaperone in the endoplasmic reticulum ; involved in protein folding and secretion Okazaki, Y. et al. J. Biol. Chem. 275, 35751-35758 (2000) ; Morello, J. P. et al. Biochemistry 40, 6766-6775. (2001) 17 7504781CD 1 429140|Canx 4. 4E-19 [Mus musculus] [Chaperones ; Small molecule-binding protein] [Endoplasmic reticulum ; Cytoplasmic] Calnexin, a lectin binding protein that functions as a chaperone in the endoplasmic reticulum ; involved in the proper folding and transport of proteins Okazaki, Y. et al. (supra) 18 7504798CD gl83142 1. lE-295 [Homo sapiens] gamma-glutmyl transpeptidase-related protein Heisterkamp, N. et al. Proc. Natl. Acad. Sci. U. S. A. 88, 6303-6307 (1991) 18 7504798CD 1 340614lGGTLAl 8. 8E-297 [Homo sapiens] [Transferase] [Unspecified membrane] Gamma-glutamyl leukotrienase (gamma-glutamyl transpeptidase-related enzyme), converts leukotriene C4 to leukotriene D4 by catalyzing the transfer of the gamma-glutamyl moiety of glutathione Heisterkamp, N. et al. (supra) 18 7504798CD 1 609685lGgtlal 1. 5E-219 [Rattus norvegicus] [Transferase] Gamma-glutamyl leukotrienase (gamma-glutamyl transpeptidase-related enzyme), converts leukotriene C4 to leukotriene D4 by catalyzing the transfer of the gamma-glutamyl moiety of glutathione, may protect lung from oxidative stress or other toxic injury Potdar, P. D. et al. Am. J. Physio. 273, L1082-L1089 (1997) 19 17504800CD1 g183142 4. 1E-294 [Homo sapiens] gamma-glutmyl transpeptidase-related protein Heisterkamp, N. et al. (supra) Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 19 7504800CD1 340614GGTLA1 3. 4E-295 [Homo sapiens] [Transferase] [Unspecified membrane] Gamma-glutamyl leukotrienase (gamma-glutamyl transpeptidase-related enzyme), converts leukotriene C4 to leukotriene D4 by catalyzing the transfer of the gamma-glutamyl moiety of glutathione Heisterkamp, N. et al. (supra) 19 7504800CD1 609685lGgtlal 1. 4E-227 [Rattus norvegicus] [Transferase] Gamma-glutamyl leukotrienase (gamma-glutamyl transpeptidase-related enzyme), converts leukotriene C4 to leukotriene D4 by catalyzing the transfer of the gamma-glutamyl moiety of glutathione, may protect lung from oxidative stress or other toxic injury Potdar, P. D. et al. (supra) 20 7504902CD1 g5630086 0. 0 [Homo sapiens] lysyl hydroxylase 3 Sulston, J. E. et al. Genome Res. 8, 1097-1108 (1998) 20 7504902CD1 337038PLOD3 0. 0 [Homo sapiens] [Oxidoreductase] Procollagen-lysine 2-oxoglutarate 5-dioxygenase 3, catalyzes the formation of hydroxylysine in collages and displays glucosyitransferase activity Heikkinen, J. et al. J. Biol. Chem. 275, 36158-36163 (2000) 20 7504902CD1 430154lPlod3 0. 0 [Mus musculus] [Oxidoreductase] Procollagen-lysine 2-oxoglutarate 5-dioxygenase 3 Ruotsalainen, H. et al. Matrix Biol. 18, 325-329 (1999) 21 7510792CD1 g2502077 2. 0E-35 [Homo sapiens] digestive tract-specific calpain ; calcium-dependent cysteine proteinase Lee, H. J. et al. Molecular cloning and characterization of a novel tissue-specific calpain predominantly expressed in the digestive tract Biol. Chem. 379, 175-183 (1998) Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 21 7510792CD1 567870lCAPN9 1. 7E-36 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Calpain 9, a digestive tract- specific member of the calpain family of calcium-dependent non-lysosomal proteases, down regulated in gastric cancer ; murine nCL-4 suppresses neoplastic transformation Liu, K. et al. Antisense RNA-mediated deficiency of the calpain protease, nCL-4, in NIH3T3 cells is associated with neoplastic transformation and tumorigenesis J Biol Chem 275, 31093-8 (2000). 21 7510792CD1 772442lCapn9 8. 7E-28 [Mus musculus] [Hydrolase ; Protease (other than proteasomal)] Digestive tract member of the calpain family of calcium-dependent non-lysosomal protease, suppresses neoplastic transformation ; human CAPN9 is down-regulated in gastric cancer 22 7510557CD1 g2462488 0. 0 [Homo sapiens] NRD2 convertase Hospital, V. et al. Human and rat testis express two mRNA species encoding variants of NRD convertase, a metalloendopeptidase of the insulinase family Biochem. J. 327 (Pt 3), 773-779 (1997) 22 7510557CD1 336658|NRD1 0. 0 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Nardilysin, a metalloendopeptidase of the insulinase family, functions in peptide hydrolysis, may contribute to neuromuscular junction development Fumagalli, P. et al. Human NRD convertase : a highly conserved metalloendopeptidase expressed at specific sites during development and in adult tissues. Genomics 47, 238-45 (1998). 22 7510557CD1 430610|Nrdl 0. 0 [Rattus norvegicus] [Hydrolase ; Protease (other than proteasomal)] N-arginine dibasic convertase, a metalloendopeptidase of the M16 family, cleaves peptides on the N terminal side of arginine residues in dibasic tracts and plays a role in cell migration Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : Winter, A. G. et al. l Gene expression of the dibasic-pair cleaving enzyme NRD convertase (N-arginine dibasic convertase) is differentially regulated in the GH3 pituitary and Mat-Lu prostate cell lines. Biochem T351, 755-764 (2000). 23 7510649CD 1 g 13516326 6. 3E-26 [Homo sapiens] marapsin 23 7510649CD1 709655MPN 5. 4E-27 [Homo sapiens] Member of the trypsin family of serine proteases, has moderate similarity to prostasin (human PRSS8), which is a transmembrane serine protease that is proteolytically released from the membrane upon secretion 23 7510649CD1 337270|PRSS8 1. 9E-20 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] [Extracellular (excluding cell wall) ; Plasma membrane] Proprostasin, precursor of an active, membrane-bound serine protease member of the chromosome 16p-tryptase-prostasin family, secreted into seminal fluid, may act as a potential suppressor of invasive prostate cancer ; overexpressed in ovarian cancer cells Chen, L. M. et al. Down-regulation of prostasin serine protease : a potential invasion suppressor in prostate cancer. Prostate 48, 93-103. (2001). Mok, S. C. et al. Prostasin, a potential serum marker for ovarian cancer : identification through microarray technology. J Natl Cancer Inst 93, 1458-64. (2001). 25 |7506464CD1 lgl2803615 8. 6E-70 [Homo sapiens] cathepsin S W Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 25 7506464CD1 340304|CTSS 9. 7E-69 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] [Lysosome/vacuole ; Cytoplasmic] Cathepsin S, endosomal and lysosomal cysteine protease that has elastinolytic activity, may mediate inflammatory and immune responses, inhibited by peptidyl vinyl sulphones ; CTSS gene expression is elevated in Alzheimer patient and Down syndrome brains Munger, J. S. et al. Lysosomal processing of amyloid precursor protein to A beta peptides : a distinct role for cathepsin S. Biochem J 311, 299-305 (1995). 25 7506464CD1 618562Ctss 4. 7E-44 [Mus musculus] [Hydrolase ; Protease (other than proteasomal)] [Endosome/Endosomal vesicles ; Secretory vesicles ; Cytoplasmic ; Other vesicles of the secretory/endocytic pathways ; Lysosome/vacuole ; Golgi ; Endoplasmic reticulum ; Plasma membrane] Cathepsin S, endosomal and lysosomal cysteine protease that processes invariant chain (Ii), mediates intracellular trafficking of li and MHC class II molecules, possible therapeutic target for regulation of immune responses in autoimmune diseases Driessen, C. et al. Cathepsin S controls the trafficking and maturation of MHC class II molecules in dendritic cells. J Cell Biol 147, 775-90. (1999). 26 7510101CD1 gl79915 1. 6E-132 [Homo sapiens] cathepsin G Salvesen, G. et al. Molecular cloning of human cathepsin G : structural similarity to mast cell and cytotoxic T lymphocyte proteinases Biochemistry 26, 2289-2293 (1987) 26 7510101CD1 334894CTSG 1. 4E-133 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Cathepsin G, a serine protease localized to azurophil granules in neutrophils and monocytes Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : Sambrano, G. R. et al. Cathepsin G activates protease-activated receptor-4 in human platelets. J Biol Chem 275, 6819-23 (2000). 26 7510101CD1 584107lCtsg 2. 2E-87 [Mus musculus] [Hydrolase ; Protease (other than proteasomal)] Cathepsin G, a trypsin- related serine protease that is expressed in cells of the monocyte macrophage lineage and also in connective tissue mast cell lines Tani, K. et al. The neutrophil granule protein cathepsin G activates murine T lymphocytes and upregulates antigen-specific IG production in mice. Biochem Biophys Res Commun 282, 971-6. (2001). 27 7510845CD1 gl3529191 l. lE-117 [Homo sapiens] proteasome (prosome, macropain) subunit, alpha type, 4 27 7510845CD1 337302lPSMA4 4. 4E-118 [Homo sapiens] [Proteasome subunit] [Cytoplasmic] Proteasome subunit alpha type 4, polypeptide subunit of the proteasome multicatalytic proteinase that is expressed at abnormally high levels in renal carcinomas Kanayama, H. et al. Changes in expressions of proteasome and ubiquitin genes in human renal cancer cells. Cancer Res 51, 6677-85 (1991). 27 7510845CD1 591337lPsma4 1. 2E-117 [Rattus norvegicus] [Proteasome subunit] [Nuclear ; Cytoplasmic] Proteasome subunit alpha type 4, polypeptide subunit of the proteasome multicatalytic proteinase ; expression in muscle is increased during chronic renal failure Bailey, J. L. et al. The acidosis of chronic renal failure activates muscle proteolysis in rats by augmenting transcription of genes encoding proteins of the ATP-dependent ubiquitin-proteasome pathway. J Clin Invest 97, 1447-53. (1996). 28 7510846CD1 g220026 1. 0E-50 [Homo sapiens] proteasome subunit C5 Tamura, T. et al.

Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : Molecular cloning and sequence analysis of cDNAs for five major subunits of human proteasomes (multi-catalytic proteinase complexes) Biochim. Biophys. Acta 1089, 95-102 (1991) 28 7510846CD1 337310lPSMBl 8. 7E-52 [Homo sapiens] [Proteasome subunit ; Hydrolase ; Protease (other than proteasomal)] [Cytoplasmic] Proteasome subunit beta type 1, the C5 subunit of the proteasome, which is a multicatalytic proteinase complex involved in cellular protein degradation, interacts with Alzheimer's disease associated protein, presenilin 1 (PSEN1) Van Gassen, G. et al. Alzheimer's disease associated presenilin 1 interacts with HC5 and ZETA, subunits of the catalytic 20S proteasome. Neurobiol Dis 6, 376-91. (1999). 28 7510846CD1 586829pPsmbl 2. 0E-43 [Mus musculus] [Proteasome subunit ; Hydrolase ; Protease (other than proteasomal)] [Nuclear ; Cytoplasmic] Proteasome subunit beta type 1, the C5 subunit of the proteasome, which is a multicatalytic proteinase complex involved in cellular protein degradation ; human PSMB1 interacts with Alzheimer's disease associated protein, presenilin 1 (human PSEN1) Nandi, D. et al. Intermediates in the formation of mouse 20S proteasomes : implications for the assembly of precursor beta subunits. z Embo Journal 16, 5363-75. (1997). 29 7510921CD 1 gl81190 2. 5E-88 [Homo sapiens] preprochymotrypsinogen (EC 3. 4. 21. 1) Tomita, N. et al. Molecular cloning and nucleotide sequence of human pancreatic prechymotrypsinogen cDNA Biochem. Biophys. Res. Commun. 158, 569-575 (1989) Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 29 7510921CD1 334880|CTRB1 2. 1E-89 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Chymotrypsinogen B1, inactive precursor of the pancreatic serine protease chymotrypsin B Wang, X. C. et al. Chymotrypsin gene expression in rat peripheral organs. Cell Tissue Res 292, 345-54 (1998). 29 7510921CD1 589997lCtrbl 1. OE-80 ! [Rattusnorvegicus] [Hydrolase ; Protease (other than proteasomal)] Chymotrypsinogen B, a serine protease that specifically cleaves peptide bonds of aromatic residues with preferential activity towards phenylalanyl and tyrosyl substrates Iovanna, J. L. et al. Transcriptional regulation by cholecystokinin-pancreozymin in rat pancreas. Regul Pept 33, 165-73 (1991). 30 ! 7505097CD1) gl905911'2. 9E-211 [Homo sapiens] calreticulin 31 7506527CD1 g3153235 8. 2E-81 [Homo sapiens] lysyl hydroxylase isoform 3 Valtavaara, M. et al. Primary structure, tissue distribution, and chromosomal localization of a novel isoform of lysyl hydroxylase (lysyl hydroxylase 3) J. Biol. Chem. 273, 12881-12886 (1998) 31 7506527CD1 3370381PLOD3 7. 0E-82 [Homo sapiens] [Oxidoreductase] Procollagen-lysine 2-oxoglutarate 5-dioxygenase 3, catalyzes the formation of hydroxylysine in collagens and displays glucosyltransferase activity Heikkinen, J. et al. Lysyl Hydroxylase 3 Is a Multifunctional Protein Possessing Collagen Glucosyltransferase Activity. J Biol Chem 275, 36158-36163 (2000). 31 7506527CD1 430154Ptod3 2. 7E-72 [Mus musculus] [Oxidoreductase] Procollagen-lysine 2-oxoglutarate 5-dioxygenase 3 Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : Ruotsalainen, H. et al. Characterization of cDNAs for mouse lysyl hydroxylase 1, 2 and 3, their phylogenetic analysis and tissue-specific expression in the mouse. Matrix Biol 18, 325-9 (1999). 32 7504894CD1 g986881 ! 6. 8E-77 [Homo sapiens] ubiquitin-activating enzyme E1-related protein Kok, K. et al. A gene in the chromosomal region 3p21 with greatly reduced expression in lung cancer is similar to the gene for ubiquitin-activating enzyme Proc. Natl. Acad. Sci. U. S. A. 90, 6071-6075 (1993) 32 7504894CD1 338764|UBElL 5. 8E-78 [Homo sapiens] [Activator ; Protein conjugation factor] Ubiquitin-activating enzyme El-like, catalyzes the activation step in the conjugation of ISG15, a ubiquitin-like protein induced by interferon ; corresponding gene is located in a chromosomal region associated with loss of heterozygosity in lung cancer McLaughlin, P. M. et al. The ubiquitin-activating enzyme El-like protein in lung cancer cell lines. Int J Cancer 85, 871-6 (2000). 32 7504894CD1 581777Ubelx 9. 5E-39 [Mus musculus] [Activator ; Protein conjugation factor] Ubiquitin-activating enzyme E1, a protein that activates ubiquitin to mark cellular proteins for degradation, may play a role in DNA repair Aoki, F. et at. Defective DNA replication and repair associated with decreases in deoxyribonucleotide pools in a mouse cell mutant with thermolabile ubiquitin-activating enzyme E1. J Biochem (Tokyo) 126, 845-51. (1999). 337510529CD1 gl73902805. 8E-96 [Homo sapiens] ubiquitin carboxyl-terminal esterase L3 (ubiquitin thiolesterase) 33 7510529CD1 343242lUCHL3 4. 9E-97 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Ubiquitin carboxyl-terminal hydrolase L3, a cysteine (thiol) protease that functions as a C-terminal peptidase for ubiquitin and the ubiquitin-like protein NEDD8 Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : Kito, K. et al. NUB1, a NEDD8-interacting protein, is induced by interferon and down-regulates the NEDD8 expression. J Biol Chem 276, 20603-9. (2001). 33 7510529CD1 477422UchI3 7. 2E-96 [Mus musculus] [Hydrolase ; Protease (other than proteasomal)] Ubiquitin carboxyl-terminal hydrolase L3, putative ubiquitin-processing peptidase, not required for viability or fertility, plays a role in maintenance of neurons within the gracile tract, the nucleus tractus solitarius, and area postrema of the medulla Kurihara, L. J. et al. Loss of Uch-L1 and Uch-L3 leads to neurodegeneration, posterior paralysis and dysphagia. Hum Mol Genet 10, 1963-70. (2001). 34 7510581CD1g2656141 0. 0 [Homo sapiens] UnpEL Frederick, A. et al. The human UNP locus at 3p21. 31 encodes two tissue-selective, cytoplasmic isoforms with deubiquitinating activity that have reduced expression in small cell lung carcinoma cell lines Oncogene 16, 153-165 (1998) 34 7510581CD1 338842JUSP4 0. 0 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] [Nuclear ; Cytoplasmic] Ubiquitin specific protease 4 (ubiquitous nuclear protein human), efficiently cleaves ubiquitin-proline bonds, expression is elevated in small cell lung carcinomas ; corresponding gene maps to a chromosomal region frequently rearranged in tumor cells Gray, D. A. et al. Elevated expression of Unph, a proto-oncogene at 3p21. 3, in human lung tumors. Oncogene 10, 2179-83 (1995).

Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 34 7510581CD1 586113Usp4 6. 7E-297 [Mus musculus] [Hydrolase ; Protease (other than proteasomal) ; Small molecule-binding protein] [Nuclear] Ubiquitin specific protease 4 (ubiquitous nuclear protein), efficiently cleaves ubiquitin-proline bonds, transforms cells when overexpressed, may bind to the retinoblastoma gene product ; expression of human USP4 is elevated in small cell lung carcinomas Gilchrist, C. A. et al. A ubiquitin-specific protease that efficiently cleaves the ubiquitin-proline bond. J Biol Chem 272, 32280-5. (1997). 35 7510582CD1 g2656143 0. 0 [Homo sapiens] UnpES Gray, D. A. et al. (supra) Frederick, A. et al. (supra) 35 7510582CD 1 586113lUsp4 0. 0 [Mus musculus] [Hydrolase ; Protease (other than proteasomal) ; Small molecule-binding protein] [Nuclear] Ubiquitin specific protease 4 (ubiquitous nuclear protein), efficiently cleaves ubiquitin-proline bonds, transforms cells when overexpressed, may bind to the retinoblastoma gene product ; expression of human USP4 is elevated in small cell lung carcinomas Gilchrist, C. A. et al. (supra) 35 7510582CD1 338842|USP4 0. 0 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] [Nuclear ; Cytoplasmic] Ubiquitin specific protease 4 (ubiquitous nuclear protein human), efficiently cleaves ubiquitin-proline bonds, expression is elevated in small cell lung carcinomas ; corresponding gene maps to a chromosomal region frequently rearranged in tumor cells Gray, D. A. et al. (supra) 36 7510583CD1 g2656143 0. 0 [Homo sapiens] UnpES Gray, D. A. et al. (supra) Frederick, A. et al. (supra) Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 36 7510583CD1 338842|USP4 0. 0 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] [Nuclear ; Cytoplasmic] Ubiquitin specific protease 4 (ubiquitous nuclear protein human), efficiently cleaves ubiquitin-proline bonds, expression is elevated in small cell lung carcinomas ; corresponding gene maps to a chromosomal region frequently rearranged in tumor cells Gray, D. A. et al. (supra) 36 7510583CD1 586113|Usp4 0. 0 [Mus musculus] [Hydrolase ; Protease (other than proteasomal) ; Small molecule-binding protein] [Nuclear] Ubiquitin specific protease 4 (ubiquitous nuclear protein), efficiently cleaves ubiquitin-proline bonds, transforms cells when overexpressed, may bind to the retinoblastoma gene product ; expression of human USP4 is elevated in small cell lung carcinomas Gilchrist, C. A. et al. (supra) 37 7510596CD1 gl3623417 3. 3E-92 [Homo sapiens] Similar to ubiquitin carboxy-terminal hydrolase LI 37 7510596CD1 430380Jchll 8. 5E-90 [Mus musculus] [Hydrolase ; Protease (other than proteasomal)] Ubiquitin carboxyl-terminal esterase (ubiquitin thiolesterase), a cysteine (thiol) protease ; mutation of the gene underlies the gracile axonal dystrophy mouse, a model for human neurodegenerative diseases Kurihara, L. J. et al. (supra) Loss of Uch-Ll and Uch-L3 leads to neurodegeneration, posterior paralysis and dysphagia. Hum Mol Genet 10, 1963-70. (2001). 37 7510596CD1 341406lUCHLl 3. 7E-87 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Ubiquitin carboxyl-terminal esterase (ubiquitin thiolesterase), a cysteine (thiol) protease that removes ubiquitin from ubiquitinated proteins, preventing them from targeted degradation by proteasomes ; increased expression may be a marker for lung cancer Hibi, K. et al. PGP9. 5 as a candidate tumor marker for non-small-cell lung cancer. Am J Pathol 155, 711-5. (1999).

Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 38 7510643CD1 gl2653165 0. 0 [Homo sapiens] ubiquitin specific protease 11 38 7510643CD1 341412JUSPII 0. 0 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Ubiquitin specific protease 11, a member of the ubiquitin-specific cysteine (thiol) protease family which removes ubiquitin from ubiquitin-conjugated protein substrates ; may play a role in oncogenesis Swanson, D. A. et al. (supra) A ubiquitin C-terminal hydrolase gene on the proximal short arm of the X chromosome : implications for X-linked retinal disorders. Hum Mol Genet 5, 533-8 (1996). 38 7510643CD1 338842lUSP4 3. 6E-204 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] [Nuclear ; Cytoplasmic] Ubiquitin specific protease 4 (ubiquitous nuclear protein human), efficiently cleaves ubiquitin-proline bonds, expression is elevated in small cell lung carcinomas ; corresponding gene maps to a chromosomal region frequently rearranged in tumor cells Gray, D : A. et al. (supra) 39 7506671CD 1 g7271475 2. 5E-127 [Homo sapiens] complement Clr-like proteinase precursor 39 7506671CD1 476011|LOC5127 2. 1E-128 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Member of the trypsin 9 family of serine proteases, contains an extracellular CUB domain, has moderate similarity to C1R (complement component Clr), mutations in the gene for which are associated with lupus erythematosus-like disease 39 7506671CD1 334394C1R 3. 7E-37 [Homo sapiens] [Structural protein ; Hydrolase ; Protease (other than proteasomal)] Complement component 1 (r subcomponent), a serine protease that activates C1, the first component of the classical complement pathway, through cleavage of C1S ; mutation of the corresponding gene is associated with lupus erythematosus-like disease Lee, S. L. et al. Familial deficiency of two subunits of the first component of complement. Clr and Cls associated with a lupus erythematosus-like disease.

Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : Arthritis Rheum 21, 958-67 (1978. 40 17510518CD1 gl7389625 5. OE-42 [Homo sapiens] caspase 4, apoptosis-related cysteine protease 40 |7510518CD1 gl7389625 5. 0E-42 [Homo sapiens] caspase 4, apoptosis-related cysteine protease 40 7510518CD1 339702|CASP13 2. 8E-23 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Caspase 13, a cysteine (thiol) protease, member of the ICE (CASP1) subfamily of caspases, activated by caspase 8 (CASP8), induces apoptosis when overexpressed and has a role in tumor necrosis factor- induced apoptosis Lin, X. Y. et al. Expression analysis of the human caspase-1 subfamily reveals specific regulation of the CASP5 gene by lipopolysaccharide and interferon-gamma J Biol Chem 275, 39920-6. (2000). 40 7510518CD1 757262Caspll 4. 7E-19 [Rattus norvegicus] Protein with strong similarity to caspase 11 (mouse Casp 11), which is involved in apoptosis, contains a caspase recruitment domain (CARD) and interleukin-1 beta converting enzyme (ICE)-like protease (caspase) plO and p20 domains 41 7510585CD1 g298124 0. 0 [Homo sapiens] complement component C2 Zhu, Z. B. et al. A variable number of tandem repeats locus within the human complement C2 gene is associated with a retroposon derived from a human endogenous retrovirus J. Exp. Med. 175, 1783-1787 (1992) 41 7510585CD1 743256lu2 0. 0 [Homo sapiens] [Structural protein ; Hydrolase ; Protease (other than proteasomal)] [Extracellular (excluding cell wall)] Complement component 2, serine protease of the classical complement pathway, member of the C3 and C5 convertase complexes, involved in pathogen defense ; mutation of corresponding gene is associated with increased incidence of autoimmune diseases Speth, C., et al.

Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : Human immunodeficiency virus type 1 induces expression of complement factors in human astrocytes. J Virol 75, 2604-15. (2001) 41 7510585CD1 586907in2 1. OE-256 [Mus musculus] [Hydrolase ; Protease (other than proteasomal)] [Extracellular (excluding cell wall)] Complement component 2, putative serine protease of the classical complement pathway, involved in pathogen defense ; mutation of corresponding human gene is associated with increased incidence of autoimmune diseases Ishikawa, N. et al. Murine complement C2 and factor B genomic and cDNA cloning reveals different mechanisms for multiple transcripts of C2 and B. J Biol Chem 265, 19040-6 (1990). 42 7510590CD1 gl2803127 3. 6E-158 [Homo sapiens] protease (prosome, macropain) 26S subunit, ATPase 5 l 42 7510590CD1 586751lPsmcS 3. 1E-159 [Mus musculus] [Proteasome subunit ; Hydrolase ; Transcription factor ; ATPase] [Nuclear ; Cytoplasmic] ATPase subunit 5 of the 26S proteasome, which is a multicatalytic proteinase complex involved in cellular protein degradation ; may also function as a transcriptional modulator Sun, D. et al. Identification of a phylogenetically conserved Sugl CAD family member that is differentially expressed in the mouse nervous system. J Neurobiol 33, 877-90 (1997). 42 7510590CD 1 705086|LOC8182 3. 1E-159 [Rattus norvegicus] [Proteasome subunit ; Hydrolase ; Transcription factor ; 7 ATPase] [Nuclear ; Cytoplasmic] ATPase subunit 5 of the 26S proteasome, which is a multicatalytic proteinase complex involved in cellular protein degradation ; may also function in ATP-dependent RNA or DNA unwinding SUG1, a component of the 26 S proteasome, is an ATPase stimulated by specific RNAs. I J Biol Chem 272, 23201-5 (1997).

Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 43 7510617CD 1 g 1743266 1. lE-220 [Homo sapiens] legumain Chen, J. M. et al. Cloning, isolation, and characterization of mammalian legumain, an asparaginyl endopeptidase J. Biol. Chem. 272, 8090-8098 (1997) 43 7510617CD1 342702|LGMN 9. 3E-222 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Protease cysteine 1 (legumain), a lysosomal cysteine endopeptidase that hydrolyzes asparaginyl bonds, inhibits osteoclast differentiation, may play a role in antigen processing for MHC class II presentation Manoury, B. et al. An asparaginyl endopeptidase processes a microbial antigen for class II MHC presentation. Nature 396, 695-9. (1998). 43 7510617CD1 586821Lgmn 2. 2E-190 [Mus musculus] [Hydrolase ; Protease (other than proteasomal)] [Lysosome/vacuole ; Cytoplasmic] Protease cysteine 1 (legumain), a lysosomal cysteine endopeptidase that hydrolyzes asparaginyl bonds, member of a family of asparaginyl endopeptidases first identified in plant seeds and parasites Choi, S. J. et al. Identification of human asparaginyl endopeptidase (legumain) as an inhibitor of osteoclast formation and bone resorption. J Biol Chem 274, 27747-53 (1999). 44 7510618CD1 gl743266 5. 7E-57 [Homo sapiens] legumain Chen, J. M. et al. (supra) 44 7510618CD1 342702lLGMN 4. 9E-58 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Protease cysteine 1 (legumain), a lysosomal cysteine endopeptidase that hydrolyzes asparaginyl bonds, inhibits osteoclast differentiation, may play a role in antigen processing for MHC class II presentation Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : Manoury, B. et al. (supra) 44 7510618CD1 586821|Lgmn 4. 8E-51 [Mus musculus] [Hydrolase ; Protease (other than proteasomal)] [Lysosome/vacuole ; Cytoplasmic] Protease cysteine 1 (legumain), a lysosomal cysteine endopeptidase that hydrolyzes asparaginyl bonds, member of a family of asparaginyl endopeptidases first identified in plant seeds and parasites Choi, S. J. et al. (supra) 45 7510620CD1 gl5778988 1. 9E-208 [Homo sapiens] Similar to carboxypeptidase A2 (pancreatic) 45 7510620CD1 342306|CPA2 7. 1E-209 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Carboxypeptidase A2, a monomeric pancreatic metalloprotease that has a substrate preference for large hydrophobic C-terminal residues and is involved in vacuolar protein degradation Reverter, D. et al. Characterisation and preliminary X-ray diffraction analysis of human pancreatic procarboxypeptidase A2. FEBS Lett 420, 7-10 (1997). 45 7510620CD1 332330lRn. 17687 9. 2E-185 [Rattus norvegicus] [Hydrolase ; Protease (other than proteasomal)] Carboxypeptidase A2, a monomeric pancreatic metalloprotease that has a substrate preference for large hydrophobic C-terminal residues Normant, E. et al. Carboxypeptidase A isoforms produced by distinct genes or alternative splicing in brain and other extrapancreatic tissues. J Biol Chem 270, 20543-9 (1995). 467510628CD1 2859035. 9E-12 [Homo sapiens] aminoacylase-1 Mitta, M. et al. The nucleotide sequence of human aminoacylase-1 Biochim. Biophys. Acta 1174, 201-203 (1993) Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 46 7510628CD1 334030ACY1 S. OE-13 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] [Cytoplasmic] Aminoacylase 1, homodimeric zinc-binding enzyme that catalyzes the hydrolysis of N-alpha-acylated amino acids ; mutational inactivation or dysregulation may contribute to the development of small cell lung cancer Cook, R. M. et al. Mutational inactivation of aminoacylase-I in a small cell lung cancer cell line. Genes Chromosomes Cancer 21, 320-5. (1998). Lindner, H. et al. 47 7510650CD gel 1071729 3. 6E-190 [Horno sapiens] putative dipeptidase Chen, J. M. et al. 47 7510650CD1 657677lLOC6417 3. 1E-191 [Homo sapiens] Protein with high similarity to renal dipeptidase (ratRn. 6051), which is a 4 zinc-dependent cell surface metalloprotease that also functions as the receptor for lung homing peptide GFE 1, member of the Rrnal dipeptidase family 47 7510650CD1 340388|DPEPI 2. 9E-76 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] [Plasma membrane] Membrane dipeptidase (renal dipeptidase), a zinc-dependent cell surface metalloprotease ; gene is frequently lost in Wilms tumor Keynan, S. et al. Stable and temperature-sensitive transformation of baby rat kidney cells by SV40 suppresses expression of membrane dipeptidase. l Oncogene 15, 1241-5 (1997). 48 7506644CD 1 g49645 5. IE-11 [Mesocricetus auratus] P5 Chaudhuri, M. M. et al. The gene for a novel protein, a member of the protein disulphide isomerase/form I phosphoinositide-specific phospholipase C family, is amplified in hydroxyurea-resistant cells Biochem. J. 281 (Pt 3), 645-650 (1992) Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score BD NO : 48 7506644CD1 342684|P5 7. 3E-12 [Homo sapiens] [Isomerase ; Chaperones] Protein disulfide isomerase-related protein, member of the protein disulfide isomerase thioredoxin-containing family of endoplasmic reticulum proteins Hayano, T. et al. l Cloning and sequencing of the cDNA encoding human P5. Gene 164, 377-8 (1995). 49 7506692CD1 |gl3278723 9. 5E-135 [Homo sapiens] serine protease inhibitor, Kunitz type 1 49 7506692CD1 341496lSPINTl 8. 1E-136 [Homo sapiens] [Inhibitor or repressor] [Extracellular (excluding cell wall) ; Unspecified membrane ; Plasma membrane] Serine protease inhibitor (Kunitz type 1), a Kunitz type serine protease inhibitor that inhibits hepatocyte growth factor activator (HGFAC), expression levels are decreased in colorectal adenocarcinomas Kataoka, H. et al. Activation of hepatocyte growth factor/scatter factor in colorectal carcinoma Cancer Res 60, 6148-59 (2000). 49 7506692CD1 588049|Spintl 6. 6E-102 [Mus musculus] [Inhibitor or repressor ; Small molecule-binding protein) [Unspecified membrane ; Extracellular (excluding cell wall)] Serine protease inhibitor (Kunitz type 1), a Kunitz type serine protease inhibitor that may inhibit hepatocyte growth factor activator (Hgfac), may also play a role in colonic mucosa regeneration Itoh, H. et al. Upregulation of HGF activator inhibitor type 1 but not type 2 along with regeneration of intestinal mucosa. Am J Physiol Gastrointest Liver Physiol 278, G635-43. (2000). 50 7504938CD1 g3818632 l. lE-21 [Rattus norvegicus] ubiquitin-conjugating enzyme UBC7 Lin, H. et al. Identification of rabbit reticulocyte E217K as a UBC7 homologue and functional characterization of its core domain loop Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : J. Biol. Chem. 274, 14685-14691 (1999) 50 7504938CD1 333470|Ubc7 9. 4E-23 [Rattus norvegicus] [Ligase ; Protein conjugation factor] Ubiquitin-conjugating enzyme 7, a putative member of the ubiquitin-conjugating enzyme family that catalyzes the ubiquitination of cellular proteins and marks them for degradation 50 7504938CD1 697470|UBE2G1 9. 4E-23 [Homo sapiens] [Ligase ; Protein conjugation factor] Ubiquitin-conjugating enzyme E2G 1, a putative member of the ubiquitin-conjugating enzyme family that catalyzes the ubiquitination of cellular proteins and marks them for degradation Imai, Y. et al. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. l Cell 105, 891-902. (2001). 51 7505625CD1 g340072 1. 8E-25 [Homo sapiens] ubiquitin-activating enzyme E1 Handley, P. M. et al. Molecular cloning, sequence, and tissue distribution of the human ubiquitin-activating enzyme E1 Proc. Natl. Acad. Sci. U. S. A. 88, 7456 (1991) 51 7505625CD1 338760|UBE1 1. 5E-26 [Homo sapiens] [Ligase ; Activator ; Protein conjugation factor] Ubiquitin-activating enzyme E1, activates ubiquitin to mark cellular proteins for degradation, expressed at low levels in quiescent cells and high levels during the cell cycle, has very strong similarity to murine Ubelx, which may function in DNA repair Reinstein, E. et al. Degradation of the E7 human papillomavirus oncoprotein by the ubiquitin-proteasome system : targeting via ubiquitination of the N-terminal residue. Oncogene 19, 5944-50 (2000). 51 7505625CD1 581777lUbelx 1. 3E-24 [Mus musculus] [Activator ; Protein conjugation factor] Ubiquitin-activating enzyme E1, a protein that activates ubiquitin to mark cellular proteins for degradation, may play a role in DNA repair Aoki, F. et al.

Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : Defective DNA replication and repair associated with decreases in deoxyribonucleotide pools in a mouse cell mutant with thermolabile ubiquitin-activating enzyme E1. J Biochem (Tokyo) 126, 845-51. (1999). 52 7506468CD1 g33985 1. 6E-29 [Homo sapiens] trypsin inhibitor Gebhard, W. et al. Complementary DNA and derived amino acid sequence of the precursor of one of the three protein components of the inter-alpha-trypsin inhibitor complex FEBS Lett. 229, 63-67 (1988) 52 7506468CD1 336078|ITIH2 1. 3E-30 [Homo sapiens] [Regulatory subunit ; Structural protein ; Inhibitor or repressor] [Extracellular matrix (cuticle and basement membrane)] Inter-alpha (globulin) inhibitor H2 polypeptide, a member of the heavy chain family of inter-alpha-trypsin inhibitor proteoglycans, which are non-catalytic subunits of a protease inhibitor complex that stabilizes the extracellular matrix Enghild, J. J. et al. Analysis of inter-alpha-trypsin inhibitor and a novel trypsin inhibitor, pre-alpha-trypsin inhibitor, from human plasma. Polypeptide chain stoichiometry and assembly by glycan. J Biol Chem 264, 15975-81 (1989). 52 7506468CD1 585103|Itih2 1. 8E-13 [Mus musculus] [Regulatory subunit ; Inhibitor or repressor ; Small molecule-binding protein] [Extracellular matrix (cuticle and basement membrane)] Inter-alpha trypsin inhibitor heavy chain 2, a member of the heavy chain family of inter-alpha-trypsin inhibitor proteoglycans, which are non-catalytic subunits of a protease inhibitor complex that stabilizes the extracellular matrix Chan, P. et al. The three heavy-chain precursors for the inter-alpha-inhibitor family in mouse : new members of the multicopper oxidase protein group with differential transcription in liver and brain.

Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : "Biochem J 306, 505-12 (1995). 53 0682CD1"gl1244764 4'4E-38 [Homo sapiens] protease M Gan, L. et al. Sequencing and expression analysis of the serine protease gene cluster located in chromosome 19ql3 region Gene 257, 119-130 (2000) 53 7510682CD1 337272KLK6 3. 8E-39 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Kallikrein 6 (neurosin, zyme, protease M), a serine proteinase that cleaves the amyloid precursor protein (APP) and may be involved in the pathogenesis of Alzheimer's disease ; mRNA expression is upregulated in the sera of patients with ovarian carcinoma Diamandis, E. P. et al. Human kallikrein 6 (zyme/protease M/neurosin) : a new serum biomarker of ovarian carcinoma. Clin Biochem 33, 579-83. (2000). Diamandis, E. P. et al. Human kallikrein 6 as a biomarker of alzheimer's disease. Clin Biochem 33, 663-7. (2000). 53 7510682CD1 585605Prssl8 4. 2E-27 [Mus musculus] [Hydrolase ; Protease (other than proteasomal)] Skin serine protease, expressed in sebaceous glands of hair follicles and the distal outer root sheath, overexpressed in skin from the nude mouse Matsui, H. et al. Molecular and biochemical characterization of a serine proteinase predominantly expressed in the medulla oblongata and cerebellar white matter of mouse brain. J Biol Chem 275, 11050-7 (2000). 54 7505420CD1 g4580598 1. 1E-126 [Homo sapiens] SUMO-1 activating enzyme subunit 1 Desterro, J. M. et al.

Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : Identification of the enzyme required for activation of the small ubiquitin-like protein SUMO-1 J. Biol. Chem. 274, 10618-10624 (1999) 54 7505420CD1 475455|SAE1 9. 4E-126 [Homo sapiens] [Activator ; Protein conjugation factor] Subunit of SUMO-1 activating enzyme 1 (sentrin-activating enzyme complex), catalyzes the transfer of SUMO-1 (UBL1), which regulates subcellular localization of a range of proteins, catalyzes the transfer of polymeric SUM02 and SUM03 Rodriguez, M. S. et al. SUMO-1 modification activates the transcriptional response of p53. Embo Journal 18, 6455-61. (1999). 54 7505420CD1 608960|Ublela 3. 4E-121 [Mus musculus] [Activator ; Protein conjugation factor] Ubiquitin-like 1 (sentrin) activating enzyme EIA, subunit of SUMO-1 activating enzyme, which is a subunit of the SUMO-1 (ubiquitin-like) activating enzyme that regulates subcellular localization of a range of proteins Desterro, J. M. et al. (supra) 55 7505604CD1 gl5425755 0. 0 [Homo sapiens] transglutaminase Z Grenard, P. et al. Evolution of transglutaminase genes : identification of a transglutaminase gene cluster on human chromosome 15ql5. structure of the gene encoding transglutaminase X and a novel gene family member, transglutaminase Z J. Biol. Chem. 276, 33066-33078 (2001) 55 7505604CD1 752485TGM7 0. 0 [Homo sapiens] Transglutaminase Z, a putative transglutaminase expressed at low levels in a wide range of tissues Grenard, P. et al. (supra) 55 7505604CD1 341358TGM5 1. 7E-129 [Homo sapiens] [Transferase] Transglutaminase 5 (transglutaminase X), catalyzes the formation of epsilon (gamma-glutamyl) lysine isopeptide bonds to cross-link proteins, may play a role in the formation of the cornified envelope Aeschlimann, D. et al.

Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : Isolation of a cDNA encoding a novel member of the transglutaminase gene family from human keratinocytes. Detection and identification of transglutaminase gene products based on reverse transcription-polymerase chain reaction with degenerate primers. J Biol Chem 273, 3452-60 (1998). 56 7505606CD 1 g219632 13. 1E-184 [Homo sapiens] transglutaminase Yamanishi, K. et al. Molecular cloning of human epidermal transglutaminase cDNA from keratinocytes in culture Biochem. Biophys. Res. Commun. 175, 906-913 (1991) 56 7505606CD1 338492TGM1 2. 6E-185 [Homo sapiens] [Transferase] [Unspecified membrane] Keratinocyte transglutaminase (protein-glutamine : amine gamma-glutamyltransferase, transglutaminase K), crosslinks proteins in the formation of epidermis ; defects are associated with lamellar ichthyosis IZou, C. P. et al. Expression of retinoic acid receptor beta is associated with inhibition of keratinization in human head and neck squamous carcinoma cells. Differentiation 64, 123-32 (1999). 56 7505606CD1 711576lTgm 1 1. 3E-160 [Rattus norvegicus] [Transferase] Keratinocyte transglutaminase (transglutaminase 1), catalyzes protein crosslinking that is required for epidermal keratinocyte cell envelope formation ; human TGM1 defects cause ichthyosis and mouse Tgml deficiency causes severe skin barrier defects Oka, M. et al. Involvement of dendritic cell response to resistance of stomach carcinogenesis caused by N- methyl-N'-nitro-N-nitrosoguanidine in rats. Cancer Res 58, 4107-12 (1998). 57 |7511044CD1 Igl2275390 7. 3E-83 [Rattus norvegicus] membrane attractin Kuramoto, T. et al.

Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : Attractin/mahogany/zitter plays a critical role in myelination of the central nervous system Proc. Natl. Acad. Sci. U. S. A. 98, 559-564 (2001) 57 7511044CD1 346432|EGFL4 0. 0 [Homo sapiens] EGF-like-domain multiple 4, a putative transmembrane protein that contains five EGF-like motifs, one laminin type EGF-like motif, may play a role in extracellular events in brain, such as cell-cell adhesion and receptor-ligand interactions Nakayama, M. et al. Identification of high-molecular-weight proteins with multiple EGF-like motifs by motif- trap screening. Genomics 51, 27-34 (1998). 57 7511044CD1 749972Egfl4 0. 0 [Rattus norvegicus] Protein of unknown function, has weak similarity to a region of attractin (rat Atrn), which is involved in myelination of the central nervous system 58 2579533CD1gl0303329 0. 0 [Mus musculus] calpain 12 Dear, T. N. et al. Gene structure, chromosomal localization, and expression pattern of capnl2, a new member of the calpain large subunit gene family Genomics 68, 152-160 (2000) l 58 2579533CD1 624120|Capnl2 1. OE-167 [Mus musculus] Member of the calpain family of cysteine proteases, has high similarity to a region of calpain 2 (mouse Capn2), which is the large subunit of the cysteine-type protease m-calpain that mediates cell adhesion, migration, and signal transduction Dear, T. N. et al. Gene structure, chromosomal localization, and expression pattern of capnl2, a new member of the calpain large subunit gene family Genomics 68, 152-60 (2000).

Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 58 2579533CD1 334452lCAPN2 1. 5E-149 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Calpain 2, large subunit of the cysteine-type protease m-calpain which may regulate the cell cycle, apoptosis, and cellular differentiation, upregulated in muscle from progressive muscular dystrophy and amyotrophic lateral sclerosis patients Imajoh, S. et al. Molecular cloning of the cDNA for the large subunit of the high-Ca2+-requiring form of human Ca2+-activated neutral protease. |Biochemistry 27, 8122-8 (1988). 59 7511097CD1 gl4250438 1. 3E-11 [Homo sapiens] tubulin-specific chaperone e 59 7511097CDI 338412ITBCE I. IE-12 [Homo sapiens] [Chaperones] [Cytoplasmic ; Cytoskeletal] Tubulin-specific chaperone e, a cochaperonin that functions in beta-tubulin folding by binding to the cofactor D-beta- tubulin complex prior to cofactor c binding, resulting in the release of native state beta- tubulin Tian, G. et al. Pathway leading to correctly folded beta-tubulin. Cell 86, 287-96 (1996). 60 7510842CD1 g3191969 3. 2E-230 [Homo sapiens] dJ337018. 2. 1 (Lysosomal Protective Protein precursor (EC 3. 4. 16. 5, Cathepsin A, Carboxypeptidase C) (isoform 1)) 60 7510842CD 1 337120lPPGB 1. 2E-230 [Homo sapiens] [Hydrolase ; Activator ; Protease (other than proteasomal)] [Lysosome/vacuole ; Endoplasmic reticulum ; Cytoplasmic] Protective protein for beta-galactosidase (cathepsin A), has serine carboxypeptidase activity, forms a complex with beta galactosidase (GLB1) and neuraminidase (NEU1), facilitates NEU1 transport and activation ; genetic mutation leads to galactosialidosis Galjart, N. J. et al. Expression of cDNA encoding the human"protective protein"associated with lysosomal beta-galactosidase and neuraminidase : homology to yeast proteases. Cell 54, 755-64 (1988).

Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 60 7510842CD1 582563Ppgb 4. 3E-200 [Mus musculus] [Hydrolase ; Inhibitor or repressor ; Protease (other than proteasomal)] [Lysosome/vacuole ; Cytoplasmic] Protective protein for beta-galactosidase (cathepsin A), forms a complex with beta galactosidase (Bgl) and neuraminidase (Neul), protecting them from proteases ; mutation of human PPGB leads to the lysosomal storage disorder galactosialidosis Galjart, N. J. et al. Mouse"protective protein". cDNA cloning, sequence comparison, and expression. J Biol Chem 265, 4678-84 (1990). o 61 7511249CD1 g857569 1. OE-82 [Homo sapiens] Yama protein Tewari ; M. et al. Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly (ADP-ribose) polymerase Cell 81, 801-809 (1995) 61 7511249CD1 743452lCASP3 8. 7E-84 [Homo sapiens] [Activator ; Hydrolase ; Protease (other than proteasomal)] [Nuclear ; Cytoplasmic] Caspase 3 (apopain), a cysteine (thiol) effector protease of the caspase family, induces apoptosis when activated by activated caspase-9 (CASP9), cleaves amyloid-beta precursor protein (APP) and may have a role in development of Alzheimer's disease Fernandes-Alnemri, T. et al. CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme. J Biol Chem 269, 30761-4 (1994). 61 7511249CD 1 589905|Casp3 5. 0E-72 [Rattus norvegicus] [Hydrolase ; Protease (other than proteasomal)] [Nuclear ; Cytoplasmic ; Cell body (soma) ; Dendrite] Caspase 3 (apopain), a cysteine (thiol) effector protease of the caspase family, induces apoptosis when activated Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : Juan, T. S. et al. Molecular characterization of mouse and rat CPP32 beta gene encoding a cysteine protease resembling interleukin-1 beta converting enzyme and CED-3. Oncogene 13, 749-55 (1996). 62 7511254CD1 gl2246830 11. 2E-109 R _ _ i Scott, H. S. et al. Insertion of beta-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness Nat. Genet. 27, 59-63 (2001) 62 7511254CD 1 685457|TMPRSS 1. 1E-110 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] [Plasma membrane] Tumor 3 associated differentially-expressed gene-12, member of serine protease family that may function at the cell surface, overexpressed in most ovarian cancers and may be used as a molecular target for therapy or a diagnostic marker for ovarian cancers Underwood, L. J. et al. Ovarian tumor cells express a novel multi-domain cell surface serine protease Biochim Biophys Acta 1502, 337-50 (2000). 62 7511254CD1 743246lTMPRSS 4. 8E-19 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] [Plasma membrane] 2 Transmembrane protease serine 2 (epitheliasin), a putative serine endopeptidase with transmembrane, LDLRA (LDL receptor class A) and SRCR (scavenger receptor cysteine- rich) domains ; highly expressed in androgen-dependent prostate cancer Paoloni-Giacobino, A. et al. Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22. 3. Genomics 44, 309-20 (1997). 63 7511274CD1 gl4250624 0. 0 Homo sapiens] nardilysin (N-arginine dibasic convertase) Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 62 7511274CD 1 430610lNrdl 0. 0 [Rattus norvegicus] [Hydrolase ; Protease (other than proteasomal)] N-arginine dibasic convertase, a metalloendopeptidase of the M16 family, cleaves peptides on the N terminal side of arginine residues in dibasic tracts and plays a role in cell migration Pierotti, A. R. et al. N-arginine dibasic convertase, a metalloendopeptidase as a prototype of a class of processing enzymes. Proc Natl Acad Sci U S A 91, 6078-82 (1994). 63 7511274CD1 336658NRD1 0. 0 [Homo sapiens] (hydrolase ; Protease (other than proteasomal)] Nardilysin, a metalloendopeptidase of the insulinase family, functions in peptide hydrolysis, may contribute to neuromuscular junction development Fumagalli, P. et al. Human NRD convertase : a highly conserved metalloendopeptidase expressed at specific sites during development and in adult tissues. ! Genomics 47, 238-45 1998). 64 7511303CD 1 g6681454 8. 5E-55 [Homo sapiens] Hippostasin ! Mitsui, S. et al. A novel isoform of a kallikrein-like protease, TLSP/hippostasin, (PRSS20), is expressed in the human brain and prostate Biochem. Biophys. Res. Commun. 272, 205-211 (2000) 64 7511303CD1 428508|KLK11 7. 3E-56 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Hippostasin (kallikrein 11), a secreted trypsin-like serine protease, member of the kallikrein family ; one alternative form is expressed in normal prostate but absent in prostate cancer cell lines Yoshida, S. et al. cDNA cloning and expression of a novel serine protease, TLSP. Biochim Biophys Acta 1399, 225-8 (1998).

Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 64 7511303CD 1 609150|Prss20 9. 1E-46 64 7511303CD1 609150Prss20 9. 1E-46 [Mus musculus] [Hydrolase ; Protease (other than proteasomal)] [Extracellular (excluding cell wall)] Hippostasin, a secreted protein in the trypsin family of serine proteases Mitsui, S. et al. cDNA cloning and tissue-specific splicing variants of mouse hippostasin/TLSP (PRSS20) (1). Biochim Biophys Acta 1494, 206-210 (2000). 65 7511309CD1 g11761715 1. 7E-213 [Homo sapiens] tubulointerstitial nephritis antigen-related protein Bromme, N. C. et al. Cloning, characterization, and expression of the human TIN-ag-RP gene encoding a novel putative extracellular matrix protein Biochem. Biophys. Res. Commun. 271, 474-480 (2000) 65 7511309CD1 626227lLIECG3 1. 5E-214 [Homo sapiens] Protein with high similarity to tubulointerstitial nephritis antigen (human TINAG), which functions in renal tubulogenesis and is defective in hereditary tubulointerstitial disorders, member of the papain family of cysteine proteases 65 7511309CD1 430346Tinag 2. 5E-86 [Mus musculus] [Extracellular matrix (cuticle and basement membrane) ; Basement membrane (extracellular matrix)] Tubulointerstitial nephritis antigen, basement membrane protein of renal tubules that contains an ATP/GTP binding site and selectively regulates renal tubulogenesis ; human TINAG is defective in hereditary tubulointerstitial disorders Kanwar, Y. S. et al. Tubulointerstitial nephritis antigen : an extracellular matrix protein that selectively regulates tubulogenesis vs. glomerulogenesis during mammalian renal development. Proc Natl Acad Sci U S A 96, 11323-8 (1999). 66 |7511314CD1 |gl4602871 0. 0 [Homo sapiens] mitochondrial intermediate peptidase Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 66 7511314CD1 343090MIPEP 0. 0 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] [Cytoplasmic ; Mitochondrial] Mitochondrial intermediate peptidase, a putative metallopeptidase that is predicted to cleave octapeptide sequences from nuclear-encoded mitochondrial precursor proteins Chew, A. et al. Cloning, expression, and chromosomal assignment of the human mitochondrial intermediate peptidase gene (MIPEP). Genomics 40, 493-6 (1997). 66 7511314CD1 704932lMipep 0. 0 [Rattus norvegicus] [Hydrolase ; Protease (other than proteasomal)] [Cytoplasmic ; Mitochondrial] Mitochondrial intermediate peptidase, a metallopeptidase that removes amino-terminal octapeptides from nuclear encoded mitochondrial precursor proteins Isaya, G. et al. Sequence analysis of rat mitochondrial intermediate peptidase : similarity to zinc metallopeptidases and to a putative yeast homologue. Proc Natl Acad Sci U S A 89, 8317-21 (1992). 67 |7511316CD1 g339977 5. 4E-126 [Homosapiens] tryptase-I Vanderslice, P. et al. Human mast cell tryptase : Multiple cDNAs and genes reveal a multigene serine protease family Proc. Natl. Acad. Sci. U. S. A. 87, 3811-3815 (1990) 67 7511316CD1 703959TPSB1 4. 6E-127 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Tryptase beta 1, a mast cell serine protease involved in angiogenesis, cell proliferation, chemotaxis, and possibly the inflammatory response, may play a role in asthma pathogenesis Miller, J. S. et al. Cloning and characterization of a second complementary DNA for human tryptase. J Clin Invest 86, 864-70 (1990).

Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : 67 7511316CD1 338664TPS1 1. 5E-117 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Alpha tryptase, a mast cell- specific serine protease Miller, J. S. et al. Cloning and characterization of complementary DNA for human tryptase. J Clin Invest 84, 1188-95 (1989). 68 7511391CD1 |gll935132 3. 8E-13 w _ o Marchenko, G. N. et al. MMP-28, a new human matrix metalloproteinase with an unusual cysteine-switch sequence is widely expressed in tumors Gene 265, 87-93 (2001) 68 7511391CD1 690642lMMP28 3. 2E-14 [Homo sapiens] Matrix metalloproteinase 28 (epilysin), a metalloprotease of the MMP19 subfamily that may have a role in tissue repair, expressed in keratinocytes and upregulated upon injury, widely expressed in carcinomas Marchenko, G. N. et al. MMP-28, a new human matrix metalloproteinase with an unusual cysteine-switch sequence is widely expressed in tumors. Gene 265, 87-93. (2001). 69 7510144CD1 gl4279329 0. 0 [Homo sapiens] ubiquitin specific protease Valero, R. et al. Alternative splicing analysis of USP25 and characterization of USP28, a close homolgue in human chromosome 11. Specific deubiquitinating isoforms in muscle and heart 69 7510144CD1 432832JUSP25 1. 1E-152 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] Ubiquitin specific protease 25, a C-terminal ubiquitin hydrolase ; loss of heterozygosity is seen in non small cell lung carcinomas, candidate for involvement in chromosome 21 Trisomy (Down syndrome) and its associated defective spermiogenesis Valero, R. et al.

Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : USP25, a novel gene encoding a deubiquitinating enzyme, is located in the gene-poor region 21 q 11. 2. Genomics 62, 395-405 (1999). 69 7510144CD1 438259|Usp25 1. 2E-150 [Mus musculus] [Hydrolase ; Protease (other than proteasomal)] Ubiquitin specific protease 25, putative C-terminal ubiquitin hydrolase, may be involved in the development and differentiation of highly proliferative tissues ; human USP25 shows loss of heterozygosity in non small cell lung carcinomas Valero, R. et al. (supra) 70 |7510810CD1 g3820614 0. 0 [Homo sapiens] E1-like protein Yuan, W. et al. Glucose-induced autophagy of peroxisomes in Pichia pastoris requires a unique E1-like protein Mol. Biol. Cell 10, 1353-1366 (1999) 70 7510810CD1 343454GSA7 0. 0 [Homo sapiens] [Hydrolase ; Activator ; ATPase ; Protein conjugation factor] [Cytoplasmic] Ubiquitin activating enzyme E1-like protein, putative E1 ubiquitin activating enzyme family member, has predicted ATP-binding and catalytic domains, putative Pichia pastoris homolog GSA7 may act in membrane fusion events during peroxisome degradation Yuan, W. P. et al. Glucose-induced autophagy of peroxisomes in Pichia pastoris requires a unique E1-like protein. Mol Biol Cell 10, 1353-1366 (1999). 70 7510810CD1 633212lorf6. 1727 7. 8E-89 [Candida albicans] [Activator ; Protein conjugation factor] Protein with high similarity to S. cerevisiae Apg7p, which is an Apgl2p-activating enzyme involved in autophagy, cytoplasm to-vacuole protein targeting, and peroxisome degradation pathways, member of the UBA/THIF-type NAD/FAD binding fold family Huang, S. et al.

Table 2 Polypeptide SEQ Incyte GenBank ID NO : Probability Annotation ID NO : Polypeptide ID or PROTEOME Score ID NO : Specificity of cotranslational amino-terminal processing of proteins in yeast. Biochemistr 26, 8242-6 (1987). 71 7511241CD 1 gl2804391 6. 7E-260 [Homo sapiens] BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) 71 7511241CD1 340062|BAP1 5. 7E-261 [Homo sapiens] [Hydrolase ; Protease (other than proteasomal)] [Nuclear] BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase), binds the RING finger domain of BRCA1 and enhances the BRCA1-mediated inhibition of breast cancer cell growth ; mutations of the gene are found in non-small cell lung cancer cell lines Jensen, D. E. et al. BAP1 : a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene 16, 1097-112 (1998). 71 7511241CD1 476549UCH37 1. 1E-50 [Homo sapiens] [Proteasome subunit ; Hydrolase ; Protease (other than proteasomal) ; Protein conjugation factor] Member of the ubiquitin carboxyl-terminal hydrolases family, which are cysteine proteases responsible for deubiquination Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites 1 2828629CD1 281 T177 T193 N167 N175 signal cleavage : M1-G37 SPSCAN N241 Cytosolic domain : M1-D12 TMHMMER Transmembrane domain : A13-V35 Non-cytosolic domain : M36-G281 Serine proteases, subtilase family, aspartic acid proteins BL00136 : BLIMPS BLOCKS V185-II97, N226-A238 Serine proteases, subtilase family, active sites : R164-P216, D208-PROFILESCAN T262 Subtilisin serine protease family (S8) signature PR00723 : G178-BLIMPSPRINTS 1197, N224-A237 PROTEASE SERINE PRECURSOR CONVERTASE SPC7 PC7 BLAST PRODOM SIGNAL HYDROLASE TRANSMEMBRANE PC8 PD021546 : M1-S53 SERINE PROTEASES, SUBTILASE FAMILY, HISTIDINE BLAST_DOMO DM00108S35366351-610 : I166-G264 DM00108|P30430|351-610 : I166-G264 DM00108|P26016|351-610 : I166-G264 DM00108lP29122l 183-443 : D165-G264 Serine proteases, subtilase family, histidine active site : H228-A238 MOTIFS 2 7509905CD1 421 S20 S150 S279 N182 N329 signal_cleavage : M1-R42 SPSCAN S341 S421 T144 N348 T205 T331 T350 T405 Cytosol aminopeptidase family, catalytic site : V187-S421HMMERPFAM I I Cytosol aminopeptidase proteins BL00631 : D195-E208, 1264- BLIMPSBLOCKS A297, A322-V362, I374-W389 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Cytosol aminopeptidase signature PR00481 : I264-K281, M286-BLIMPSPRINTS I307, E323-T344, V345-A365, I374-W389 AMINOPEPTIDASE HYDROLASE LEUCINE ZINC LAP BLAST PRODOM LEUCYL CYTOSOL PROLINE PROLYL PROTEIN PD002804 : F130-A387 CYTOSOL AMINOPEPTIDASE DM01145 lP34629l 152-482 : BLAST_DOMO L180-Q384 DM01145p47631I7-443 : V187-G382 DM01145|Q10401|1-338 : V187-A387 DM01145|P47707| 130-457 : D185-A387 ATP/GTP-binding site motif A (P-loop) : G277-T284 MOTIFS ytosol aminopeptidase signature : N349-L356 MOTIFS 3 7502048CD1 277 S78 S90 S152 signal cleavage : M1-T23 SPSCAN S240 S249 T115 Deoxyhypusine synthase : Y42-Q272 HMMER_PFAM dhys : deoxyhypusine synthase, putative : Q30-G276 HMMER_TIGRFAM DEOXYHYPUSINE SYNTHASE HYPUSINE BIOSYNTHESIS BLAST PRODOM OXIDOREDUCTASE NAD PROTEIN ALTERNATIVE SPLICING 3DSTRUCTURE PD007730 : G50-V260 DEOXYHYPUSINE SYNTHASE EC 1. 1. 1. 249 HYPUSINEBLASTPRODOM BIOSYNTHESIS OXIDOREDUCTASE NAD ALTERNATIVE SPLICING 3DSTRUCTURE PD128627 : M1-F49 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites do DEOXYHYPUSINE ; SYNTHASE ; DMO4591IP4936611-368 : BLASE-DOM M1-E261 DM04591IP3879111-386 : A16-K251 DM04591 P49365 1-352 : E6-E261 4 7510031CD1 870 S47 S173 S253 N90 N251 signal-cleavage : M1-T22 SPSCAN S448 S504 S519 N407 N430 S532 S541 S605 N561 N682 S632 S685 S690 N820 S761 S789 S822 T 184 T217 T233 T648 T689 T746 T769 T800 Y589 Signal Peptide : M1-A20, M1-D24, M1-R25HMMER i Ubiquitin carboxyl-terminal hydrolases family : C266-N297 HMMER_PFAM Ubiquitin carboxyl-terminal hydrolases family 2 proteins BL00972 : BLIMPS_BLOCKS G267-L284, Y353-L362, I411-C425, K828-G852 UBIQUITIN CARBOXYLTERMINAL HYDROLASE 12 EC BLAST PRODOM 3. 1. 2. 15 THIOLESTERASE UBIQUITIN SPECIFIC PROCESSING PROTEASE DEUBIQUITINATING ENZYME CONJUGATION THIOL MULTIGENE FAMILY PD178331 : R554-R737 PROTEASE UBIQUITIN HYDROLASE UBIQUITIN SPECIFIC BLAST PRODOM CARBOXYLTERMINAL THIOLESTERASE PROCESSING DEUBIQUITINATING ENZYME PROTEIN PD011543 : F435- E553 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites PROTEASE UBIQUITIN HYDROLASE ENZYME UBIQUITIN BLAST PRODOM SPECIFIC CARBOXYLTERMINAL DEUBIQUITINATING THIOLESTERASE PROCESSING CONJUGATION PD000590 : K260-T434 PROTEASE UBIQUITIN HYDROLASE UBIQUITIN SPECIFIC BLAST PRODOM CARBOXYLTERMINAL THIOLESTERASE PROCESSING DEUBIQUITINATING ENZYME UBIQUITOUS PD009843 : L53- G86, P85-F259 UBIQUITIN CARBOXYL-TERMINAL HYDROLASES FAMILY BLAST DOMO 2 DM00659lP51784l41-331 : L271-N561 DM08763|P51784|332-608 : N562-G839 DM00659lP35123l 139-432 : L271-R554 DM00659|P40818|782-1103 : L271-E454, L738-H845 Ubiquitin carboxyl-terminal hydrolases family 2 signature 1 : G267-MOTIFS Q282 5 7510116CD1 648 S45 S185 S286 N81 N207 signal cleavage : M1-A28 SPSCAN S305 S366 S407 N517 N577 S510 S525 S535 S562 S564 T26 T54 T63 T121 T231 T384 T389 T594 Y146 Signal Peptide : MI-H23, M1-Q24, M1-T27, M1-A28 HMMER von Willebrand factor (vWF) type A domain : P272-E456HMMERSMART von Willebrand factor type A domain : N274-V457 HMMER_PFAM Inosine-uridine preferring nucleosid hydrolase family signature BLIMPS BLOCKS BL01247 : I298-L312, N353-S397, A531-N542 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites INHIBITOR HEAVY CHAIN CH PD01101 : BLIMPSPRODOM Q65-K98, N256-D308, G348-N367, R439-V493, W548-L557 HEAVY CHAIN PRECURSOR INTERALPHATRYPSIN BLAST PRODOM INHIBITOR ITI SERINE PROTEASE REPEAT SIGNAL PD004379 : Q24-K273 HEAVY CHAIN PRECURSOR INTERALPHATRYPSIN BLAST PRODOM INHIBITOR ITI SERINE PROTEASE REPEAT SIGNAL PD004369 : A430-Y627 INTER-ALPHA-TRYPSIN INHIBITOR COMPLEX BLAST DOMO COMPONENT II DM03009|JX0368|372-855 : L372-P637 DM03690lJX0368l96-278 : K96-I279 DM03009lS30350l378-841 : L372-E610 DM03690 S30350 102-284 : K96-I279 Cell attachment sequence : R646-D648 MOTIFS ATP/GTP-binding site motif A P-loo : A 107-S 114 (MOTIFS 6 7500548CD1 719 S45 S142 S197 N76 N121 signal_cleavage : M1-S45 SPSCAN S241 S318 S322 N140 N153 S348 S454 S483 N195 N336 S492 S517 S532 N459 N476 S554 S615 S647 N638 S686 T14 T53 T339 T361 T404 T461 T498 T543 T714 Y371 Y612 Y625 PA domain : S165-G265 HMMER ? FAM Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Cytosolic domain : M1-W20 TMHMMER Transmembrane domain : L21-I43 Non-cytosolic domain : K44-A719 PROTEIN AMINOPEPTIDASE P PD01795 : BLIMPS PRODOM V372-S380, D387-V399 RECEPTOR ANTIGEN CARBOXYPEPTIDASE TRANSFERRIN BLAST_PRODOM PROSTATE SPECIFIC MEMBRANE TRANSMEMBRANE GLYCOPROTEIN SIGNALANCHOR PROTEIN PD011438 : G490-S656, K657-S716 MEMBRANE ANTIGEN CARBOXYPEPTIDASE PROSTATE BLAST PRODOM SPECIFIC C35C5. 2 PROTEIN HOMOLOG NAAG PEPTIDASE GLUTAMATE II PD008362 : D63-G168 PROTEIN AMINOPEPTIDASE ANTIGEN RECEPTOR BLAST PRODOM TRANSMEMBRANE MEMBRANE CARBOXYPEPTIDASE TRANSFERRIN HYDROLASE PROSTATE SPECIFIC PD001808 : N76-D114, G332-K479 MEMBRANE ANTIGEN CARBOXYPEPTIDASE PROSTATE BLAST PRODOM SPECIFIC PROTEIN HOMOLOG NAAG PEPTIDASE GLUTAMATE II HYDROLASE PD008557 : N262-F337 TRANSFERRIN RECEPTOR BLAST DOMO DM02366|Q04609|279-712 : Y279-I660 DM02366lA48592l317-713 : A284-K500, Y549-I660 DM02366 S29548 322-719 : A284-K500, Y549-I660 do PROSTATE ; ANTIGEN ; MEMBRANE DM06452|Q04609l DOMO 227 : M1-A278 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites 7 7504807CD1 394 S33 5151 S208 signal cleavage : M1-C18 SPSCAN S282 S288 T60 T125 T165 T221 T359 T374 Signal Peptide : M1-C18, M1-T21, M3-C18 HMMER Carboxypeptidase activation peptide : Q26-N103 HMMER_PFAM Zinc carboxypeptidase : Y123-E377 HMMER_PFAM Zinc carboxypeptidases, zinc-binding region 1 proteins BL00132 : BLIMPS BLOCKS Y123-F163, P170-W183, Y200-R240, S244-D258, P270-H296, K298-K319, S330-G347 Zinc carboxypeptidases, zinc-binding regions signatures : E285-I340 PROFILESCAN Carboxypeptidase A metalloprotease (M14) family signature BLIMPS PRINTS PR00765 : I149-L161, P170-V184, G250-D258, I303-Y316 CARBOXYPEPTIDASE PRECURSOR SIGNAL HYDROLASE BLAST PRODOM ZINC ZYMOGEN PROTEIN D B GP180 CARBOXYPEPTIDASE PD001916 : Y123-Y316, Y333-E376 CARBOXYPEPTIDASE PRECURSOR HYDROLASE ZINC BLAST PRODOM ZYMOGEN SIGNAL B A 3D STRUCTURE A1 PD005637 : Y17- E105 ZINC CARBOXYPEPTIDASES, ZINC-BINDING REGION 1 BLASE-DOM DM00683lPl9222l111-416 : E113-K322, T321-P393 DM00683P48052111-416 : E113-Y350, T321-P393 DM00683|A56171| 111-416 : E113-Y350, T321-P393 DM006831PI50851112-418 : F118-K319, T321-P393 Zinc carboxypeptidases, zinc-binding region 1 signature : P170-MOTIFS T192 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Zinc carboxypeptidases, zinc-binding region 2 signature : H306-MOTIFS Y316 8 7504988CD1 215 |S118 S135 S174 l signal_cleavage : M1-A15 SPSCAN Signal Peptide : M1-A16 M1-F18 HMMER Trypsin-like serine protease : K23-I207 HMMER SMART Trypsin : I24-I207 HMMER_PFAM Type I fibronectin domain proteins BL01253 : L81-S117, S117-BLIMPSJBLOCKS G155, K161-S174, G176-T210 Serine proteases, trypsin family, active sites : I147-Q190 PROFILESCAN Chymotrypsin serine protease family (S 1) signature PR00722 : T71-BLIMPSPRINTS A85, K161-V173 PROTEASE SERINE PRECURSOR SIGNAL HYDROLASE BLAST PRODOM ZYMOGEN GLYCOPROTEIN FAMILY MULTIGENE FACTOR PD000046 : 179-1207, Y37-Y143, I24-N52 TRYPSIN BLAST DOMO DM00018P0747824-242 : 124-1211 s DM00018|P35030l81-299 : 124-1211 DMOO018IS37538136-254 : 124-1211 DM00018|P07477l24-242 : 124-1211 Serine proteases, trypsin family, serine active site : D162-V173 MOTIFS 9 7505051CD1 417 S72 S152 S162 N70 N172 signal cleavage : M1-A24 SPSCAN S253 S305 S389 T280 Y221 Signal Peptide : M1-G19, M1-A22, M1-A24HMMER Cytosolic domain : M1-W4 TMHMMER Transmembrane domain : L5-L27 Non-cytosolic domain : R28-V417 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites PROTEIN CARBOXYPEPTIDASE LYSOSOMAL PROX BLAST PRODOM SIMILAR HUMAN CHROMOSOME III F23B2. 12 F23B2. 11 PD149833 : G270-K406 THYMUS SPECIFIC SERINE PEPTIDASE PD173171 : M1-G50 BLASTPRODOM CARBOXYPEPTIDASE LYSOSOMAL PROX PROTEIN BLAST PRODOM SIMILAR HUMAN F23B2. 11 THYMUS SPECIFIC SERINE PD 150357 : V126-F218 PROTEIN CARBOXYPEPTIDASE LYSOSOMAL PROX BLAST PRODOM SIMILAR HUMAN CHROMOSOME III K12H4. 7 F23B2. 12 PD003976 : P51-G103 do LYSOSOMAL ; PRO-X ; CARBOXYPEPTIDASE ; BLAST_DOMO DM03192|P42785|3-487 : L12-V212, A194-K406 DM03192|P34528|84-584 : Q64-L229, F182-L405 DM03192|P34676| 1-498 : G60-S305, W276-K406 DM03192 P34610 31-480 : W61-V212, Y332-L405 10 7505079CD1 736 S54 S91 S118 N255 N266 signal cleavage : M1-G19 SPSCAN S177 S345 S379 N427 N539 S383 S424 S507 S509 S558 S608 T79 T188 T214 T215 T267 T268 T307 T388 T410 T707 Y37 Signal Peptide : M1-G16, M1-G18, M1-G19, M1-G22 HMMER Homologues of snake disintegrins : E454-P538HMMERSMART Disintegrin : E454-K537 HIVIMER PFAM Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Cytosolic domain : K685-R736 TMHMMER Transmembrane domain : 1662-1684 Non-cytosolic domain : M1-W661 Neutral zinc metallopeptidases, zinc-binding region proteins BLIMPS BLOCKS BL00142 : T368-G378 Disintegrins signature : G378-P532 PROFILESCAN KUZBANIAN NEUROGENESIS ADAM10 DISINTEGRIN BLAST PRODOM METALLOPROTEASE PRECURSOR MYELIN ASSOCIATED METALLOPROTEINASE MADM INTEGRIN HYDROLASE PD007620 : P536-K709 ADAM10 DISINTEGRIN METALLOPROTEASE PRECURSOR BLAST PRODOM MYELIN ASSOCIATED METALLOPROTEINASE MADM INTEGRIN HYDROLASE METALLOPROTEASE TRANSMEMBRANE PD023867 : I144-S257 PRECURSOR SIGNAL PROTEASE METALLOPROTEASE BLAST PRODOM KUZBANIAN TNF ALPHA CONVERTING ENZYME TACE ADAM10 PD008594 : F258-N400, S327-E433, R426-V453 KUZBANIAN ADAM10 DISINTEGRIN METALLOPROTEASE BLAST_PRODOM PRECURSOR MYELIN ASSOCIATED METALLOPROTEINASE MADM INTEGRIN HYDROLASE METALLOPROTEASE PD012997 : L25-Y143 DISINTEGRINSBLASTDOMO DM00425lS52477l252-33 1 : G444-C524 DM00425JC22451-72 : P446-C518 DM00425P174971-72 : P446-K647 DM00425 S47656 382-460 : I447-D517, C555-S597 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Neutral zinc metallopeptidases, zinc-binding region signature : T368 MOTIFS F377 11 7505159CD1 313 S29 S52 S56 S138 signal cleavage : M1-A18 SPSCAN S163 S174 S298 T172 T206 T225 T266 Y214 Signal Peptide : M1-V16, M1-A18, M1-T20, M1-V22 HMMER Eukaryotic aspartyl protease : I19-A312 HMMER_PFAM Eukaryotic and viral aspartyl proteases proteins BL00141 : F87-BLIMPS BLOCKS S102, D177-A188, R208-G217, I287-V310 Pepsin (A1) aspartic protease family signature PR00792 : 180-V100, BLIMPS PRINTS S203-T216, W286-D301 PROTEASE ASPARTYL HYDROLASE PRECURSOR SIGNAL BLAST PRODOM ZYMOGEN GLYCOPROTEIN ASPARTIC PROTEINASE MULTIGENE PD000182 : L66-S 189, F236-A312 EUKARYOTIC AND VIRAL ASPARTYL PROTEASES BLAST_DOMO DM00126lP00794l18-379 : I19-L193, G234-A312, R198-A249 DM00126lPl6476l16-381 : I19-E190, G234-A312, R198-T225 DMOO126IP28713116-385 : I19-A192, G234-A312, G181-T225 DM00126 P00793 1-365 : A18-A192, D237-L309, F176-A226 Eukaryotic and viral aspartyl proteases active site : L89-V100MOTIFS 12 7510086CD1 464 S49 S91 S161 N338 N448 motif in proteasome subunits, Int-6, Nip-1 : T363-I446HMMERSMART S234 S286 S292 S314 S340 S399 S408 T18 T103 T182 T305 T464 Y457 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites PCI domain : H364-L443 HMMERPFAM F59B2. 5 19S PROTEOSOME SUBUNIT SIMILAR PROTEIN BLAST PRODOM CHROMOSOME III PD009963 : E148-I361 PROTEASOME SUBUNIT P44. 5 26S SIMILAR F59B2. 5 19S BLAST PRODOM PROTEOSOME PD014069 : M1-E106 PROTEIN SUBUNIT PROTEASOME 26S REGULATORY BLAST PRODOM CHROMOSOME S3 FACTOR NUCLEAR INITIATION PD006956 : I361-L443 13 7510131CD1 596 S376 S502 S513 N167 N175 signal_cleavage : M1-G37 SPSCAN S541 T177 T193 N241 N511 T388 T427 T440 T576 T587 Proprotein convertase P-domain : V482-G596 HMMER_PFAM Subtilase family : F145-W470HMMERPFAM Cytosolic domain : M1-D12 TMHMMER Transmembrane domain : A13-V35 Non-cytosolic domain : M36-G596 Serine proteases, subtilase family, aspartic acid proteins BL00136 : BLIMPS_BLOCKS V185-I197, N226-A238, G404-G414 Serine proteases, subtilase family, active sites : R164-P216, D208-PROFILESCAN D262, S376-V436 Subtilisin serine protease family (S8) signature PR00723 : G178-BLIMPS PRINTS 1197, N224-A237, T403-M419 PROTEASE SERINE PRECURSOR CONVERTASE SPC7 PC7 BLAST_PRODOM SIGNAL HYDROLASE TRANSMEMBRANE PC8 PD021546 : M1-S53 Table 3 z SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites PROTEASE PRECURSOR SERINE HYDROLASE SIGNAL BLAST PRODOM GLYCOPROTEIN ZYMOGEN CONVERTASE ENDOPROTEASE PROHORMONE PD000717 : A476-V595 PROTEASE SERINE PRECURSOR SIGNAL HYDROLASE BLAST PRODOM ZYMOGEN PROTEIN GLYCOPROTEIN PROTEINASE CONVERTASE PD000223 V186-D355, I351-I499 SERINE PROTEASES, SUBTILASE FAMILY, HISTIDINE BLAST DOMO DMOO108IS353661351-610 : I166-D430 DM00108lP30430l351-610 : I166-D430 DM00108lP26016l351-610 : I166-D430 DM00108|P29122| 183-443 : D 165-D430 ATP/GTP-binding site motif A (P-loop) : G289-T296 MOTIFS Serine proteases, subtilase family, histidine active site : H228-A238 MOTIFS Serine proteases, subtilase family, serine active site : G404-G414 MOTIFS 14 7510137CD1 424 S 117 S369 S421 N127 N353 ATPases associated with a variety of cellular proteins : P198-D337 HMMER SMART T186 T272 T279 T311 T349 ATPase family associated with various cellular proteins : G201-HMMERJPFAM D380 26Sp45 : 26S proteasome subunit P45 family : Y44-Q400 HMMERTIGRFAM AAA-protein family proteins BL00674 : Y164-P184, P199-A220, BLIMPS BLOCKS G232-R274, E291-D337 l SUBUNIT PROTEASE 26S REGULATORY PROTEASOME BLAST PRODOM ATP BINDING PROTEIN NUCLEAR HOMOLOG 6B PD001147 : L37-P144 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites PROTEIN ATPBINDING PROTEASE SUBUNIT HOMOLOG BLAST PRODOM REPEAT CELL DIVISION ATP DEPENDENT NUCLEAR PD000092 : T213-C386 26S PROTEASE REGULATORY SUBUNIT 6B PROTEASOME BLAST PRODOM ATP BINDING NUCLEAR PROTEIN TAT BINDING PD022005 : M1-R43 AAA-PROTEIN FAMILY BLAST DOMO DM00024lP43686l159-321 : K159-L322 DMOO024IP547751159-321 : K159-L322 DM00024P46507jl56-318 : K159-L322 DM00024P54778 154-316 : K159-L322 AAA-protein family signature : V305-R323 MOTIFS ATP/GTP-binding site motif A (P-loop) : G206-T213 MOTIFS 15 7510690CD1 90 S45 S68 S74 signal_cleavage : M1-A18 SPSCAN Signal Peptide : M1-A16, M1-A18, M1-E20, M1-G23 HMMER Kringle domain proteins BL00021 : C49-W66 BLIMPS BLOCKS Serine proteases, trypsin family, histidine proteins BL00134 : C49-BLIMPS_BLOCKS C65 Serine proteases, trypsin family, active sites : W41-R90, P33-G83 PROFILESCAN Chymotrypsin serine protease family (S 1) signature PR00722 : G50-BLIMPS_PRINTS C65 TRYPSIN BLASE-DOM DMOO0181PO8311121-241 : 121-S68 DM000181P20718121-242 : 121-S68 DM00018Q0660520-244 : E20-S68 M00018|P80219|1-221 : I21-S68 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Serine proteases, trypsin family, histidine active site : L60-C65 MOTIFS 16 7510695CD1 500 S99 S226 S282 N357 Calpain-like thiol protease family. : A7-S329HMMERSMART S431 S457 T42 T52 T110 T123 T207 T332 Calpain family cysteine protease : L13-T322 HMMER_PFAM Calpain cysteine protease (C2) family signature PR00704 : M1-A21, BLIMPS PRINTS W43-V65, Q67-Q83, Y105-C130, L135-V158, G160-L187, Q297- G318, S351-W368 PROTEASE CALPAIN HYDROLASE SUBUNIT NEUTRAL BLAST PRODOM THIOL LARGE CALCIUM ACTIVATED PROTEINASE CANP PD001545 : L13-V317 CALPAIN CATALYTIC DOMAIN DMO13051POO78913-507 : L13-BLAST_DOMO K426 DM01305lP20807l19-581 : L13-K188, H238-E376 DM01305P0738411-517 : L13-E376 DM01305lA48764l1-507 : L13-E376 Eukaryotic thiol (cysteine) proteases cysteine active site : Q67-A78 MOTIFS 17 7504781CD1 83 S45 S55 S74 signal cleavage : M1-A20 SPSCAN Signal Peptide : M1-A16, M1-V18, M1-A20, M1-D22, M1-G23 HMMER CALNEXIN PRECURSOR CALCIUM BINDING BLAST-PRODOM ENDOPLASMIC RETICULUM TRANSMEMBRANE SIGNAL REPEAT CHAPERONE PP90 PD014729 : Q43-E83 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites 18 7504798CD1 554 S66 S345 S385 N98 N172 signal cleavage : M1-A21 SPSCAN T165 T190 T205 N271 N315 T224 T293 T520 N503 N518 Y554 Signal Peptide : M1-A19, M1-A21, M1-A26, M1-S30 HMMER Gamma-glutamyltranspeptidase : R58-E550 PIMMER PFAM yg) uttrans : gamma-glutamyltranspeptidase : G37-R546 HMMERTIGRFAM Cytosolic domain : M1-G6 TMHMMER Transmembrane domain : A7-L29 Non-cytosolic domain : S30-Y554 Gamma-glutamyltranspeptidase proteins BL00462 : A44-M86, 1106- BLIMPS-BLOCKS H142, F170-T224, T356-E395, P431-I443 Gamma-glutamyltranspeptidase signature : P413-A466 PROFILESCAN TRANSFERASE GAMMAGLUTAMYLTRANSPEPTIDASE BLAST PRODOM ACYLTRANSFERASE ZYMOGEN GLUTATHIONE BIOSYNTHESIS PRECURSOR GLYCOPROTEIN TRANSMEMBRANE GGT PD002339 : I60-G102, T101-P307, G220-E550 GAMMAGLUTAMYLTRANSPEPTIDASE 5 PRECURSOR EC BLAST PRODOM 2. 3. 2. 2 GAMMA GLUTAMYLTRANSFERASE GGTREL TRANSFERASE ACYLTRANSFERASE ZYMOGEN GLYCOPROTEIN TRANSMEMBRANE GLUTATHIONE BIOSYNTHESIS SIGNALANCHOR PD127342 : I23-Q64 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites GAMMA-GLUTAMYLTRANSPEPTIDASE DM01065P3626949-BLASTDOMO 585 : D49-G102, T101-Y554 DM01065P1944045-568 : A48-T101, G102-Y554 DM01065JC457044-568 : D49-G102, G102-G553 DM01065 A3507445-367 : A48-T101, G102-R308 Cell attachment sequence : R336-D338 MOTIFS Gamma-glutamyltranspeptidase signature : T356-G380 MOTIFS 19 7504800CD1 552 S66 S120 S377 N98 N204 signal_cleavage : M1-A21 SPSCAN S417 T101 T197 N303 N347 T222 T237 T256 N501 N516 T325 T518 Y552 Signal Peptide : M1-A19, M1-A21, M1-A26, M1-S30 HMMER < Gamma-glutamyltranspeptidase : R58-E548HMMERPFAM l y-glut-trans : gamma-glutamyltranspeptidase : G37-R544 HMMERTIGRFAM Cytosolic domain : M1-G6 TMHMMER Transmembrane domain : A7-L29 Non-cytosolic domain : S30-Y552 Gamma-glutamyltranspeptidase proteins BL00462 : A44-M86, I138-BLIMPS_BLOCKS H174, F202-T256, T388-E427 TRANSFERASE GAMMAGLUTAMYLTRANSPEPTIDASE BLAST PRODOM ACYLTRANSFERASE ZYMOGEN GLUTATHIONE BIOSYNTHESIS PRECURSOR GLYCOPROTEIN TRANSMEMBRANE GGT PD002339 : I60-I248, G155-P486, K450-E548 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites GAMMAGLUTAMYLTRANSPEPTIDASE 5 PRECURSOR EC BLAST PRODOM 2. 3. 2. 2 GAMMA GLUTAMYLTRANSFERASE GGTREL TRANSFERASE ACYLTRANSFERASE ZYMOGEN GLYCOPROTEIN TRANSMEMBRANE GLUTATHIONE BIOSYNTHESIS SIGNALANCHOR PD127342 : I23-Q64 GAMMA-GLUTAMYLTRANSPEPTIDASE DM01065 |P36269|49 BLAST_DOMO 585 : D49-G458, E433-Y552 DM01065P1944045-568 : A48-A446, K450-Y552 DM01065JC457044-568 : D49-A446, K450-G551 DM01065|A35074|45-367 : A48-R340 Cell attachment sequence : R368-D370 MOTIFS Gamma-lutamyltranspeptidase signature : T388-G412 MOTIFS 20 7504902CD1 689 S23 S25 S121 N63 N548 signal cleavage : M1-A24 SPSCAN S367 S433 S483 S485 S496 S519 S614 S653 S685 T65 T159 T402 T471 T487 T518 Y64 Y388 Signal Peptide : M1-S23, M1-A24, M1-R27 HMMER 20G-Fe (II) oxygenase superfamily : R598-P689HMMERPFAM PROCOLLAGENLYSINE 2-OXOGLUTARATE 5-BLAST PRODOM DIOXYGENASE PRECURSOR LYSYL HYDROXYLASE OXIDOREDUCTASE DIOXYGENASE SIGNAL IRON PD011980 L13-D285 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites PROCOLLAGENLYSINE 2-OXOGLUTARATE 5-BLAST PRODOM DIOXYGENASE PRECURSOR LYSYL HYDROXYLASE OXIDOREDUCTASE DIOXYGENASE SIGNAL IRON PD009947 : P296-K541 PROCOLLAGENLYSINE 2-OXOGLUTARATE 5-BLAST PRODOM DIOXYGENASE PRECURSOR LYSYL HYDROXYLASE OXIDOREDUCTASE DIOXYGENASE SIGNAL IRON PD011578 : E542-H595, A597-P689 LYSYL HYDROXYLASE CHAIN DM079201P24802l1-729 : L12-BLAST_DOMO G593, W568-P689 DM07920lQ02809l1-726 : P15-E596, E579-P689 l Cell attachment sequence : R468-D470 MOTIFS 21 17510792CD1 176 S58 T41 Y76 N52 Calpain cysteine protease (C2) family signature PR00704 : Q27-A50 BLIMPS PRINTS DIGESTIVE TRACTSPECIFIC CALPAIN EC 3. 4. 22. 17 BLAST PRODOM HYDROLASE PD 164983 : M 1-T41 22 7510557CD1 1189 S61 S86 S94 S106 N139 N332 Insulinase (Peptidase family M16) : E273-G405HMMERPFAM S 131 S 160 S289 N566 N932 S311 S700 S707 N1036 N1076 S714 S895 S998 N1145 S1068 S1069 S1140 S1146 T6 T13 T140 T141 T206 T207 T223 T335 T418 T561 T577 T736 T934 T1003 T1033 Y113 Y1128 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Insulinase family, zinc-binding region proteins BL00143 : V285-BLIMPSBLOCKS S311, N332-V346, H527-G539 Insulinase family, zinc-binding region signature : Q271-N332 PROFILESCAN CONVERTASE HYDROLASE NARDILYSIN NARGININE BLAST PRODOM DIBASIC NRD PRECURSOR METALLOPROTEASE ZINC SIGNAL PD012981 : M1-T141 HYDROLASE METALLOPROTEASE ZINC CONVERTASE BLAST PRODOM INSULIN-DEGRADING PROTEASE ENZYME PD002224 : S400-L645, L800-F915 HYDROLASE METALLOPROTEASE ZINC CONVERTASE BLAST PRODOM INSULIN-DEGRADING PROTEASE PROTEIN ENZYME PD003953 : V925-V 1125 R 1120-R 1173 HYDROLASE METALLOPROTEASE ZINC CONVERTASE BLAST PRODOM INSULIN-DEGRADING ENZYME INSULINASE PROTEASE PD004687 : I648-L800 INSULINASE FAMILY, ZINC-BINDING REGION BLAST_DOMO DM01533|I59311|170-648 : G161-L215, E269-N706, D142-E170 INSULINASE FAMILY, ZINC-BINDING REGION BLASE-DOM DM01533 P47245 170-648 : G161-L215, E269-N706 INSULINASE FAMILY, ZINC-BINDING REGION BLASE-DOM DM015331I593111170-648 : E152-K205 INSULINASE FAMILY, ZINC-BINDING REGION BLAST DOMO DM01533 P47245 170-648 : E152-K205 INSULINASE DM01973lP47245 l650-1065 : S707-H 1123 BLAST_DOMO INSULINASE DM01973 I59311650-1065 : S707-H 1123 BLAST_DOMO Insulinase family, zinc-binding region signature : G288-S311 MOTIFS Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites I 23 7510649CD1 274 S82 S120 T31 T37 Kringle domain proteins BL00021 : C148-F165BLIMPSBLOCKS T42 Serine proteases, trypsin family, histidine proteins BL00134 : C148-BLIMPSBLOCKS C164 Serine proteases, trypsin family, active sites : I140-H187 PROFILESCAN Chymotrypsin serine protease family (S1) signature PR00722 : BLIMPS PRINTS G149-C164 | TRYPSIN DM000181P059811163-403 : 1123-A183, V205-Q223 BLAST DOMO TRYPSIN DM00018 A57014l45-284 I 123-S 167, L210-Q223 BLASE DOM TRYPSIN DM00018|P26262|391-624 : I123-Rl96, L210-Q223 BLASE-DOM | |TRYPSIN DM000181P03952l392-624 : V124-P169, L210-Q223 BLASE-DOM Serine proteases, trypsin family, histidine active site : L159-C164 MOTIFS Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites I j 24 7510264CD1 1649 S2 S60 S90 S198 N237 N459 Ubiquitin carboxyl-terminal hydrolases family : K31-L64 HMMERPFAM S380 S417 S421 N633 N971 S428 S429 S446 N1024 N1230 S534 S547 S574 S625 S630 S655 S665 S676 S696 S701 S702 S704 S761 S767 S819 S825 S876 S893 S967 S1010 S1066 S1089 S1096 S1108 S1123 S1128 S1129 S1153 S1163 S1215 S1251 S1282 S1327 S1337 S1381 S1390 S1501 S 1551 T66 T98 T106 T140 T159 T240 T396 T407 T416 T450 T467 T525 T540 T922 T946 T1072 T1082 T1260 T1277 T1350 T1465 T1488 T1536 T1621 Y1083 Y1119 Y1372 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites EG : EG0002. 3 PROTEIN PD185691 : Q85-G209, F231-Q375, BLAST_PRODOM Q615-P842, G604-S685, P960-D996, F1087-S1154, P847-A959, H1266-Y1288 Cell attachment sequence : R1012-D1014 MOTIFS 25 17506464CD1 148 S94 T84 T106 N104 Signal cleavage : M1-A16 SPSCAN T128 Signal Peptide : M1-A16 HMMER Signal Peptide : M1-L18 HMMER Signal Peptide : M1-K20 HMMER PROTEASE PRECURSOR SIGNAL CYSTEINE PROTEINASE BLAST PRODOM HYDROLASE THIOL ZYMOGEN GLYCOPROTEIN CATHEPSIN PD000247 : W31-V97 EUKARYOTIC THIOL (CYSTEINE) PROTEASES CYSTEINE BLAST_DOMO DM00081 IP25774l 18-330 : L18-E131 EUKARYOTIC THIOL (CYSTEINE) PROTEASES CYSTEINE BLAST DOMO DM00081 Q02765 16-329 : P22-E 131 EUKARYOTIC THIOL (CYSTEINE) PROTEASES CYSTEINE BLAST DOMO DM00081 P43235 16-328 : L18-R133 EUKARYOTIC THIOL (CYSTEINE) PROTEASES CYSTEINE BLAST DOMO DM00081 P06797 19-332 : D21-R133 26 7510101CD1 269 S26 5129 5165 N85 Signal cleavage : M1-A18 SPSCAN S258 T14 T104 T170 T172 T255 Signal Peptide : M1-A18HMMER" Signal Peptide : M1-A21HMMER I I I Signal Peptide : M1-S22 HMMER I I l Trypsin : 135-1252HMMERPFAM l l l I _ Trypsin-like serine protease : E34-I252HMMERSMART Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Kringle domain proteins BL00021 : C63-W80, V141-G162, F211-BLIMPS BLOCKS 1252 Serine proteases, trypsin family, histidine proteins BL00134 : C63-BLIMPSBLOCKS C79, A209-G232, P239-I252 Type I fibronectin domain proteins BL01253 : C63-A76, R130-BLIMPSJBLOCKS M166, K208-C221, C221-T255 Serine proteases, trypsin family, active sites : S56-T99 PROFILESCAN Serine proteases, trypsin family, active sites : L150-V237 PROFILESCAN Chymotrypsin serine protease family (S1) signature PR00722 : G64-BLIMPS PRINTS C79, T118-V132, K208-L220 PROTEASE SERINE PRECURSOR SIGNAL HYDROLASE BLAST PRODOM ZYMOGEN GLYCOPROTEIN FAMILY MULTIGENE FACTOR PD000046 : I35-V132, I199-I252, S82-G236 TRYPSIN DM000181P08311121-241 : I35-M256 BLAST DOMO TRYPSIN DM000181P28293121-241 : 135-M256 BLAST-DOMO TRYPSIN DM00018 P80219 1-221 : 135-M256 BLAST-DOMO TRYPSIN DM000181P20718121-242 : 135-M256 BLAST DOMO ATP/GTP-binding site motif A (P-loop) : G227-S234 MOTIFS Serine proteases, trypsin family, histidine active site : L74-C79 MOTIFS Serine proteases, trypsin family, serine active site : A209-L220 MOTIFS 27 7510845CD1 230 S2 S31 T154 N135 N167 Proteasome A-type and B-type : A16-K149 HMMER PFAM Proteasome A-type subunits proteins BL00388 : K33-I74, Q88-BLIMPSBLOCKS D109, L116-Q146 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites PROTEASOME HYDROLASE PROTEASE SUBUNIT BLAST PRODOM MULTICATALYTIC COMPLEX ENDOPEPTIDASE MACROPAIN COMPONENT PROTEIN PD000280 : E32-K164 PROTEASOME SUBUNIT MULTICATALYTIC BLAST PRODOM ENDOPEPTIDASE COMPLEX HYDROLASE PROTEASE COMPONENT C9 MACROPAIN PD095446 : L159-H209 PROTEASOME A-TYPE SUBUNITS DM00341lP25789l3-225 : BLASE-DOM R3-V28 A16-R195 PROTEASOME A-TYPE SUBUNITS DM00341lS38530l3-225 : BLAST DOMO R3-V28 A16-R195 PROTEASOME A-TYPE SUBUNITS DM00341|P18053|3-228 : BLASE-DOM R3-V28 A16-V193 PROTEASOME A-TYPE SUBUNITS DM00341lP52427l3-224 : BLAST DOMO R3-V28 E17-A183 28 7510846CD1 112 S68 T75 Signal cleavage : M1-G60 SPSCAN PROTEASOME COMPONENT C5 MACROPAIN SUBUNIT BLAST PRODOM GAMMA CHAIN MULTICATALYTIC ENDOPEPTIDASE COMPLEX PD034623 : S4-G38 PROTEASOME B-TYPE SUBUNIT BL00854 : A42-G87 BLIMPS_BLOCKS PROTEASOME B-TYPE SUBUNITS DM00618P206189-235 : BLASE-DOM S9-M102 PROTEASOME B-TYPE SUBUNITS DM006181P40304l1-229 : BLASE-DOM L15-K101 PROTEASOME B-TYPE SUBUNITS DM00618|P34286|22-251 : BLAST DOMO R29-L 100 PROTEASOME B-TYPE SUBUNITS DM00618lP23724l8-235 : BLAST_DOMO P25-K101 Table 3 S SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Proteasome B-type subunits signature : L41-D88MOTIFS 29 7510921CD1 | 166 S50 S93 S143 Signal_cleavage : M1-G18 SPSCAN Signal Peptide : M1-G18 HMMER Signal Peptide : M1-G20 HMMER Signal Peptide : M1-A23 HMMER Signal Peptide : M1-P26HMMER l Trypsin : I34-G166 HMMER_PFAM Trypsin-like serine protease : R33-G166 HMMER SMART Cytosolic domain : M1-M1 TMHMMER Transmembrane domain : A2-I24 Non-cytosolic domain : H25-G166 Serine proteases, trypsin family, histidine proteins BL00134 : C60-BLIMPS_BLOCKS C76 l Serine proteases, trypsin family, active sites : Q52-Q99 PROFILESCAN Chymotrypsin serine protease family (S1) signature PR00722 : G61-BLIMPS_PRINTS C76, T116-A130 PROTEASE SERINE PRECURSOR SIGNAL HYDROLASE BLAST PRODOM ZYMOGEN GLYCOPROTEIN FAMILY MULTIGENE FACTOR PD000046 : I34-T135, D90-G166 CHYMOTRYPSINOGEN PRECURSOR HYDROLASE SERINE BLAST PRODOM PROTEASE DIGESTION PANCREAS ZYMOGEN SIGNAL B PD021175 : M1-R33 TRYPSIN DM00018|P04813|33-259 : R33-Y164 BLAST_DOMO TRYPSIN DM00018 P47796 33-259 : R33-N165 BLAST DOMO TRYPSIN DM00018 P80646 16-241 : I34-N165 BLAST_DOMO TRYPSIN DM00018lP40313l33-260 : R33-K161 BLAST DOMO ATP/GTP-binding site motif A (P-loop) : A155-T162 MOTIFS Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Serine proteases, trypsin family, histidine active site : V71-C76 MOTIFS 30 7505097CD1 387 S53 S85 S189 N344 Signal cleavage : M1-A17 SPSCAN S195 S214 S231 T34 T68 T96 T141 T325 T333 Y285 Signal Peptide : M1-A17 HMMER Signal Peptide : M1-P19 HMMER Signal Peptide : M1-Y22 HMMER Signal Peptide : M1-F23 HMMER Calreticulin family : V21-I332 HMMER_PFAM Calreticulin family proteins BL00803 : S35-K48, D63-F81, L91-BLIMPSBLOCKS F113, Y128-G138, D166-L196, I225-E255, D258-D302, A337- A353 Calreticulin signaturePR00626 : E100-D118, S126-K142, K215-BLIMPSPRINTS P228, 1242-P264, I280-Y299, V313-T333 PRECURSOR CALCIUM-BINDING SIGNAL REPEAT BLAST PRODOM CALRETICULIN ENDOPLASMIC RETICULUM CALNEXIN TRANSMEMBRANE CHAPERONE PD001866 : F46-N310, V21- I305, K185-I332 CALRETICULIN FAMILY DM01012 P52193 1-178 : E18-L196 BLAST DOMO CALRETICULIN FAMILY DM01012 JH0795 1-204 : L3-I208 BLAST DOMO CALRETICULIN FAMILY DM01012|P29413|3-208 : S4-K209 BLAST DOMO CALRETICULIN FAMILY DM01012 P27798 1-203 : L9-K209 BLAST DOMO Calreticulin family signature 1 : K98-F113 MOTIFS Calreticulin family signature 2 : I130-G138 MOTIFS Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Calreticulin family repeated motif signature : I208-D220, 1225- MOTIFS D237, I242-D254 31 7506527CD1 192 S23 S25 S121 N63 Signal cleavage : M1-A24 SPSCAN S165 S173 T65 Y64 Signal Peptide : M1-S23 HMIER Signal Peptide : M1-A24 HMMER Signal Peptide : M1-R27 HMMER PROCOLLAGENLYSINE 20XOGLUTARATE BLAST PRODOM 5DIOXYGENASE PRECURSOR LYSYL HYDROXYLASE OXIDOREDUCTASE DIOXYGENASE SIGNAL IRON PD011980 : L13-P155 LYSYL HYDROXYLASE CHAIN DM07920|P24802|1-729 : L12-BLASTDOMO P155 LYSYL HYDROXYLASE CHAIN DM07920Q028091-726 : P15-BLASTDOMO P155 32 7504894CD1 163 S79 S86 T60 Y15 Signal cleavage : M1-A45 SPSCAN ThiF family : Q31-L163HMMERPFAM UBIQUITIN-ACTIVATING ENZYME BL00536 : E13-M54, G57-BLIMPS_BLOCKS R100 PROTEIN ENZYME UBIQUITIN-ACTIVATING UBIQUITIN BLAST PRODOM E1 CONJUGATION LIGASE REPEAT BIOSYNTHESIS MULTIGENE PD000731 : Q31-G156 UBIQUITIN-ACTIVATING ENZYME DM004121P41226|4-255 : BLAST DOMO L4-GI56 UBIQUITIN-ACTIVATING ENZYME DM00412P2231444-293 : BLAST DOMO L10-G156 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites UBIQUITIN-ACTIVATING ENZYME DM00412P225158-256 : BLASE-DOM L4-G156 UBIQUITIN-ACTIVATING ENZYME DM00412P2097337-288 : BLAST DOMO L10-A157 33 7510529CD1 197 S130 S151 S161 Signal_cleavage : M1-K61 SPSCAN S 188 T59 T67 T118 Ubiquitin carboxyl-terminal hydrolase : R5-P197 HMMER_PFAM Ubiquitin carboxyl-terminal hydrolase : P8-M37, E40-P57, V84-BLIMPS_BLOCKS K108, H169-F198 Ubiquitin C-terminal hydrolase (C12) family signature PR00707 : BLIMPS PRINTS P8-L25, V45-P57, Q89-N106, E164-H175 CARBOXYLTERMINAL UBIQUITIN HYDROLASE BLAST PRODOM CONJUGATION THIOL PROTEASE THIOLESTERASE PROTEIN FAMILY ISOZYME PD006115 : W6-L183 UBIQUITIN CARBOXYL-TERMINAL HYDROLASE FAMILY BLAST DOMO 1 PUTATIVE DM02064 P15374 1-229 : M1-L183 UBIQUITIN CARBOXYL-TERMINAL HYDROLASE FAMILY BLAST DOMO 1 PUTATIVE DM02064|P09936| 1-221 : P8-L 183 UBIQUITIN CARBOXYL-TERMINAL HYDROLASE FAMILY BLAST DOMO 1 PUTATIVE DM020641P3512211-224 : W6-G194 UBIQUITIN CARBOXYL-TERMINAL HYDROLASE FAMILY BLAST DOMO 1 PUTATIVE DM02064lP35127l1-233 : E2-L183 Ubiquitin carboxyl-terminal hydrolase family 1 cysteine active-site : MOTIFS Q89-A105 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites 34 7510581CD1 632 S76 S157 S196 N232 N470 Ubiquitin carboxyl-terminal hydrolases family : C255-D288 HMMER PFAM S462 S495 S500 l T15 T82 T201 T390 T513 T566 T594 T595 T606 T610 T629 Y440 Ubiquitin carboxyl-terminal hydrolases family 2 proteins BL00972 : BLIMPS BLOCKS G256-Q273, Y284-L293 PROTEASE UBIQUITIN-SPECIFIC UBIQUITIN BLAST PRODOM CARBOXYLTERMINAL HYDROLASE THIOLESTERASE PROCESSING DEUBIQUITINATING ENZYME UBIQUITOUS PD 152487 : R407-K590 PROTEASE UBIQUITIN HYDROLASE UBIQUITIN-SPECIFIC BLAST PRODOM CARBOXYLTERMINAL THIOLESTERASE PROCESSING DEUBIQUITINATING ENZYME UBIQUITOUS PD009843 : D52 A269, M1-E79 PROTEASE UBIQUITIN HYDROLASE ENZYME UBIQUITIN-BLAST PRODOM SPECIFIC CARBOXYLTERMINAL DEUBIQUITINATING THIOLESTERASE PROCESSING CONJUGATION PD000590 : P252-Q271 Q271-Y312 PROTEASE UBIQUITIN HYDROLASE UBIQUITIN-SPECIFIC BLAST PRODOM CARBOXYLTERMINAL THIOLESTERASE PROCESSING DEUBIQUITINATING ENZYME PROTEIN PD011543 : D317- E406 UBIQUITIN ; HYDROLASE ; TERMINAL ; CARBOXYL ; BLAST DOMO DM08763 P35123 433-705 : Y421-K631 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites I UBIQUITIN CARBOXYL-TERMINAL HYDROLASES FAMILY BLAST DOMO 2 DM00659P35123139-432 : Q271-A324, Y312-L420, L260-E291 UBIQUITIN CARBOXYL-TERMINAL HYDROLASES FAMILY BLASE-DOM 2 DM00659lP51784l41-331 : Q271-D323 D317-R407, L260-Y284 UBIQUITIN ; HYDROLASE ; TERMINAL ; CARBOXYL ; BLAST DOMO DM08763|P51784l332-608 : L420-V632 Ubiquitin carboxyl-terminal hydrolases family 2 signature 1 : G256-MOTIFS Q271 1 35 7510582CD1 840 S76 S157 S196 N232 N396 Ubiquitin carboxyl-terminal hydrolases family : C255-D286, R738-HMMERPFAM S317 S595 S706 N603 N727 R799 S736 T15 T82 N734 N778 T201 T523 T623 T651 T652 T663 T667 T686 T717 Y573 Y805 Ubiquitin carboxyl-terminal hydrolases family 2 proteins BL00972 : BLIMPS BLOCKS G256-L273, Y342-L351, I400-C414, V741-N765, N768-T789 PROTEASE UBIQUITIN HYDROLASE UBIQUITIN-SPECIFIC BLAST PRODOM CARBOXYLTERMINAL THIOLESTERASE PROCESSING DEUBIQUITINATING ENZYME UBIQUITOUS PD009843 : D52- A269, M1-E79 PROTEASE UBIQUITIN HYDROLASE ENZYME UBIQUITIN-BLAST PRODOM SPECIFIC CARBOXYLTERMINAL DEUBIQUITINATING THIOLESTERASE PROCESSING CONJUGATION PD000590 : P252-T423 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites PROTEASE UBIQUITIN-SPECIFIC UBIQUITIN BLAST PRODOM CARBOXYLTERMINAL HYDROLASE THIOLESTERASE PROCESSING DEUBIQUITINATING ENZYME UBIQUITOUS PD 152487 : R540-K648, L588-K647 PROTEASE UBIQUITIN HYDROLASE UBIQUITIN-SPECIFIC BLAST PRODOM CARBOXYLTERMINAL THIOLESTERASE PROCESSING DEUBIQUITINATING ENZYME PROTEIN PD011543 : F424- E539 UBIQUITIN CARBOXYL-TERMINAL HYDROLASES FAMILY BLAST DOMO 2 DM00659 P35123 139-432 : L260-L553 l l UBIQUITIN CARBOXYL-TERMINAL HYDROLASES FAMILY BLASE-DOM 2 DM00659|P51784|41-331 : L260-R540 UBIQUITIN CARBOXYL-TERMINAL HYDROLASES FAMILY BLAST DOMO 2 DM006591P408181782-1103 : L260-L434 Q631-L795 UBIQUITIN ; HYDROLASE ; TERMINAL ; CARBOXYL ; BLAST DOMO DM08763|P35123l433-705 : L588-G752, Y554-E622 Ubiquitin carboxyl-terminal hydrolases family 2 signature 1 : G256-MOTIFS Q271 Ubiquitin carboxyl-terminal hydrolases family 2 signature 2 : Y742-MOTIFS Y759 36 7510583CD1 788 S76 S157 S196 N232 N475 Ubiquitin carboxyl-terminal hydrolases family : C255-D286, R686-HMMERPFAM S317 S467 S500 N675 N682 R747 S505 S654 S684 N726 T15 T82 T201 T395 T518 T571 T599 T600 T611 T615 T634 T665 Y445 Y753 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Ubiquitin carboxyl-terminal hydrolases family 2 proteins BL00972 : BLIMPS BLOCKS G256-L273, V689-N713, N716-T737 PROTEASE UBIQUITIN-SPECIFIC UBIQUITIN BLAST-PRODOM CARBOXYLTERMINAL HYDROLASE THIOLESTERASE PROCESSING DEUBIQUITINATING ENZYME UBIQUITOUS PD152487 : R412-K595 PROTEASE UBIQUITIN HYDROLASE UBIQUITIN-SPECIFIC BLAST PRODOM CARBOXYLTERMINAL THIOLESTERASE PROCESSING DEUBIQUITINATING ENZYME UBIQUITOUS PD009843 : D52 A269, M1-E79 PROTEASE UBIQUITIN HYDROLASE UBIQUITIN-SPECIFIC BLAST PRODOM ENZYME DEUBIQUITINATING CARBOXYLTERMINAL THIOLESTERASE PROCESSING CONJUGATION PD017412 : Y584-V680 PROTEASE UBIQUITIN-SPECIFIC UBIQUITIN BLAST PRODOM CARBOXYLTERMINAL HYDROLASE THIOLESTERASE PROCESSING DEUBIQUITINATING ENZYME UBIQUITOUS PD013016 : S728-N788 UBIQUITIN ; HYDROLASE ; TERMINAL ; CARBOXYL ; BLAST DOMO DM087631P351231433-705 : Y426-G700 UBIQUITIN CARBOXYL-TERMINAL HYDROLASES FAMILY BLAST DOMO 2 DM00659|P35123|139-432 : L260-V332, R326-L425 UBIQUITIN ; HYDROLASE ; TERMINAL ; CARBOXYL ; BLAST DOMO DM08763lP51784l332-608 : L425-G700 UBIQUITIN CARBOXYL-TERMINAL HYDROLASES FAMILY BLAST DOMO 2 DM006591P408181782-1103 : L260-D342 Q579-L743 Ubiquitin carboxyl-terminal hydrolases family 2 signature 1 : G256-MOTIFS Q271 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Ubiquitin carboxyl-terminal hydrolases family 2 signature 2 : Y690-MOTIFS Y707 37 7510596CD1 181 S76 S119 S125 Signal_cleavage : M1-H59 SPSCAN T121 T163 Ubiquitin carboxyl-terminal hydrolase : Q2-V170 HMMER_PFAM Ubiquitin carboxyl-terminal hydrolase family 1 cysteine activ. BLIMPS BLOCKS BL00140 : P5-L34, E37-P54, V79-Q 103, S 119-F162 Ubiquitin C-terminal hydrolase (C12) family signature PR00707 : BLIMPS PRINTS P5-V22, V42-P54, Q84-N101 CARBOXYLTERMINAL UBIQUITIN HYDROLASE BLAST PRODOM CONJUGATION THIOL PROTEASE THIOLESTERASE PROTEIN FAMILY ISOZYME PD006115 : P5-A155, H143-E169 UBIQUITIN CARBOXYL-TERMINAL HYDROLASE FAMILY BLAST DOMO 1 PUTATIVE DM02064lP09936l1-221 : Ml-V158, H143-A180 UBIQUITIN CARBOXYL-TERMINAL HYDROLASE FAMILY BLAST DOMO 1 PUTATIVE DM02064|P15374|1-229 : P5-Q151, H143-A180 UBIQUITIN CARBOXYL-TERMINAL HYDROLASE FAMILY BLASE-DOM 1 PUTATIVE DM02064|P35122|1-224 : P5-F162 UBIQUITIN CARBOXYL-TERMINAL HYDROLASE FAMILY BLASE-DOM 1 PUTATIVEDM02064|Q10171|1-221 : K4-A147 Ubiquitin carboxyl-terminal hydrolase family 1 cysteine active-site : MOTIFS Q84-A100 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites 38 7510643CD1 851 S47 5173 S253 N90 N251 Signal cleavage : M1-T22 SPSCAN S448 S504 S519 N407 N430 S536 S563 S616 N613 N751 S621 S692 S720 S753 T184 T217 T233 T579 T620 T677 T700 T731 Signal Peptide : M1-A20 HMMER Signal Peptide : M1-R25 HMMER Signal Peptide : M1-D24 HMMER Ubiquitin carboxyl-terminal hydrolases family : C266-N297, E756-HMMERPFAM R817 Ubiquitin carboxyl-terminal hydrolases family 2 proteins BL00972 : BLIMPS BLOCKS G267-L284, Y353-L362, I411-C425, K759-N783, S786-S807 UBIQUITIN CARBOXYLTERMINAL HYDROLASE 12 EC BLAST PRODOM 3. 1. 2. 15 THIOLESTERASE UBIQUITIN-SPECIFIC PROCESSING PROTEASE DEUBIQUITINATING ENZYME CONJUGATION THIOL MULTIGENE FAMILY PD178331 : R529-R668 PROTEASE UBIQUITIN HYDROLASE ENZYME UBIQUITIN-BLAST PRODOM SPECIFIC CARBOXYLTERMINAL DEUBIQUITINATING THIOLESTERASE PROCESSING CONJUGATION PD000590 : K260-T434 PROTEASE UBIQUITIN HYDROLASE UBIQUITIN-SPECIFIC BLAST PRODOM CARBOXYLTERMINAL THIOLESTERASE PROCESSING DEUBIQUITINATING ENZYME UBIQUITOUS PD009843 : L53- G86, P85-F259 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites PROTEASE UBIQUITIN HYDROLASE UBIQUITIN-SPECIFIC BLAST PRODOM CARBOXYLTERMINAL THIOLESTERASE PROCESSING DEUBIQUITINATING ENZYME PROTEIN PD011543 : F435- D540 UBIQUITIN CARBOXYL-TERMINAL HYDROLASES FAMILY BLASE-DOM 2 DM00659lP51784l41-331 : L271-T532 UBIQUITIN ; HYDROLASE ; TERMINAL ; CARBOXYL ; BLASE-DOM DM087631P517841332-608 : R529-G770 UBIQUITIN CARBOXYL-TERMINAL HYDROLASES FAMILY BLASE-DOM 2 DM00659 P35123 139-432 : L271-D540 UBIQUITIN CARBOXYL-TERMINAL HYDROLASES FAMILY BLAST DOMO 2 DM006591P408181782-1103 : L271-E454, L669-L813 Ubiquitin carboxyl-terminal hydrolases family 2 signature 1 : G267-MOTIFS Q282 Ubiquitin carboxyl-terminal hydrolases family 2 signature 2 : Y760-MOTIFS Y777 39 7506671CD1 251 S67 5131 5134 N147 N166 Signal cleavage : M1-A35 SPSCAN S235 S249 T138 T215 Signal Peptide : M24-T38 HMMER Signal Peptide : M24-G40 HMMER Signal Peptide : M24-V42 HMMER CUB domain : G40-Y160HMMERPFAM Domain first found in C I r, C Is, AEGF, and bone morphogenetic HMMER_SMART protein : R39-V163 C1R/C1SREPEATDM00162P0073611-141 : C36-V163 BLAST_DOMO C1R/C1S REPEAT DM001621P1515615-135 : Q51-Y160 lBLAST DOMO C1R/C1SREPEATDM00162P4874013-138 : Q51-V163 BLAST DOMO Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites I I CIR/CIS REPEAT DM00162 P09871 1-129 : M24-Y160 BLAST DOMO 40 7510518CD1 105 S60 Y45 Caspase recruitment domain : A2-V91 HMMERPFAM Caspase recruitment domain : M1-Y89 HMMER SMART PRECURSOR HYDROLASE THIOL PROTEASE ZYMOGEN BLAST PRODOM APOPTOSIS PROTEIN CONVERTING ENZYME CELL PD006849 : M1-Q81 41 7510585CD1 690 S125 S136 S202 N29 N228 Signal_cleavage : M1-A18 SPSCAN S204 S259 S322 N271 N405 S366 S411 S575 N409 N559 S651 T172 T325 N589 T421 T429 T537 T606 Signal Peptide : M5-S20 HMMER Signal Peptide : M1-A18 HAMMER Signal Peptide : M1-S20 HMMER Signal Peptide : M1-S23 HMMER Sushi domain (SCR repeat) : C89-C142, C24-P73 HMMER-PFAM Trypsin : G402-L677 HMMER PFAM von Willebrand factor type A domain : N192-M390HMMERPFAM Domain abundant in complement control proteins : C89-C142, C24-HMMERSMART T76 Trypsin-like serine protease : T399-L677 HMMER_SMART von Willebrand factor (vWF) type A doma : H190-K395 HMMER_SMART Serine proteases, trypsin family, histidine proteins BL00134 : C430-BLIMPS_BLOCKS C446, S611-L634, R664-L677 Apple domain proteins BL00495 : G432-K464, C603-W637 BLIMPS BLOCKS Serine proteases, trypsin family, active sites : I422-E470 PROFILESCAN Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Von Willebrand factor type A domain signature PR00453 : L191-BLIMPSPRINTS F208, S230-M244, A308-K316 Chymotrypsin serine protease family (S1) signature PR00722 : R431 BLIMPS PRINTS C446, F495-V509, E610-F622 COMPLEMENT PRECURSOR SIGNAL C2 C3/C5 BLAST PRODOM CONVERTASE PATHWAY PLASMA GLYCOPROTEIN HYDROLASE PD008321 : H541-F671 COMPLEMENT B FACTOR PRECURSOR MHC C3/C5 BLAST PRODOM CONVERTASE GLYCOPROTEIN PATHWAY PLASMA PD007194 : L4-P86 COMPLEMENT C2 PRECURSOR C3/C5 CONVERTASE BLAST PRODOM PATHWAY PLASMA GLYCOPROTEIN HYDROLASE SERINE PD036606 : R143-L191 PROTEASE SERINE PRECURSOR SIGNAL HYDROLASE BLAST PRODOM ZYMOGEN GLYCOPROTEIN FAMILY MULTIGENE FACTOR PD000046 : C430-G638 TRYPSIN DM00018 P06681466-741 : G404-H680 BLAST_DOMO COMPLEMENT C2 DM04854 P06681211-464 : D149-V403 BLAST DOMO TRYPSIN DM00018|P2 11 80|473-749 : G404-H680 BLAST_DOMO COMPLEMENT C2 DM048541P211801217-471 : D149-V403 BLAST DOMO Serine proteases, trypsin family, histidine active site : L441-C446 MOTIFS Serine proteases, trypsin family, serine active site : S611-F622 MOTIFS Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites 42 7510590CD1 387 S26 S127 S196 N99 N318 ATPase family associated with various cellular proteins : G166-HMMERPFAM S237 S238 S244 N379 R353 S314 S336 S376 S381 T175 T253 T276 T360 Y129 ATPases associated with a variety of cellular proteins : Q163-N302 HMMERSMART ------------------------------------------------- 26Sp45 : 26S proteasome subunit P45 family : I28-M372 HMMER_TIGRFAM AAA-protein family proteins BL00674 : Y129-P149, P164-A185, BLIMPS_BLOCKS G197-R239, E256-N302, G334-R353 AAA-protein family signature : M254-I328 PROFILESCAN PROTEIN ATPBINDING PROTEASE SUBUNIT HOMOLOG BLAST PRODOM REPEAT CELL DIVISION ATP-DEPENDENT NUCLEAR PD000092 : T178-V357 SUBUNIT 26S PROTEASE REGULATORY PROTEASOME BLAST PRODOM ATPBINDING PROTEIN HOMOLOG NUCLEAR TATBINDING PD006796 : E354-K387 PROTEIN ATPBINDING SUBUNIT CELL DIVISION BLAST PRODOM HOMOLOG PROTEASE 26S REGULATORY PROTEASOME PD002755 : L108-K165 AAA-PROTEIN FAMILY DMOO024IP472101143-305 : V 124-L287 BLAST DOMO AAA-PROTEIN FAMILY DM00024lQ019391142-304 : V124-L287 BLAST-DOMO AAA-PROTEIN FAMILY DMOO024IP418361139-302 : V 124-L287 BLAST DOMO I I I Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites AAA-PROTEIN FAMILY DM0002445176139-302 : V 124-L287 BLAST_DOMO Leucine zipper pattern : L45-L66 MOTIFS AAA-protein family signature : I270-R288 MOTIFS ATP/GTP-bindin site motif A-loop) : G171-T178 MOTIFS 43 7510617CD1 429 S129 S241 S291 N91 N167 Signal cleavage : M1-A17 SPSCAN S348 S359 S368 N263 N272 S395 T104 T227 T277 T300 T397 Y172 Signal Peptide : M1-G16 HMMER Signal Peptide : M1-A17 HMMER Peptidase C13 family : A6-E327 HMMER PFAM Hemoglobinase (C13) cysteine protease signature PR00776 : W30-BLINWS-PRINTS Q54, I55-G84, D102-L117, K131-S150, Y179-M195 HYDROLASE PRECURSOR SIGNAL THIOL PROTEASE BLAST PRODOM PROCESSING ENZYME VACUOLAR PROTEINASE VPE PD003740 : V18-N272 7 HYDROLASE PRECURSOR SIGNAL THIOL PROTEASE BLAST PRODOM PROCESSING ENZYME VACUOLAR PROTEINASE VPE PD003740 : G98-K289 LEGUMAIN PRECURSOR ENDOPEPTIDASE HYDROLASE BLAST PRODOM SIGNAL ASPARAGINYL THIOL PROTEASE BEAN VICILIN PD132125 : A290-C429 VACUOLAR PROCESSING ENZYME CHAIN BLAST_DOMO DM01183|S51117|6-316 : G14-N272 VACUOLAR PROCESSING ENZYME CHAIN BLAST DOMO i-DMO1183IP4904316-316 : G14-N272 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites VACUOLAR PROCESSING ENZYME CHAIN BLAST DOMO DM0 11 831P4904413-3 11 : P1 9-N272 VACUOLAR PROCESSING ENZYME CHAIN BLAST DOMO DM01183 P49047 5-301 : P19-N272 Cell attachment sequence : R118-D120 MOTIFS 44 7510618CD1 138 T104 N91 Signal-cleavage : Ml-A17 SPSCAN Signal Peptide : M1-G16 HMMER Signal Peptide : M1-A17 HMMER Hemoglobinase (C 13) cysteine protease signature PR00776 : W30-BLIMPSPRINTS Q54, 155-G84 HYDROLASE PRECURSOR SIGNAL THIOL PROTEASE BLAST PRODOM PROCESSING ENZYME VACUOLAR PROTEINASE VPE PD003740 : V 18-V 110 VACUOLAR PROCESSING ENZYME CHAIN BLAST_DOMO DM01183 S51117 6-316 : G14-V110 VACUOLAR PROCESSING ENZYME CHAIN BLAST DOMO DM01183 ! P49043 ! 6-316 : G14-V110 VACUOLAR PROCESSING ENZYME CHAIN BLAST-DOMO DM01183 1831P4904715-301 : P19-D107 VACUOLAR PROCESSING ENZYME CHAIN BLAST DOMO DM0 11 831P49044l3-3 11 : P 19-L 124 45 7510620CD1 387 S33 5119 5176 Signal_cleavage : Ml-C18 SPSCAN S250 S256 S307 T60 T133 T189 T289 T352 T367 I I I Signal Peptide : M3-C18 HMMER , ç | Signal Peptide : M1-C18 HMMER Signal Peptide : M1-T21 HMMER Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Carboxypeptidase activation peptide : Q26-M101 HMMER PFAM Zinc carboxypeptidase : Y88-E370HMMERPFAM Zinc carboxypeptidases, zinc-binding region 1 proteins BL00132 : BLIMPS BLOCKS M91-F131, P138-W151, Y168-R208, S212-D226, P238-H264, K266-K287, S323-G340 l Zinc carboxypeptidases, zinc-binding regions signatures : E253-PROFILESCAN L308 CARBOXYPEPTIDASE A PR00765 : I117-L129, P138-V152, BLIMPS PRINTS G218-D226, I271-Y284 CARBOXYPEPTIDASE PRECURSOR SIGNAL HYDROLASE BLAST PRODOM ZINC ZYMOGEN PROTEIN D B GP180CARBOXYPEPTIDASE PD001916 : Q96-E369 I CARBOXYPEPTIDASE PRECURSOR HYDROLASE ZINC BLAST PRODOM ZYMOGEN SIGNAL B A 3D STRUCTURE Al PD005637 : Y17- D102 ZINC CARBOXYPEPTIDASES, ZINC-BINDING REGION 1 BLASE-DOM DM00683 P48052 111-416 : Q96-P386 ZINC CARBOXYPEPTIDASES, ZINC-BINDING REGION 1 BLAST DOMO DM00683 A56171 111-416 : Q96-P386 ZINC CARBOXYPEPTIDASES, ZINC-BINDING REGION 1 BLAST DOMO DM00683 P19222 111-416 : Q96-P386 ZINC CARBOXYPEPTIDASES, ZINC-BINDING REGION 1 BLAST DOMO DM00683lPl5085l112-418 : Q96-P386 Zinc carboxypeptidases, zinc-binding region 1 signature : P138-MOTIFS T160 Zinc c Zinc carboxypeptidases, zinc-binding region 2 signature : H274-MOTIFS Y284 46 |7510628CD1 139 |T2 ! |MOTIFS Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites 47 7510650CD1 376 S4 S162 S164 N111 N176 Signal_cleavage : M1-C32 SPSCAN S171 S225 S291 N235 N326 S371 T117 T178 T329 T362 Signal Peptide : M1-C32, R14-C32, G13-C32, P9-A33, MI-A33 HMMER Renal dipeptidase : M54-S376 HMMER PFAM Renal dipeptidase proteins BL00869 : K173-R209, Y210-E244, BLIMPS BLOCKS K245-V266, E272-N294, V295-N322, P323-T362 Secretin receptor signature PR00490 : W 15-L27, P296-V310 BLIMPS PRINTS DIPEPTIDASE MICROSOMAL PRECURSOR MDP BLAST PRODOM HYDROLASE MICROSOME SIGNAL GPI-ANCHOR GLYCOPROTEIN ZINC PD005626 : S68-L155 W132-K360 RENAL DIPEPTIDASE DM02775 P164441-356 : Q73-G354 BLASE-DOM RENAL DIPEPTIDASE DM02775 P43477 1-356 : Q73-K357 BLAST DOMO _ RENAL DIPEPTIDASE DM02775lP31430l1-356 : S68-G354 BLAST DOMO RENAL DIPEPTIDASE DM02775 P31428 1-356 : S68-G354 BLAST DOMO Renal dipeptidase active site : V187-R209 MOTIFS 48 7506644CD1 90 S34 Signal cleavage : M 1-C24 SPSCAN Signal Peptide : M1-C24 HMMER Signal Peptide : M1-D30 HMMER Thioredoxin : C24-L90 HMMER ? FAM pdidom : protein disulfide-isomerase dom : D32-L90 HMMERJTIGRFAM Thioredoxin family proteins BL00194 : L45-K57 BLIMPS ? LOCKS Thioredoxin family active site : E29-P76 PROFILESCAN l THIOREDOXIN FAMILY DM00054lP38660l160-264 : K25-T85 BLAST DOMO Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites THIOREDOXIN FAMILY DM00054P34329187-293 : N40-T85 BLASE-DOM THIOREDOXIN FAMILY DM00054 P13667 171-277 : E33-L90 BLAST DOMO THIOREDOXIN FAMILY DM000541P386571375-479 : E29-S86 BLAST DOMO Thioredoxin family active site : L45-W63 MOTIFS 49 7506692CD1 328 S148 5242 S266 N66 N235 Signal cleavage : M1-A35 SPSCAN T74 T80 T225 Signal Peptide : M7-T27 HMMER I Signal Peptide : M7-G29 HMMER Signal Peptide : M7-G32 HMMER Signal Peptide : M7-A35 HMMER Repeats in polycystic kidney disease 1 (PKD1) : G168-L241 HMMER SMART Cytosolic domain : M1-R11 ; Transmembrane domain : L12-Q34 ; TMHMMER Non-cytosolic domain : A35-V328 HEPATOCYTE GROWTH FACTOR ACTIVATOR INHIBITOR BLAST PRODOM GLYCOPROTEINPD120361 : M1-D248 Cell attachment sequence : R193-D195 MOTIFS 50 7504938CD1 50 UBIQUITIN-CONJUGATINGENZYMESDM00225P344771-BLAST_DOMO 162 : Q5-Y50 UBIQUITIN-CONJUGATING ENZYMES DM00225lP42747l3-|BLAST_DOMO 164 : Q5-Y50 51 7505625CD1 149 S7 S13 S46 S67 N44 UBIQUITIN-ACTIVATING ENZYME E1 UBIQUITIN |BLAST-PRODOM S95 T115 CONJUGATION LIGASE MULTIGENE FAMILY REPEAT A1S9 PD022015 : M1-G63 52 7506468CD1 75 S17 T5 Signal cleavage : M1-G18 SPSCAN I I l I I Signal Peptide : M1-V16 HMMER Signal Peptide : M1-G18HMMER Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites INTERALPHATRYPSIN INHIBITOR HEAVY CHAIN H2 BLAST_PRODOM PRECURSOR ITI SERINE PROTEASE REPEAT PD017450 : M1- Q53 INTER-ALPHA-TRYPSIN INHIBITOR COMPLEX BLASE-DOM COMPONENT II DM033591PI9823132-13 1 : Y32-E66 53 7510682CD1 155 S88 S138 S151 N112 N136 Signal_cleavage : M1-A16 SPSCAN T77 Signal Peptide : M1-A16 HMMER Signal Peptide : M1-E18 HMMER Signal Peptide : M1-K21 HMMER Serine proteases, trypsin family, active sites : L39-E80 PROFILESCAN Chymotrypsin serine protease family (S1) signature PR00722 : G48-BLIMPS_PRINTS C63 TRYPSIN DM00018 P49862 30-248 : L22-K64, T78-I109 BLAST_DOMO TRYPSIN DM00018 P00752 1-227 : L22-S88 BLAST DOMO TRYPSIN DM00018tP06871 J23-242 : K21-K65, T99-K 111 BLAST_DOMO TRYPSIN DM00018lP05620l1-225 : L22-C63, S88-W108, V137-BLAST_DOMO P153 Serine proteases, trypsin family, histidine active site : L58-C63 MOTIFS 54 7505420CD 1 266 S 12 S 150 S226 Signal cleavage : M1-A49 SPSCAN S248 T64 T72 T124 T194 T236 | T237 l 1 T237 ThiF family : R35-G170HMMERPFAM UBIQUITIN-ACTIVATING ENZYME BL00536 : A17-A58, K61-BLIMPS BLOCKS | P104, K117-T155 Table 3 | SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ) D Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites PROTEIN ENZYME UBIQUITINACTIVATING UBIQUITIN E1 BLAST PRODOM CONJUGATION LIGASE REPEAT BIOSYNTHESIS MULTIGENE PD000731 : S37-F166 UBIQUITIN-ACTIVATING ENZYME DM004121P41226|4-255 : BLAST DOMO Yl9-E189 UBIQUITIN-ACTIVATING ENZYME DM00412|P20973 |37-288 : BLAST DOMO A7-S248 UBIQUITIN-ACTIVATING ENZYME DM00412lP22314144-293 : BLASE-DOM G9-P192 55 7505604CD1 561 S16 S53 S90 S145 N200 N312 Transglutaminase-like superfamily : V274-T363HMMERPFAM S214 S232 S252 N421 S267 S378 S430 S445 S452 S463 T6 T34 T117 T317 T328 T542 T550 Transglutaminase family : V4-G125HMMERPFAM Transglutaminase/protease-like homologues : G271-P364 HMMER_SMART Transglutaminases proteins BL00547 : N19-L45, F137-F187, R216-BLIMPS_BLOCKS P253, V274-Y318, D332-Q366, P376-W407, I425-A462 Transglutaminases active site : W256-T314 PROFILESCAN TRANSGLUTAMINASE TRANSFERASE BLAST PRODOM ACYLTRANSFERASE PROTEINGLUTAMINE GAMMAGLUTAMYLTRANSFERASE CALCIUM-BINDING TGASE TISSUE C MEMBRANE PD002491 : K21-E454 TRANSGLUTAMINASES DM00983 Q01841 10-693 : L7-G483 BLASE DOM TRANSGLUTAMINASES DM00983 P51176 2-685 : L7-S463 BLAST DOMO Table 3 | SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites TRANSGLUTAMINASES DM009831A4430212-549 : L7-S463 BLASE DOM TRANSGLUTAMINASES DM00983 jQ08188j l-692 : V4-D556 BLASE DOM 56 7505606CD1 362 S35 S52 S87 S119 N270 N320 Transglutaminase family : L110-D229 HMMER_PFAM S 120 S 160 S272 S359 T77 T104 T223 T226 Transglutaminases protein signature BL00547 : N 125-L 151, 1243-BLIMPS-BLOCKS F293, R315-P352 TRANSGLUTAMINASE TRANSFERASE BLAST PRODOM ACYLTRANSFERASE PROTEINGLUTAMINE GAMMAGLUTAMYLTRANSFERASE CALCIUM-BINDING TGASE TISSUE C MEMBRANE PD002491 : R126-M328 PROTEINGLUTAMINE GAMMAGLUTAMYLTRANSFERASE BLAST PRODOM K TRANSGLUTAMINASE TGASE EPIDERMAL TRANSFERASE ACYLTRANSFERASE CALCIUM-BINDING MEMBRANE PD151793 : P90-N125 PROTEINGLUTAMINE GAMMAGLUTAMYLTRANSFERASE BLAST PRODOM K TRANSGLUTAMINASE TGASE EPIDERMAL TRANSFERASE ACYLTRANSFERASE CALCIUM-BINDING MEMBRANE PD018665 : F43-P65 TRANSGLUTAMINASES DM00983IP227351110-787 : L110-BLAST_DOMO M328 | TRANSGLUTAMINASES DM00983lP00488l45-726 : L110-M328 BLASTDOMO I I Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites TRANSGLUTAMINASES DM00983|P49221 l5-678 : L 110-M328 BLAST_DOMO TRANSGLUTAMINASES DM00983|Q05187|60-763 : L110-M328 BLAST_DOMO Cell attachment sequence : R315-D317 MOTIFS Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites 57 7511044CD1 2789 S93 S105 S115 N50 N134 Signal cleavage : M1-A27 SPSCAN S136 S219 S226 N217 N261 S417 S493 S511 N421 N637 S533 S695 S788 N693 N810 S923 S931 S942 N962 N1048 S951 S1279 S1307 N1115 N1201 S1358 S1404 N1226 N1271 S1543 S1545 N1391 N1399 S1564 S1748 N1463 N1600 S1825 S1865 N1831 N1913 S1918S2013 N1934 N2010 S2149S2175 N2134 N2158 S2224 S2259 N2173 N2192 S2266 S2274 N2219 N2300 S2289 S2302 N2345 N2572 S2356 S2358 N2783 S2553 T354 T413 T435 T669 T780 T922 T955 T1011 T1117 T1186 T1482 T1493 T1514 T1550 T1626 T1874 T1895 T1966 T2242 T2332 T2429 T2450 T2523 T2749 Y543 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Signal Peptide : M9-A27HMMER Signal Peptide : M1-A27HMMER Signal Peptide : M1-C30 HMMER Signal Peptide : M1-G24 HMMER Signal Peptide : M1-S22 HMMER CUB domain : C30-F137 HMMER_PFAM EGF-like domain : C1078-C1114, C1449-C1480, C142-C169, HMM1ER_PFAM C2126-C2163, C1407-C1444, C1118-P1146, C174-C202, C2167- C2193 Kelch motif : A278-A325, P1565-Q1613, E447-A498, P1728-HMMER PFAM T1773, E1784-S1845, G1671-Q1722, A388-D440 Laminin EGF-like (Domains III and V) : C1211-C1259, C1163-HMMER_PFAM C1208, C2197-C2246 Domain first found in Clr, Cls, uEGF, and bone morphogenetic HMMERSMART protein : Q33-S140 Domain found in Pleins, Semaphorins and Integrins : G2064-HMMERSMART P2121, L949-R991, E1868-R1923, S1005-P1073, S847-P899, P2004-S2062, P1820-S1860, Y561-Q613, L900-P947 Cytosolic domain : K2615-L2789 ; Transmembrane domain : L2592-TMHMMER W2614 ; Non-cytosolic domain : M1-D2591 Type III EGF-like signature PR00011 : C1224-C1242, C1462-BLIMPSPRINTS C1480 ATTRACTIN GLYCOPROTEIN PROTEIN F33C8. 1 BLAST_PRODOM CHROMOSOME X PRECURSOR LAMININ EGFLIKE DOMAIN PD139135 : D256-P312 K941-L1044 GLYCOPROTEIN DOMAIN EGFLIKE PROTEIN PRECURSOR BLAST PRODOM SIGNAL RECEPTOR INTRINSIC FACTORB 12 REPEAT PD000165 : N50-F137 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Cell attachment sequence : R537-D539 MOTIFS Aspartic acid and asparagine hydroxylation site : C1091-C1102, MOTIFS C2139-C2150 C-type lectin domain signature : C848-C872 MOTIFS EGF-like domain signature 1 : C158-C169, C191-C202, C1231-MOTIFS C1242, C1433-C1444, C1469-C1480, C2182-C2193 EGF-like domain signature 2 : C158-C169, C191-C202, Cl 100-MOTIFS C 1114, C 1433-C 1444, C 1469-C 1480, C2148-C2163, C2182- C2193 Calcium-binding EGF-like domain pattern signature : D1074-C1100 MOTIFS Laminin-type EGF-like (LE) domain signature : C1179-C1208, MOTIFS C1231-C1259, C2214-C2243, C2295-C2321 58 2579533CD1 719 S5 S67 S93 S244 N567 Calpain large subunit, domain III : G353-V528 HMMER PFAM S465 S484 S521 T266 T388 T421 T490 T516 T526 T588 T665 T708 Calpain family cysteine protease : L45-S341HMMERPFAM Calpain-like thiol protease family. : F27-P349 HMMER_SMART Eukaryotic thiol (cysteine) proteases active sites IPB000169 : Q99-BLIMPSBLOCKS L108, F139-D151, L278-W294 Calpain cysteine protease (C2) family signature PR00704 : Q30-BLIMPS PRINTS A53, W75-V97, Q99-T115, Y135-V160, L165-L188, G190-L217, E317-C338, N368-F385, C494-E522 PROTEASE CALPAIN HYDROLASE SUBUNIT NEUTRAL BLAST PRODOM THIOL LARGE CALCIUMACTIVATED PROTEINASE CANP PD001545 : L45-S341 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites PROTEASE CALPAIN HYDROLASE SUBUNIT LARGE BLAST PRODOM NEUTRAL THIOL CALCIUMACTIVATED PROTEINASE CANP PD001874 : W354-E401 C424-R524 CALPAIN SUBUNIT PROTEASE NEUTRAL BLAST PRODOM CALCIUMBINDING CALCIUMACTIVATED PROTEINASE CANP HYDROLASE LARGE PD002827 : L618-V681 CALPAIN CATALYTIC DOMAIN DM01305lPl7655l1-505 : D14-BLASTDOMO G402 C424-R524 CALPAIN CATALYTIC DOMAIN DM01305P0738411-517 : BLAST DOMO E16-G402 G418-R523 CALPAIN CATALYTIC DOMAIN DM01305P007893-507 : G18-BLAST_DOMO E400 C424-R524 CALPAIN CATALYTIC DOMAIN DM01305|A48764l1-507 : Ml-BLASTDOMO G402 G418-R524 EF-hand calcium-binding domain : D633-L645 MOTIFS Eukaryotic thiol (cysteine) proteases cysteine active site : Q99-A110 MOTIFS 59 7511097CD1 46 T22 T35 signal_cleavage : M1-G34 SPSCAN COFACTOR E PD162851 : M1-A33 BLAST PRODOM 60 7510842CD1 421 S24 S46 S69 S89 N145 N274 signal cleavage : M1-A23 SPSCAN S135 S152 S328 T392 T402 Signal Peptide : P8-A23HMMER Signal Peptide : P6-A23HMMER l Signal Peptide : A4-A23 HMMER Signal Peptide : M1-A23 HMMER Signal Peptide : M1-R25 HMMER l l Signal Peptide : M1-A28HMMER Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Serine carboxypeptidase : P39-K418 HMMER PFAM Serine carboxypeptidase (S10) IPB001563 : S46-H61, P77-P100, BLIMPS BLOCKS N113-Y136, L172-P185, Y331-L356, G380-L416 Serine carboxypeptidases, active sites : L157-L201 PROFILESCAN Serine carboxypeptidases, active sites : D373-Y421 PROFILESCAN Carboxypeptidase C serine protease (S 10) family signature BLIMPS PRINTS PR00724 : N113-Y125, L126-Y136, F160-P185, I388-P401 CARBOXYPEPTIDASE SERINE HYDROLASE PRECURSOR BLAST PRODOM GLYCOPROTEIN PROTEIN SIGNAL PUTATIVE ZYMOGEN I PD001189 : Q36-Y219 G209-N417 CARBOXYPEPTIDASE HYDROLASE PRECURSOR BLAST PRODOM GLYCOPROTEIN SIGNAL ZYMOGEN SERINE Y III YSCY PD150036 : Q296-N417 SERINE CARBOXYPEPTIDASES, SERINE DM00460 ! P10619 ! 33 BLASTDOMO 479 : D33-Y216 L201-Y421 SERINE CARBOXYPEPTIDASES, SERINE DM00460|P52715|22 BLAST DOMO 453 : I35-N210 N210-Y232 P271-K418 SERINE CARBOXYPEPTIDASES, SERINE DM00460P52717717 7 BLAST DOMO 468 : D33-I215 L201-P420 SERINE CARBOXYPEPTIDASES, SERINE DM00460|P52716|22 BLAST_DOMO 529 : D33-L218 V208-C222 C272-L416 Serine carboxypeptidases, histidine active site : I388-P405 MOTIFS Serine carboxypeptidases, serine active site : L174-G181 MOTIFS 61 7511249CD1 182 S12 S36 S65 S104 ICE-like protease (caspase) p20 domain : E43-V162HMMERPFAM S109 S113 S120 S176 T62 T67 T77 T92 T 140 T 152 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Caspase, interleukin-1 beta converting enzy : S36-P181 HMMER_SMART ICE-like protease (caspase) p20 domain IPB001309 : G45-F55, BLIMPS BLOCKS M61-I96, D107-G129, C148-L165 Interleukin-lB converting enzyme signature PR00376 : E43-H56, BLIMPS PRINTS R64-K82, K82-M100, F114-G122, C148-G166 PRECURSOR PROTEASE HYDROLASE THIOL ZYMOGEN BLAST PRODOM APOPTOSIS PROTEIN APOPTOTIC CASPASE1 CYSTEINE PD001408 : G45-Q161 APOPAIN PRECURSOR CYSTEINE PROTEASE CPP32 YAMA BLAST PRODOM PROTEIN CPP32 CASPASE3 CASP3 PD008427 : M1-M44 INTERLEUKIN-1 BETA CONVERTING ENZYME FAMILY BLAST_DOMO HISTIDINE DM01067 P42574 7-177 : S7-Q161 INTERLEUKIN-1 BETA CONVERTING ENZYME FAMILY BLAST DOMO HISTIDINE DM01067|P55210l34-204 : Y37-Q161 INTERLEUKIN-1 BETA CONVERTING ENZYME FAMILY BLAST DOMO HISTIDINE DM01067|P55211l128-311 : D34-Q161 INTERLEUKIN-1 BETA CONVERTING ENZYME FAMILY BLAST_DOMO HISTIDINE DM01067 P55212 8-184 : Y37-Q161 Caspase family histidine active site : H108-G122 MOTIFS 62 7511254CD1 218 S14 S74 S82 S124 signal_cleavage : M1-G68 SPSCAN S159 Y105 Low-density lipoprotein receptor domain : F71-R109 HMMER_PFAM Low-density lipoprotein receptor domain class A : D72-R109 HMMER SMART Scavenger receptor Cys-rich : V108-T205 HMMER_SMART Cytosolic domain : D72-V218 Transmembrane domain : F49-F71 TMHMMER Non-cytosolic domain : M1-F48 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : D Residues Sites Sites Low density lipoprotein (LDL)-receptor class A IPB002172 : C85-BLIMPS_BLOCKS E104 Speract receptor repeated domain signature : I89-R216 PROFILESCAN Speract receptor signature PR00258 : A123-K134, A138-P148 BLIMPS PRINTS TRANSMEMBRANE PROTEASE, SERINE 2 EC 3. 4. 21. BLAST PRODOM HYDROLASE PROTEASE SIGNALANCHOR PD072395 : I52- C207 LDL-receptor class A (LDLRA) domain signature : C85-C107 MOTIFS 63 7511274CD1 1121 S61 S86 S94 S106 N139 N264 Insulinase (Peptidase family M16) : E198-G337 HMMER_PFAM S131 S160 S221 N498 N864 S243 S632 S639 N968 N1008 S646 S827 S930 N1077 S1000 S1001 S 1072 S 1078 T6 T13 T140 T141 T206 T207 T267 T350 T493 T509 T668 T866 T935 T965 Y 113 Y 1060 Insulinase family (Peptidase family M16) IPB001431 : G230-S243, BLIMPS-BLOCKS N264-V278, H459-G471 Insulinase family, zinc-binding region signature : R199-N264 PROFILESCAN CONVERTASE HYDROLASE NARDILYSIN NARGININE BLAST_PRODOM DIBASIC NRD PRECURSOR METALLOPROTEASE ZINC SIGNAL PD012981 : M1-T141 HYDROLASE METALLOPROTEASE ZINC CONVERTASE BLAST_PRODOM INSULINDEGRADING PROTEASE ENZYME INSULINASE INSULIN INSULIN PD002224 : S332-L577 L732-F847 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites l l HYDROLASE METALLOPROTEASE ZINC CONVERTASE BLAST PRODOM INSULINDEGRADING PROTEASE PROTEIN ENZYME INSULINASE INSULYSIN PD003953 : V857-V1057 R1052- R1105 HYDROLASE METALLOPROTEASE ZINC CONVERTASE BLAST PRODOM INSULINDEGRADING ENZYME INSULINASE PROTEASE INSIJLYSIN INSULIN PD004687 : I580-L732 INSULINASE FAMILY, ZINC-BINDING REGION BLASTDOMO DM01533lI593111170-648 : D142-E170 G161-N638 INSULINASE FAMILY, ZINC-BINDING REGION BLAST DOMO DM015331P472451170-648 : D142-E170 G161-N638 INSULINASE DM01973|P47245|650-1065 : S639-H1055 BLASTpOMO INSULINASE DM01973 I59311650-1065 : S639-H 1055 BLASTpOMO Insulinase family, zinc-binding region signature : G220-S243 MOTIFS 64 7511303CD1 141 S13 S81 T45 T51 N56 N72 N101 signal cleavage : MI-R47 SPSCAN T58 T118 T137 Signal Peptide : M33-L48 HMMER Signal Peptide : M33-T51 HMMER Signal Peptide : M33-R53 HMMER Signal Peptide : M33-C54 HMMER I I Trypsin : Ml-1134HMMERPFAM Trypsin-like serine protease : R3-I134 HMMER SMART Serine proteases, trypsin family IPB001254 : D88-G111, P121-I134 BLIMPSBLOCKS l l I l I Serine proteases, trypsin family, active sites : I73-Al 16 PROFILESCAN l l l l I PROTEASE SERINE PRECURSOR SIGNAL HYDROLASE BLAST-PRODOM ZYMOGEN GLYCOPROTEIN FAMILY MULTIGENE FACTOR PD000046 : P49-I134 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites SERINE PROTEASE TLSP PROTEASE SERINE PROTEASE BLAST PRODOM PD166965 : M1-T45 TRYPSIN DM00018 555066 26-244 : P49-M138 BLAST_DOMO TRYPSIN DM00018 S13813 24-242 : V46-MI38 BLAST DOMO I TRYPSIN DM00018 P00763 24-242 : V46-MI38 BLAST DOMO TRYPSIN DM000 1 8lP06872l24-242 : P49-M 138 BLASTpOMO Serine proteases, trypsin family, serine active site : D88-V99 MOTIFS 65 7511309CD1 440 S210 5239 S296 N78 N161 signal cleavage : Ml-G21 SPSCAN T80 T117 T126 T 169 T 180 T205 T406 T431 Signal Peptide : M1-H17HMMER Signal Peptide : M1-A19 HMMER Signal Peptide : M1-G21 HMMER Signal Peptide : M1-A22HMMER Signal Peptide : M1-Q24 HMMER , Signal Peptide : M1-G27 HMMER Signal Peptide : M1-G25 HMMER Signal Peptide : M1-Q23 HMMER Papain family cysteine protease : L203-A401HMMERPFAM Eukaryotic thiol (cysteine) proteases active sites IPB000169 : P204-BLIMPS_BLOCKS W213, Q223-F232, P252-C262, Q267-L275, S289-G297 Somatomedin B signature PR00022 : A69-T80, S82-L93 BLIMPS PRINTS F26E4. 3 PROTEIN TUBULOINTERSTITIAL NEPHRITIS BLAST PRODOM ANTIGEN PD037748 : G45-I193 EUKARYOTIC THIOL (CYSTEINE) PROTEASES CYSTEINE BLAST DOMO DM0008 1 |A57480|83-465 : F76-Q364 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites EUKARYOTIC THIOL (CYSTEINE) PROTEASES CYSTEINE BLASE-DOM DM00081|P07688|20-329 : P139-Q364 EUKARYOTIC THIOL (CYSTEINE) PROTEASES CYSTEINE BLAST DOMO DM00081 P0078720-329 : D145-Q364 EUKARYOTIC THIOL (CYSTEINE) PROTEASES CYSTEINE BLAST DOMO DM00081 lP43233120-330 : L203-Q364 Lipocalin signature : G269-L282 MOTIFS 66 7511314CD1 688 S37 S54 S72 S244 N241 N569 Peptidase family M3 : L254-S674 HMMER_PFAM S258 S287 S302 S325 S329 S477 S570 S664 S674 T147 T154 T179 T332 T451 Y377 Y463 Y583 Neutral zinc metallopeptidases, zinc-binding region IPB000130 : BLIMPS BLOCKS N492-H502 HYDROLASE METALLOPROTEASE ZINC OLIGOPEPTIDASE BLAST PRODOM PRECURSOR MITOCHONDRIAL ENDOPEPTIDASE MITOCHONDRION TRANSIT PEPTIDE PD002945 : A73-N224 N350-Q551 V525-V669 L282-R456 MITOCHONDRIAL INTERMEDIATE PEPTIDASE BLAST PRODOM PRECURSOR HYDROLASE MIP METALLOPROTEASE ZINC TRANSIT PEPTIDE PD043824 : G11-Q103 do ZINC ; METALLOPEPTIDASE ; NEUTRAL ; BLAST DOMO OLIGOPEPTIDASE ; DM01184|Q01992|30-697 : A33-Q551 Q551- L676 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites do ZINC ; METALLOPEPTIDASE ; NEUTRAL ; BLAST DOMO OLIGOPEPTIDASE ; DM01184|P37932|40-760 : A45-Q464 Y463- F543 Q551-V665 do ZINC ; METALLOPEPTIDASE ; NEUTRAL ; BLAST DOMO OLIGOPEPTIDASE ; DM01184|P51980|43-766 : L58-P226 D260- 1452 P444-T572 do ZINC ; METALLOPEPTIDASE ; NEUTRAL ; BLAST DOMO OLIGOPEPTIDASE ; DM01184 P51980 43-766 : F543-D666 do ZINC ; METALLOPEPTIDASE ; NEUTRAL ; BLASE-DOM OLIGOPEPTIDASE ; DM01184Q1041532-751 : G64-N347 R456- T549 do ZINC ; METALLOPEPTIDASE ; NEUTRAL ; BLAST DOMO OLIGOPEPTIDASE ; DM01184lQ 10415l32-751 : S258-R456 do ZINC ; METALLOPEPTIDASE ; NEUTRAL ; BLAST_DOMO OLIGOPEPTIDASE ; DMO1184 Q 10415 32-751 : E524-K661 Leucine zipper pattern : L376-L397 MOTIFS Neutral zinc metallopeptidases, zinc-binding region signature : N492 MOTIFS M501 67 7511316CD1 237 S54 S181 S205 N195 signal_cleavage : M1-A25SPSCAN T160 T177 Signal Peptide : M8-A23 HMMER Signal Peptide : M8-A25 HMMER l Signal Peptide : M1-A23 HMMER Signal Peptide : M1-A25 HMMER Trypsin : 138-1229HMMERPFAM Trypsin-like serine protease : G37-I229 HMMER SMART Kringle domain IPB000001 : G40-L55, C66-V83, Q124-V138, BLIMPS_BLOCKS G188-I229 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Apple domain IPB000177 : E99-P137, L172-W206, G207-K235 BLIMPS BLOCKS Serine proteases, trypsin family IPB001254 : C66-C82, D180-V203, BLIMPS BLOCKS P216-I229 Serine proteases, trypsin family, active sites : H64-Q107 PROFILESCAN Serine proteases, trypsin family, active sites : V167-Q212 PROFILESCAN Chymotrypsin serine protease family (S1) signature PR00722 : G67-BLIMPS_PRINTS 82 Q124-V138 R179-V191 PROTEASE SERINE PRECURSOR SIGNAL HYDROLASE BLAST PRODOM ZYMOGEN GLYCOPROTEIN FAMILY MULTIGENE FACTOR PD000046 : 138-V138 K139-I229 TRYPSIN DM000181P 15157131-270 : I38-V 140 P137-V233 BLAST_DOMO TRYPSIN DM00018lP21845131-271 : G37-II44 P137-V233 BLAST-DOMO TRYPSIN DM00018|P15944l31-270 : 138-1144 P137-V233 BLAST DOMO TRYPSIN DM000181Q02844129-268 : I38-V 140 P137-V233 BLAST_DOMO Serine proteases, trypsin family, histidine active site : L77-C82 MOTIFS Serine proteases, trypsin family, serine active site : D180-V191 MOTIFS 68 7511391CD1 50 signal cleavage : M1-A22 SPSCAN l l l Signal Peptide : Ml-A22 HMMER l l l Signal Peptide : M1-R27HMMER Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites 69 7510144CD1 583 S47 S76 S109 N282 N310 Ubiquitin carboxyl-terminal hydrolases family : V162-Y193 HMMER_PFAM S 113 S 137 S205 N373 S228 S248 S279 S347 S368 S453 S479 S494 S503 S504 S517 S520 S550 T130 T134 T207 T260 T484 T489 T532 T534 Ubiquitin carboxyl-terminal hydrolase family 2 IPB001394 : G163-BLIMPS_BLOCKS L180 PROTEASE UBIQUITIN HYDROLASE ENZYME BLAST PRODOM UBIQUITINSPECIFIC CARBOXYLTERMINAL DEUBIQUITINATING THIOLESTERASE PROCESSING CONJUGATION PD000590 : P161-N286 70 7510810CD1 650 S20 S68 S95 S115 N318 N381 S173 S331 S355 N392 N617 S437 S509 S553 S554 S578 S597 S621 S645 T31 T120 T135 71 7511241CD1 711 S58 S63 S70 S104 N102 N290 Ubiquitin carboxyl-terminal hydrolase, : G4-I221HMMERPFAM S271 S377 S437 N472 N677 S446 S567 S579 S610 S679 S703 T64 T177 T203 T236 T248 T255 T405 T477 Table 3 SEQ Incyte Amino Potential Potential Signature Sequences, Domains and Motifs Analytical Methods ID Polypeptide Acid Phosphorylation Glycosylation and Databases NO : ID Residues Sites Sites Ubiquitin carboxyl-terminal hydrolases family 1 IPB001578 : G23-BLIMPSBLOCKS K51, M80-S105, R163-E200 Ubiquitin C-terminal hydrolase (C 12) family signature PR00707 : BLIMPS PRINTS E7-V24, C39-K51, Q85-N102, L180-P190 BRCA1 ASSOCIATED PROTEIN 1 MYELOBLAST KIAA0272 BLAST PRODOM PD143369 : I221-Q711 CARBOXYLTERMINAL UBIQUITIN HYDROLASE BLAST PRODOM CONJUGATION THIOL PROTEASE THIOLESTERASE PROTEIN FAMILY ISOZYME PD006115 : W5-E212 UBIQUITIN CARBOXYL-TERMINAL HYDROLASE FAMILY BLAST DOMO 1 PUTATIVE DM02064 Q09444 1-225 : W5-I214 UBIQUITIN CARBOXYL-TERMINAL HYDROLASE FAMILY BLAST DOMO 1 PUTATIVE DM02064 P35122 1-224 : W5-E212 UBIQUITIN CARBOXYL-TERMINAL HYDROLASE FAMILY BLAST_DOMO 1 PUTATIVE DM02064 P15374 1-229 : W5-R213 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 72/2828629CB1/1-595, 172-363, 172-368, 172-384, 172-415, 172-646, 172-663, 172-675, 172-685, 172-695, 172-702, 172-708, 172-728, 172-743, 172-745, 2939 172-749, 172-754, 172-772, 172-775, 172-777, 172-778, 172-779, 172-788, 172-811, 172-814, 172-817, 172-822, 172-835, 172-845, 172- 846, 172-847, 172-852, 172-865, 172-870, 172-873, 172-874, 172-888, 172-889, 172-892, 172-895, 172-900, 172-909, 172-912, 172-931, 172-941, 172-942, 172-943, 172-957, 172-959, 172-961, 172-973, 172-976, 172-977, 172-989, 172-1019, 174-914, 175-950, 176-896, 177- 1072, 180-941, 184-957, 185-943, 186-670, 186-780, 186-862, 186-895, 186-918, 186-938, 186-976, 186-977, 186-1001, 186-1012, 186- 1025, 187-974, 190-790, 194-952, 198-900, 273-1019, 274-1165, 287-840, 309-873, 311-877, 328-982, 354-871, 364-1202, 383-1224, 391- 1219, 404-1232, 413-1268, 431-1419, 444-1274, 453-1280, 454-1163, 495-1329, 496-1294, 520-1424, 526-1238, 545-1340, 548-1284, 552- 1072, 573-1245, 576-1377, 583-1250, 583-1346, 612-1633, 632-1509, 637-1452, 638-1530, 642-1331, 657-1366, 674-1320, 676-1100, 692-1510, 697-1530, 704-1171, 706-1532, 722-1566, 727-1526, 728-1215, 730-1203, 733-1275, 742-1565, 754-1605, 769-1430, 769-1555, 778-1478, 785-1519, 795-1341, 795-1693, 799-1313, 853-1321, 854-1521, 870-1727, 878-1497, 882-1435, 885-1617, 887-1683, 893-1165, 894-1658, 912-1733, 913-1594, 916-1346, 917-1727, 918-1640, 922-1523, 924-1523, 934-1531, 942-1673, 950-1675, 952-1692, 960-1695, 961-1733, 975-1624, 994-1528, 1038-1733, 1044-1482, 1044-1488, 1055-1748, 1057-1535, 1058-1530, 1058-1534, 1069-1152, 1075-1748, 1076-1733, 1076-1748, 1079-1601, 1080-1748, 1088-1733, 1091-1748, 1103-1748, 1104-1714, 1104- 1748, 1109-1733, 1124-1748, 1126-1748, 1128-1748, 1130-1714, 1134-1733, 1134-1743, 1142-1748, 1145-1748, 1147-1748, 1150-1748, 1167-1687, 1171-1733, 1175-1748, 1175-1954, 1200-1733, 1206-1733, 1212-1680, 1216-1707, 1230-2016, 1239-1733, 1242-1748, 1243- 1748, 1247-1748, 1256-1744, 1258-1733, 1282-1733, 1301-1748, 1308-1733, 1308-1748, 1317-1733, 1324-1733, 1325-1733, 1330-1733, 1348-1733, 1350-2027, 1353-1945, 1354-1733, 1366-1748, 1375-1993, 1376-1733, 1377-1733, 1380- 1733, 1396-1981, 1397-1822, 1398-1733, 1446-1733, 1452-1691, 1453-1733, 1462-1733, 1464-1733, 1470-1863, 1496-1733, 1499-1733, 1504-1733, 1515-1733, 1531-1748, 1548-1733, 1554-1733, 1644-2180, 1649-1733, 1670-1733, 1704-1994, 1817-2660, 1825-2316, 1835- 2662, 1855-2492, 1856-2412, 1871-2656, 1881-2543, 1884-2662, 1904-2513, 1904-2531, 1929-2510, 1947-2407, 1964-2605, 1965-2269, 1968-2618, 1990-2666, 1997-2237, 1997-2238, 1998-2252, 2005-2248, 2024-2536, 2028-2670, 2035-2661, 2040-2528, 2041-2527, 2061- 2939, 2068-2687, 2077-2318, 2081-2344, 2093-2714, 2125-2566, 2139-2853, 2176-2431, 2204-2659, 2207-2461, 2212-2763, 2218-2459, 2223-2378, 2224-2797 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 73/7509905CB1/1-128, 1-2604, 127-425, 127-573, 127-600, 127-641, 127-746, 127-846, 132-364, 132-600, 133-1021, 134-556, 134-600, 138-643, 143-425, 2604 143-852, 149-599, 149-600, 149-812, 149-862, 150-401, 150-600, 156-600, 158-600, 189-433, 189-600, 199-360, 204-1016, 284-784, 294- 600, 294-926, 294-1163, 300-1128, 307-948, 312-983, 312-989, 314-600, 318-956, 330-599, 330-600, 333-901, 335-1065, 342-925, 346- 662, 350-934, 356-944, 358-920, 359-1000, 362-1049, 367-967, 370-1139, 375-1025, 385-600, 392-595, 392-1148, 393-1083, 396-600, 399- 1003, 399-1028, 402-600, 408-956, 412-1147, 414-904, 425-724, 430-1146, 432-704, 434-913, 438-1148, 445-950, 449-683, 450-600, 450- 1048, 452-600, 458-1063, 466-1146, 472-798, 474-1033, 491-1091, 492-1145, 492-1149, 493-1113, 494-1143, 501-1145, 509-1112, 515- 1021, 525-600, 526-785, 529-600, 542-796, 556-1148, 561-1098, 565-1226, 569-873, 578-1195, 580-1255, 588-1093, 595-852, 600-1156, 602-855, 604-1253, 608-1047, 611-1174, 612-995, 615-1213, 635-1188, 644-868, 645-1238, 649-1273, 650-1231, 652-1269, 653-1269, 657-975, 668-1195, 675-1156, 684-955, 699-1143, 699-1147, 699-1148, 701-1492, 726-958, 734-1012, 735-1020, 736- 1567, 740-958, 746-1003, 747-1017, 759-1029, 767-1138, 768-1008, 768-1054, 772-1018, 787-1489, 792-1091, 794-1314, 801-999, 801- 1138, 811-1481, 819-1147, 819-1148, 835-1725, 841-1112, 843-1115, 843-1116, 866-1581, 878-1810, 881-1511, 912-1147, 949-1228, 953- 1149, 1060-1545, 1063-1147, 1063-1763, 1065-1140, 1065-1147, 1065-1148, 1065-1149, 1149-1697, 1149-1707, 1149-1735, 1149-1748, 11149-1833, 1158-1527, 1176-1811, 1176-1834, 1176-1854, 1204-1466, 1204-1697, 1204-1714, 1204-1725, 1204-1727, 1204-1729, 1204- 1733, 1204-1759, 1204-1763, 1204-1832, 1204-1833, 1204-1850, 1204-1853, 1204-1857, 1204-1878, 1205-1874, 1220-1887, 1229-1532, 1250-1896, 1260-1863, 1283-1690, 1283-1734, 1294-2023, 1324-1583, 1373-1640, 1373-1803, 1373-1899, 1373-1924, 1373-1932, 1373- 1958, 1373-1959, 1373-1971, 1373-2094, 1373-2214, 1374-2108, 1398-1772, 1408-1644, 1408-2221, 1490-2017, 1493-2279, 1543-1798, 1548-2322, 1551-2062, 1556-2235, 1557-1762, 1558-1822, 1567-2368, 1568-1723, 1568-1854, 1568-1998, 1585- 1783, 1598-1837, 1643-2177, 1656-2286, 1669-1934, 1671-1932, 1684-1934, 1741-2005, 1760-1919, 1773-2136, 1783-2177, 1789-1903, 1848-2127, 1897-2164, 1910-2165 74/7502048CB1/1-575, 20-525, 26-2563, 28-471, 28-537, 28-2584, 44-487, 53-507, 53-651, 53-694, 54-546, 54-558, 100-658, 195-732, 238-641, 249-854, 2819 253-894, 271-528, 322-813, 324-532, 333-553, 343-578, 344-457, 352-809, 353-889, 354-655, 354-902, 360-698, 365-658, 368-653, 386- 503, 430-728, 464-719, 476-731, 481-744, 482-644, 501-702, 508-786, 508-790, 508-797, 510-739, 516-769, 520-730, 523-790, 549-803, 552-1223, 564-817, 569-746, 588-874, 591-874, 594-817, 594-873, 595-843, 598-873, 600-799, 623-902, 629-806, 655-902, 663-902, 665- 880, 763-1065, 800-1016, 1130-1304, 1130-1316, 1130-1405, 1130-1453, 1130-1461, 1130-1482, 1130-1507, 1130-1565, 1130-1581, 1130- 1651, 1130-1662, 1131-1415, 1131-1422, 1131-1450, 1131-1471, 1131-1477, 1131-1494, 1131-1585, 1131-1607, 1131-1684, 1132-1541, 1132-1636, 1133-1300, 1134-1616, 1136-1441, 1140-1585, 1140-1628, 1141-1460, 1141-1581, 1162-1589, 1180-1696, 1189-1441, 1198- 1840, 1228-1497, 1232-1743, 1232-1875, 1243-1518, 1253-1895, 1288-1783, 1303-1603, 1319-1805, 1343-1581, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 1374-1685, 1388-1783, 1396-1883, 1404-1685, 1405-2112, 1409-2111, 1416-1690, 1426-1997, 1439-1899, 1456-1873, 1472-1685, 1498- 1749, 1526-2080, 1543-2128, 1549-2136, 1551-2134, 1562-2080, 1562-2090, 1568-2119, 1588-1826, 1673-1932, 1677-1932, 1722-1873, 1728-2164, 1763-1848, 1766-1888, 1815-2126, 1908-2304, 1909-2344, 2094-2338, 2242-2488, 2242-2819 75/7510031CB1/1-452, 1-562, 11-281, 16-538, 28-197, 28-340, 28-420, 28-493, 28-601, 30-293, 30-316, 31-759, 32-385, 32-395, 32-466, 32-3028, 33-155, 3028 33-168, 33-195, 33-245, 33-466, 33-631, 33-678, 34-760, 35-321, 35-685, 36-291, 36-308, 36-658, 36-664, 36-853, 39-250, 39-274, 39-300, 39-304, 39-332, 39-357, 39-500, 39-509, 39-527, 39-540, 39-564, 39-587, 39-593, 39-601, 39-610, 39-635, 39-725, 40-303, 40-557, 40-590, 41-259, 41-308, 41-672, 42-678, 42-881, 43-281, 43-322, 43-325, 43-333, 43-461, 43-504, 43-609, 43-651, 43-658, 43-934, 44-293, 45-295, 45-604, 45-612, 45-680, 45-792, 45-829, 45-881, 46-442, 46-445, 46-544, 46-648, 47-664, 49-527, 50-217, 50-280, 50-295, 50-306, 50-310, 50-313, 50-597, 50-607, 50-904, 51-552, 52-748, 53-308, 53-319, 53-552, 53-585, 54-282, 57-361, 61-478, 62-487, 62-816, 66-881, 72-881, 76-932, 89-370, 95-144, 95-249, 95-266, 95-276, 95-280, 95-302, 95-311, 95-352, 95-372, 95-458, 95-525, 96-336, 97-344, 109-838, 112- 881, 115-881, 117-881, 165-619, 169-748, 187-879, 190-881, 196-746, 225-1020, 251-800, 276-748, 276-907, 277-765, 278-716, 279-784, 284-558, 284-909, 290-526, 291-437, 313-984, 314-792, 328-1042, 343-965, 344-579, 344- 908, 346-625, 348-752, 355-759, 370-1006, 382-803, 401-966, 402-1015, 416-919, 419-991, 421-666, 422-884, 430-672, 430-874, 441- 652, 441-744, 441-827, 441-956, 441-977, 441-983, 441-987, 455-998, 460-686, 461-996, 493-699, 493-962, 496-938, 500-768, 507-1184, 521-1143, 528-944, 537-1207, 545-1141, 549-775, 549-1214, 566-1219, 568-1214, 576-1082, 577-1039, 590-1233, 596-853, 611-989, 620- 1122, 622-1001, 624-1003, 630-1162, 637-1125, 637-1257, 637-1305, 639-898, 663-1222, 665-789, 673-999, 684-1292, 686-929, 702-953, 704-995, 704-1334, 714-1260, 736-1433, 745-1257, 747-1021, 748-930, 750-1037, 752-987, 758-1017, 759-1007, 763-1026, 766-1290, 777- 1396, 779-1180, 779-1259, 779-1324, 779-1387, 779-1544, 791-1060, 791-1084, 792-1285, 793-1366, 794-1279, 794-1284, 833-957, 838- 1091, 838-1479, 845-1560, 856-1438, 862-1444, 866-1423, 877-1139, 879-1349, 879-1493, 880-1179, 883-1348, 883-1440, 895-1435, 900-1435, 901-1166, 905-1384, 910-1533, 919-1409, 920-1128, 921-1255, 921-1401, 932-1496, 948-1539, 951-1347, 952-1287, 953-1344, 959-1545, 961-1475, 962-1229, 974-1106, 975-1535, 976-1252, 980-1117, 987-1252, 991-1541, 1006-1254, 1006- 1483, 1006-1548, 1035-1160, 1036-1594, 1038-1238, 1077-1638, 1078-1211, 1079-1670, 1085-1699, 1089-1729, 1092-1333, 1098-1637, 1102-1394, 1104-1712, 1133-1845, 1141-1385, 1143-1407, 1145-1770, 1154-1618, 1155-1687, 1161-1699, 1163-1433, 1163-1496, 1169- 1730, 1184-1938, 1200-1698, 1205-1481, 1205-1495, 1205-1813, 1206-1421, 1206-1452, 1214-1289, 1226-1510, 1226-1750, 1231-1732, 1248-1594, 1283-1545, 1284-1582, 1287-1751, 1308-1901, 1309-1681, 1318-1850, 1323-1590, 1325-1591, 1344-1512, 1344-1564, 1344- 1777, 1348-1621, 1351-1618, 1358-1483, 1361-1602, 1362-1518, 1373-1953, 1383-1847, 1386-2018, 1392-2001, 1396-1677, 1399-1660, 1408-1863, 1410-1648, 1420-1551, 1431-1686, 1432-1537, 1433-1665, 1433-1684, 1437-1636, 1437-1663, 1441-1997, 1446-1944, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 1451-1702, 1451-1771, 1455-1946, 1465-2075, 1467-2033, 1471-1901, 1476-2025, 1476-2105, 1484-1746, 1484-1756, 1485-2049, 1488- 2064, 1491-1925, 1494-2036, 1496-2145, 1499-1862, 1500-2056, 1502-2157, 1503-2089, 1509-1776, 1512-1980, 1525-2105, 1528-1783, 1540-2076, 1541-1708, 1542-2184, 1545-1841, 1545-2173, 1546-1807, 1546-2137, 1557-2188, 1570-1875, 1573-2102, 1574-1813, 1586- 2190, 1589-1798, 1594-1812, 1603-1868, 1605-2316, 1605-2369, 1607-1882, 1613-2123, 1625-1778, 1628-1908, 1639-2200, 1662-1960, 1663-2229, 1669-1914, 1669-2261, 1675-2214, 1677-2324, 1680-1929, 1680-2130, 1684-2277, 1692-1987, 1695-2310, 1698-2342, 1703- 2366, 1712-2218, 1713-2289, 1726-2184, 1750-1902, 1751-2083, 1751-2095, 1752-1935, 1757-2305, 1759-2141, 1760-2314, 1761-2341, 1761-2468, 1761-2574, 1762-1961, 1763-1971, 1764-2245, 1775-2020, 1775-2289, 1775-2448, 1775-2583, 1779-2042, 1781-2366, 1784- 2056, 1785-1987, 1785-2023, 1786-2066, 1790-2025, 1803-2331, 1805-2094, 1808-2560, 1808-2564, 1808-2578, 1808-2581, 1808-2583, 1812-2577, 1813-2084, 1815-2093, 1816-2324, 1818-2387, 1820-2186, 1826-2030, 1826-2033, 1826-2091, 1830-2376, 1839- 2451, 1841-2411, 1850-2309, 1850-2488, 1852-2090, 1854-2103, 1854-2526, 1856-2118, 1871-2097, 1871-2546, 1879-2174, 1880-2127, 1880-2134, 1880-2142, 1882-2134, 1887-2413, 1888-2025, 1888-2154, 1889-2112, 1898-2530, 1900-2521, 1901-2147, 1901-2409, 1906- 2235, 1906-2236, 1907-2415, 1913-2504, 1928-2205, 1928-2405, 1930-2205, 1933-2210, 1942-2488, 1942-2525, 1946-2192, 1946-2339, 1946-2399, 1948-2583, 1958-2241, 1959-2583, 1966-2202, 1974-2472, 1975-2414, 1990-2246, 1990-2583, 1996-2249, 2001-2244, 2001- 2263, 2001-2277, 2001-2389, 2003-2304, 2003-2416, 2010-2578, 2012-2274, 2041-2495, 2058-2437, 2059-2507, 2060-2568, 2087-2336, 2093-2331, 2098-2352, 2103-2340, 2127-2377, 2132-2449, 2135-2376, 2136-2432, 2158-2349, 2158-2387, 2168-3025, 2174-2392, 2176- 2433, 2177-2449, 2193-2429, 2196-2398, 2203-2439, 2210-2439, 2211-2468, 2279-2537, 2294-2546, 2295-2445, 2307-2468, 2404-3024, 2420-2697, 2426-2560, 2428-2686, 2465-3005, 2467-2732, 2467-3028, 2468-3016, 2468-3028, 2512-2749, 2599-3025, 2608- 3023, 2626-2921, 2626-3028, 2627-3028, 2640-2914, 2673-3018, 2707-3028, 2760-3021, 2775-2813, 2775-2818, 2775-2820, 2775-2821, 2796-2976, 2800-3015, 2800-3028, 2832-3028, 2840-3021, 2848-3017 76/7510116CB1/1-799, 1-845, 1-851, 1-870, 1-880, 1-894, 1-907, 1-942, 1-3094, 8-171, 11-229, 15-390, 19-619, 199-790, 270-1115, 288-898, 299-804, 339- 3144 790, 350-859, 360-629, 391-890, 396-988, 461-739, 545-1115, 587-1301, 595-738, 621-1216, 632-981, 736-1009, 736-1288, 741-1363, 790- 1019, 814-1581, 853-1339, 854-1114, 864-1206, 868-1340, 872-1479, 874-1195, 898-1165, 904-1173, 948-1626, 991-1220, 1029-1387, 1037-1250, 1047-1803, 1093-1751, 1127-1664, 1160-1409, 1190-1874, 1193-1429, 1235-1576, 1241-1506, 1272-1819, 1297-1463, 1302- 1896, 1370-1491, 1370-1624, 1390-1779, 1401-1574, 1404-1868, 1437-1886, 1442-1854, 1456-1756, 1474-1888, 1495-1759, 1529-1805, 1542-1901, 1544-1797, 1581-2223, 1656-2502, 1691-1962, 1704-1866, 1710-1886, 1746-2004, 1831-2422, 1976-2237, 2031-2641, 2076- 2649, 2076-2699, 2112-2577, 2116-2649, 2116-2709, 2137-2548, 2153-3094, 2177-3094, 2192-2425, 2200-3094, 2210-2545, 2222-3094, 2228-3094, 2244-3094, 2245-3094, 2251-2612, 2269-2794, 2292-2587, 2300-2417, 2320-2927, 2328-2587, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 2341-2904, 2341-3017, 2343-2854, 2344-2626, 2348-2843, 2375-2924, 2378-3012, 2385-2981, 2395-2929, 2397-2704, 2413-3059, 2425- 3094, 2436-2620, 2458-3035, 2497-2720, 2504-3026, 2513-2773, 2518-2840, 2519-2763, 2531-3144, 2544-3082, 2547-2666, 2562-3085, 2577-2828, 2579-3082, 2584-3049, 2586-2819, 2602-3025, 2604-2939, 2611-2869, 2623-2755, 2625-2891, 2625-2904, 2634-3063, 2648- 3054, 2665-2883, 2672-3094, 2672-3112, 2672-3124, 2691-3100, 2693-2910, 2699-3056, 2718-3102, 2730-3094, 2734-2990, 2735-2988, 2770-2935, 2773-3076, 2779-3029, 2780-3022, 2787-3027, 2787-3054, 2787-3094, 2787-3104, 2845-3094, 2899-3093, 2906-3104 77/7500548CB1/1-230, 1-622, 1-2481, 7-239, 7-263, 7-368, 7-391, 7-438, 7-483, 7-486, 7-526, 7-601, 8-731, 18-581, 26-325, 30-595, 45-336, 48-305, 55- 2481 381, 58-542, 63-680, 78-783, 78-821, 78-856, 78-894, 78-895, 78-897, 78-908, 78-922, 78-943, 112-386, 119-640, 130-373, 146-697, 154- 765, 162-410, 199-701, 217-410, 299-507, 302-688, 302-693, 305-874, 370-939, 374-945, 397-773, 401-1078, 472-948, 478-1014, 493- 1167, 695-970, 735-1014, 737-884, 791-1050, 804-1045, 908-1174, 953-1213, 966-1588, 1019-1212, 1090-1408, 1107-1775, 1138-1488, 1138-1492, 1150-1375, 1150-1434, 1188-1759, 1281-1485, 1311-1830, 1345-1958, 1377-1628, 1402-1617, 1420-1716, 1424-1496, 1458- 1945, 1459-1714, 1465-1727, 1477-1727, 1495-1544, 1496-2000, 1541-1835, 1558-1854, 1564-1819, 1571-1821, 1571-2105, 1600-1843, 1600-1859, 1608-2395, 1636-1904, 1683-1955, 1684-1942, 1688-1943, 1730-1987, 1736-2476, 1740-1993, 1773-2001, 1802-2331, 1803- 1965, 1819-2098, 1849-2099, 1874-2104, 1919-2155, 1980-2249, 2011-2468, 2054-2469, 2072-2305, 2072-2466, 2072-2481, 2078-2472, 2179-2481, 2222-2464, 2224-2307, 2231-2469, 2272-2470 78/7504807CB1/1-264, 11-206, 14-314, 14-320, 14-1279, 22-296, 22-303, 23-146, 23-282, 29-285, 31-299, 31-316, 31-317, 31-322, 31-323, 31-386, 31-642, 1279 31-766, 40-286, 40-321, 43-307, 45-576, 46-272, 47-286, 47-302, 47-314, 48-256, 48-293, 48-294, 48-322, 48-616, 50-336, 50-337, 50-549, 50-590, 50-636, 51-178, 51-239, 51-260, 51-284, 51-292, 51-305, 51-337, 51-347, 52-472, 53-326, 53-335, 54-208, 54-229, 54-246, 54-262, 54-274, 54-286, 54-290, 54-297, 54-301, 54-302, 54-304, 54-305, 54-307, 54-313, 54-315, 54-320, 54-321, 54-329, 54-331, 54-333, 54-335, 54-337, 54-340, 54-341, 54-343, 54-347, 54-350, 54-351, 54-532, 54-611, 54-631, 54-704, 54-752, 55-296, 55-313, 55-322, 55-323, 55-332, 55-336, 55-338, 55-342, 55-348, 55-352, 55-612, 56-175, 56-273, 56-290, 56-317, 56-325, 56-345, 56-351, 56-352, 56-357, 56-457, 56-551, 56-560, 56-687, 57-192, 57-209, 57-297, 57-303, 57-306, 57-312, 57-314, 57-315, 57-318, 57-326, 57-329, 57-330, 57-338, 57-343, 57-344, 57-347, 57-521, 57-575, 57-608, 57-616, 57-643, 58-219, 58-303, 58-309, 58-313, 58-318, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 58-336, 58-340, 58-580, 59-291, 59-304, 59-323, 59-327, 59-337, 60-289, 60-310, 60-333, 60-336, 60-338, 60-391, 61-346, 61-355, 62-352, 62-587, 62-623, 63-280, 63-316, 63-328, 63-333, 63-364, 63-471, 63-540, 63-693, 64-327, 64-348, 64-471, 64-545, 67-316, 67-336, 67-344, 67-471, 67-472, 67-521, 69-243, 69-332, 69-558, 69-583, 70-327, 71-472, 74-729, 75-343, 76-277, 76-284, 76-286, 76-325, 76-362, 76-548, 76-579, 76-597, 76-604, 76-650, 77-305, 77-324, 77-341, 77-360, 77-367, 77-427, 77-643, 78-352, 78-531, 78-612, 79-445, 96-649, 107- 359, 108-416, 111-293, 111-384, 115-745, 116-229, 124-419, 125-379, 125-398, 125-732, 131-279, 131-291, 131-419, 133-330, 133-337, 135-336, 135-337, 136-390, 152-420, 154-421, 157-438, 162-401, 162-448, 163-448, 163-853, 172-393, 172-398, 176-470, 183-445, 183- 471, 184-514, 185-440, 185-477, 187-476, 188-272, 188-389, 188-432, 188-459, 188-471, 188-548, 189-477, 191-468, 192-313, 192-473, 193-358, 193-438, 193-864, 195-423, 195-435, 195-444, 204-494, 205-485, 206-433, 219-853, 243-398, 248-521, 248-526, 281-562, 290-1010, 291-575, 293-530, 312-561, 329-568, 339-612, 362-568, 372-512, 400-550, 446-792, 462- 608, 484-980, 531-734, 692-970, 693-875, 884-1279, 917-1279, 1015-1252, 1015-1279, 1016-1247, 1029-1279, 1033-1279, 1036-1238, 1036-1279, 1038-1197, 1038-1279, 1040-1279, 1043-1279, 1045-1279, 1054-1279, 1058-1279, 1059-1275, 1068-1279, 1071-1279, 1073- 1279, 1074-1279, 1077-1279, 1082-1279, 1088-1193, 1091-1188, 1092-1239, 1098-1279, 1100-1279, 1103-1279, 1105-1273, 1106-1279, 1109-1279, 1119-1279, 1120-1256, 1122-1279, 1123-1279, 1124-1279, 1126-1279, 1128-1279, 1129-1279, 1130-1279, 1134-1231, 1134- 1279, 1135-1279, 1139-1279, 1145-1279, 1161-1279, 1163-1279, 1184-1279, 1185-1279, 1187-1279, 1189-1279, 1190-1279, 1206-1279, 1220-1279, 1224-1279, 1227-1279 79/7504988CB1/706 1-120, 2-120, 3-95, 3-120, 5-109, 5-120, 6-120, 6-665, 7-110, 7-120, 7-532, 7-590, 7-613, 7-621, 7-642, 7-675, 7-686, 7-706, 8-120, 9-120, 10-113, 10-120, 13-96, 14-91, 14-101, 14-111, 14-119, 14-120, 15-120, 19-120, 114-185, 114-229, 114-312, 114-355, 114-361, 114-375, 114-396, 114-437, 114-497, 114-633, 114-637, 114-664, 114-696, 115-142, 115-175, 115-190, 117-342, 117-364, 117-415, 117-632, 118- 392, 118-403, 119-422, 121-672, 122-387, 123-671, 124-308, 124-381, 125-370, 126-368, 127-385, 127-391, 127-418, 127-427, 127-438, 130-658, 131-392, 133-403, 134-433, 135-288, 135-367, 135-379, 135-385, 135-388, 135-391, 135-424, 136-407, 138-406, 138-652, 139- 414, 140-356, 141-397, 144-376, 145-402, 147-685, 148-378, 150-418, 150-420, 153-362, 153-366, 153-375, 153-394, 153-400, 153-401, 153-404, 153-419, 153-422, 153-433, 153-436, 153-641, 154-379, 154-385, 154-423, 155-377, 155-389, 155-434, 155-437, 155-461, 156- 393, 156-405, 158-399, 158-408, 158-412, 158-416, 160-345, 160-358, 160-371, 160-414, 160-415, Table 4 Polynucleotide Sequence Fragments SEQ ID NO : l Incyte ID/Sequence Length 160-416, 160-511, 161-360, 161-404, 163-437, 165-367, 168-392, 169-702, 171-698, 174-351, 175-363, 175-384, 175-700, 178-414, 178- 439, 178-454, 179-449, 179-467, 180-433, 180-456, 180-457, 180-462, 180-468, 182-316, 182-376, 182-387, 182-396, 182-416, 182-422, 182-647, 182-687, 182-706, 183-428, 183-429, 183-476, 184-322, 184-367, 184-450, 185-693, 186-382, 187-396, 187-410, 187-441, 187- 556, 189-448, 189-454, 189-472, 190-706, 192-391, 192-410, 192-415, 192-523, 192-702, 196-393, 196-423, 196-454, 196-470, 198-425, 198-468, 198-490, 199-457, 200-503, 201-455, 201-706, 204-419, 204-433, 204-456, 204-473, 204-481, 205-482, 207-472, 207-480, 209- 445, 209-450, 209-459, 209-493, 209-505, 209-702, 212-393, 212-543, 212-646, 214-412, 215-436, 215-485, 217-461, 217-470, 217-472, 217-504, 218-465, 218-475, 218-485, 218-521, 218-530, 219-385, 219-451, 219-452, 219-457, 219-461, 219-474, 219-491, 219-512, 219- 521, 220-388, 220-414, 220-420, 220-545, 221-587, 222-600, 222-706, 224-423, 224-450, 224-457, 224-474, 224-485, 224-486, 224-516, 225-474, 225-504, 226-442, 226-460, 226-497, 227-454, 227-457, 228-419, 229-421, 229-512, 230- 573, 231-702, 233-396, 233-412, 233-467, 233-471, 233-523, 233-700, 233-706, 234-451, 234-499, 237-702, 238-420, 238-469, 238-478, 238-702, 238-706, 240-446, 240-481, 240-489, 240-492, 240-517, 241-493, 241-494, 242-499, 243-453, 243-515, 243-539, 243-568, 244- 407, 244-706, 245-498, 245-703, 249-423, 249-471, 249-476, 249-489, 249-501, 249-521, 252-500, 253-512, 254-469, 254-519, 254-520, 254-706, 255-440, 255-484, 255-485, 255-703, 256-460, 256-699, 259-470, 259-510, 261-518, 261-531, 261-547, 262-424, 262-464, 262- 468, 262-481, 262-498, 262-501, 262-503, 264-464, 264-494, 264-502, 264-509, 264-537, 264-541, 265-549, 265-706, 266-418, 266-454, 266-518, 269-437, 269-505, 269-533, 269-559, 270-470, 271-427, 271-452, 271-493, 271-514, 272-522, 272-546, 272-555, 274-521, 276- 508, 278-476, 278-502, 278-504, 278-510, 278-512, 278-515, 278-524, 278-662, 278-701, 279-511, 280-475, 280-517, 280-532, 280-543, 280-546, 280-559, 280-702, 281-425, 281-531, 282-498, 282-572, 282-573, 283-470, 283-703, 285-566, 285- 572, 286-702, 286-706, 287-561, 288-575, 288-657, 288-702, 289-522, 289-526, 289-565, 289-566, 289-582, 289-702, 289-706, 291-520, 291-702, 291-706, 294-573, 294-701, 295-572, 295-706, 296-415, 296-493, 296-560, 297-464, 297-534, 297-546, 297-700, 298-506, 298- 515, 298-532, 298-539, 298-542, 298-706, 299-589, 300-570, 300-706, 301-569, 301-706, 302-445, 302-608, 302-706, 303-476, 303-491, 303-706, 304-498, 304-507, 304-561, 304-565, 304-566, 304-568, 305-513, 306-578, 306-608, 306-706, 307-519, 307-546, 307-575, 307- 595, 308-565, 308-701, 308-702, 308-706, 310-481, 310-497, 310-559, 310-706, 311-530, 311-657, 313-562, 313-582, 316-591, 317-516, 317-591, 317-701, 318-623, 318-706, 319-706, 320-703, 321-572, 321-604, 322-702, 322-706, 323-594, 323-702, 323-703, 323-706, 324- 701, 325-520, 325-566, 325-587, 325-699, 326-703, 327-706, 328-700, 330-617, 330-702, 330-706, 331-699, 334-489, 334-701, 334-703, 335-706, 337-448, 338-617, 339-533, 339-575, 339-664, 340-514, 340-618, 341-700, 342-472, 342-502 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 80/750505 lCB l/~ 80/7505051CB1/1-268, 1-2406, 51-615, 264-567, 357-556, 359-556, 671-942, 673-912, 679-1261, 717-1412, 740-1297, 742-1014, 742-1130, 742-1250, 742- 2406 1251, 742-1270, 742-1324, 743-1315, 746-1247, 748-1468, 775-892, 775-1069, 805-1489, 824-1467, 831-1477, 865-1305, 893-1051, 909- 1483, 940-1468, 949-1421, 958-1222, 966-1699, 973-1507, 1026-1606, 1041-1312, 1041-1342, 1041-1530, 1041-1539, 1041-1572, 1041- 1633, 1041-1675, 1060-1414, 1060-1602, 1073-1707, 1091-1381, 1114-1516, 1125-1393, 1159-1480, 1169-1485, 1177-1903, 1225-1480, 1233-1489, 1256-1762, 1257-1866, 1317-1509, 1317-1574, 1317-1755, 1321-1907, 1351-1866, 1369-1866, 1419-1551, 1434-1651, 1440- 1694, 1449-1700, 1466-1740, 1506-1732, 1507-1758, 1513-1866, 1912-2406, 1935-2406, 1952-2017, 1952-2020, 1973-2238, 1983-2020, 1991-2380, 1999-2020, 2005-2073, 2026-2073, 2036-2309, 2052-2393, 2061-2397, 2062-2298, 2063-2354, 2064-2319, 2112-2377, 2112- 2391. 2112-2406, 2146-2397, 2285-2369 81/7505079CB1/1-490, 29-2944, 43-886, 51-324, 65-774, 94-745, 94-765, 94-772, 94-829, 94-837, 94-870, 94-886, 95-886, 161-719, 340-477, 340-754, 380- 2956 833, 505-767, 505-1157, 543-786, 717-1264, 741-1165, 936-1343, 939-1452, 940-1229, 986-1379, 1016-1879, 1055-1724, 1075-1699, 1106-1405, 1126-1369, 1168-1392, 1178-1435, 1200-1780, 1223-1448, 1223-1460, 1223-1755, 1223-1852, 1223-1919, 1223-2009, 1244- 1880, 1251-1523, 1296-1820, 1321-2125, 1330-1949, 1330-2131, 1421-1997, 1468-1752, 1474-2074, 1501-1763, 1506-2419, 1511-1742, 1511-1751, 1511-2096, 1527-2219, 1527-2241, 1527-2260, 1527-2265, 1527-2327, 1528-2075, 1538-2422, 1557-1761, 1579-1843, 1585- 2421, 1597-1896, 1613-2202, 1615-2253, 1628-2075, 1669-2460, 1675-1939, 1677-1960, 1691-2359, 1695-2258, 1705-2199, 1710-2199, 1764-2342, 1769-2422, 1819-2540, 1822-2540, 1861-2273, 1877-2159, 1879-2540, 1897-2567, 1899-2368, 1904-2743, 1946-2488, 1947- 2574, 1951-2482, 1965-2427, 1966-2512, 1970-2512, 1999-2773, 2017-2717, 2032-2299, 2046-2598, 2064-2722, 2088-2657, 2118-2761, 2139-2680, 2139-2870, 2141-2533, 2141-2566, 2159-2528, 2159-2614, 2159-2621, 2159-2623, 2159-2636, 2159-2640, 2159-2641, 2159- 2644, 2159-2645, 2159-2646, 2185-2431, 2189-2453, 2190-2900, 2212-2757, 2223-2896, 2258-2716, 2263-2718, 2268-2933, 2280-2744, 2290-2907, 2353-2940, 2356-2618, 2356-2692, 2359-2719, 2384-2840, 2393-2931, 2402-2707, 2409-2655, 2409-2744, 2417-2916, 2418- 2688, 2420-2916, 2422-2884, 2424-2922, 2425-2887, 2435-2672, 2444-2944, 2445-2890, 2445-2916, 2447-2916, 2448-2916, 2465-2916, 2466-2753, 2468-2712, 2468-2739, 2470-2710, 2479-2940, 2486-2940, 2492-2615, 2492-2881, 2492-2909, 2492-2914, 2492-2925, 2506- 2916, 2510-2916, 2512-2916, 2514-2784, 2526-2941, 2538-2823, 2546-2833, 2546-2940, 2549-2916, 2560-2647, 2578-2856, 2596-2938, 2601-2896, 2603-2944, 2637-2884, 2639-2908, 2698-2951, 2706-2943, 2722-2956, 2731-2951, 2736-2939, 2789-2921, 2805-2944 82/7505159CB1/1-1038, 598-1036, 635-1045, 689-1043, 704-1038, 883-1045, 884-1045, 893-1045 1045 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 83/7510086CB1/1-2253, 41-694, 47-341, 113-719, 547-1067, 588-1121, 621-1173, 693-1211, 783-1001, 799-1024, 827-1310, 839-1360, 1013-1531, 1043- 2253 1607, 1064-1770, 1116-1687, 1126-1607, 1138-1475, 1210-1676, 1219-1454, 1248-1670, 1295-1782, 1302-1755, 1309-1762, 1312-1568, 1312-1755, 1346-1782, 1356-1806, 1364-1755, 1389-1639, 1417-1715, 1505-1755, 1531-1703, 1571-1762, 1574-1755, 1577-2070, 1578- 2082, 1588-1755, 1591-1755, 1603-1754, 1621-1764, 1629-1808, 1652-1806, 1655-2128, 1702-2089, 1703-1916, 1785-2065, 1785-2070, 1807-2086, 1960-2130, 1960-2213 84/7510131CB1/1-280, 1-348, 1-353, 1-374, 1-585, 1-591, 1-595, 1-628, 1-651, 1-2797, 4-237, 5-649, 13-280, 20-783, 21-258, 21-537, 21-582, 21-602, 21- 2810 628, 21-652, 21-653, 21-662, 21-684, 21-708, 21-709, 21-719, 21-721, 21-726, 21-769, 21-796, 21-816, 21-831, 21-847, 21-850, 22-520, 22- 557, 22-609, 22-788, 23-289, 24-388, 25-619, 28-242, 30-612, 31-331, 32-475, 32-617, 32-623, 32-638, 32-649, 32-665, 32-669, 32-680, 32- 696, 32-720, 32-721, 32-739, 32-747, 32-748, 32-762, 32-817, 32-833, 32-847, 32-850, 32-851, 34-576, 40-813, 40-815, 43-285, 50-303, 54- 815, 55-328, 58-831, 60-544, 60-654, 60-736, 60-769, 60-792, 60-812, 60-875, 60-899, 61-848, 64-664, 68-780, 161-714, 192-464, 202- 856, 228-745, 257-551, 268-451, 326-1042, 338-898, 351-722, 397-996, 429-998, 445-732, 446-657, 446-913, 457-1083, 471-720, 474- 999, 500-1031, 542-834, 549-1015, 549-1237, 563-1210, 564-1184, 567-858, 620-1117, 651-1160, 651-1274, 678-1226, 690-1222, 700- 1393, 717-1179, 718-1177, 722-1361, 738-1193, 739-1195, 746-1313, 749-1448, 753-1376, 784-1337, 794-934, 827-1363, 846-1540, 862-1109, 890-1444, 899-1544, 905-1480, 917-1397, 971-1539, 974-1550, 975-1117, 990-1619, 1019-1119, 1035-1298, 1040- 1713, 1044-1566, 1048-1584, 1049-1528, 1056-1703, 1075-1755, 1095-1679, 1134-1640, 1177-1645, 1181-1672, 1186-1725, 1253-1500, 1318-1910, 1340-1958, 1362-1787, 1417-1656, 1417-1660, 1428-1681, 1492-1733, 1496-1713, 1496-1957, 1511-1962, 1560-1793, 1605- 1869, 1639-1892, 1669-1959, 1694-1940, 1739-2182, 1829-2430, 1850-1961, 1855-1964, 1878-2168, 1914-1964, 2016-2299, 2045-2284, 2045-2285, 2045-2454, 2045-2703, 2045-2709, 2045-2713, 2052-2295, 2068-2174, 2071-2583, 2075-2717, 2082-2708, 2087-2575, 2088- 2574, 2115-2734, 2124-2365, 2128-2391, 2140-2761, 2172-2613, 2251-2596, 2251-2706, 2254-2508, 2256-2427, 2259-2477, 2259-2810, 2266-2566, 2308-2600, 2322-2581, 2329-2655, 2331-2576, 2331-2600, 2344-2618, 2345-2578, 2346-2618, 2382-2637, 2399-2517, 2404- 2650, 2409-2552, 2409-2606, 2409-2658, 2409-2659, 2410-2689, 2413-2692, 2424-2671, 2442-2795, 2447-2712, 2448-2720, 2451-2727, 2454-2739, 2455-2661, 2458-2704, 2459-2582, 2466-2736, 2468-2773, 2470-2685, 2483-2764, 2487-2718, 2487-2752, 2498- 2742, 2502-2712, 2521-2799, 2525-2810, 2535-2793, 2549-2783, 2561-2762, 2606-2786 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 85/7510137CB1/1-175, 1-185, 1-246, 1-293, 1-450, 1-497, 1-1658, 2-321, 2-324, 2-854, 8-249, 10-248, 13-434, 15-441, 19-278, 21-266, 21-288, 21-388, 23- 1658 215, 23-274, 24-385, 26-223, 26-671, 27-224, 27-279, 27-331, 28-294, 28-334, 31-264, 31-268, 31-272, 31-275, 31-282, 31-287, 31-288, 31- 289, 31-298, 31-308, 31-319, 31-321, 31-322, 31-338, 31-505, 31-669, 31-771, 32-257, 32-279, 32-305, 33-256, 33-258, 33-262, 33-264, 33- 274, 33-291, 33-297, 33-299, 33-304, 33-316, 33-319, 33-325, 33-345, 33-388, 33-416, 33-498, 33-554, 33-653, 34-314, 34-406, 35-275, 35- 323, 35-327, 35-426, 35-701, 36-289, 37-318, 37-320, 37-322, 37-330, 38-241, 38-291, 38-313, 40-338, 40-510, 40-567, 41-178, 41-249, 41- 280, 41-299, 42-542, 42-734, 43-670, 46-291, 46-580, 46-642, 46-698, 47-125, 47-284, 47-320, 47-584, 49-238, 49-312, 50-338, 52-260, 52- 296, 52-695, 53-294, 55-261, 55-287, 55-337, 55-340, 55-343, 55-803, 57-304, 57-338, 57-360, 57-561, 57-771, 58-636, 59-306, 59-335, 60- 334, 61-326, 63-375, 64-385, 65-289, 65-319, 65-323, 65-329, 65-330, 65-341, 66-320, 66-597, 69-487, 71-689, 76-331, 76-541, 78-655, 81-448, 85-704, 91-341, 91-573, 93-623, 96-702, 99-354, 105-344, 114-724, 117-448, 120- 666, 137-344, 140-723, 147-661, 155-390, 161-397, 168-389, 173-619, 182-825, 183-287, 183-514, 183-806, 184-427, 195-452, 196-399, 196-407, 196-446, 196-448, 202-442, 211-825, 224-784, 226-471, 228-464, 235-534, 235-576, 235-811, 243-740, 247-839, 248-485, 250- 543, 253-648, 262-567, 280-504, 283-932, 291-484, 303-969, 309-547, 310-800, 328-617, 337-919, 337-992, 342-557, 345-547, 362-647, 379-638, 397-601, 398-534, 398-675, 399-481, 407-667, 409-652, 409-1038, 413-933, 423-677, 441-863, 443-1020, 459-698, 465-627, 469- 748, 470-729, 475-771, 476-899, 481-722, 482-620, 492-801, 493-779, 500-1074, 508-767, 509-1060, 511-795, 541-711, 547-814, 556- 993, 559-993, 561-798, 582-715, 582-840, 583-850, 583-884, 583-887, 585-909, 609-860, 609-903, 619-747, 626-857, 628-925, 645-1133, 650-861, 650-948, 650-966, 657-909, 658-912, 664-928, 671-889, 671-933, 683-934, 687-912, 688-968, 709-935, 711-1011, 716-947, 729-927, 748-1004, 751-981, 778-1017, 782-915, 798-1350, 817-1079, 826-1135, 836-1101, 856-1086, 857-1124, 878-1118, 895- 1136, 1059-1553 86/7510690CB1/1-313, 2-249, 17-221, 17-1138, 324-454, 324-573, 324-594, 329-568, 338-606, 353-625, 356-603, 363-616, 365-612, 367-629, 367-631, 1152 375-631, 376-626, 378-631, 382-631, 387-490, 391-631, 403-622, 408-615, 408-628, 408-631, 409-628, 409-631, 412-631, 413-552, 413- 613, 413-625, 413-627, 413-631, 414-631, 416-626, 420-631, 429-629, 431-686, 432-602, 434-631, 435-629, 435-631, 436-562, 511-631, 628-746, 628-880, 628-927, 628-1084, 628-1102, 630-1082, 631-1084, 632-866, 647-907, 661-1139, 661-1142, 666-975, 667-757, 691- 905, 693-1142, 701-936, 701-947, 701-970, 706-1152, 724-1152, 727-1107, 730-968, 732-996, 735-1142, 737-1000, 738-1152, 751-1139, 764-992, 782-1058, 785-1152, 789-1002, 796-1152, 799-989, 799-1084, 810-1142, 821-1152, 830-1088, 856-1152, 873-1078, 883-1142, 889-1059, 889-1082, 898-1141, 1064-1152, 1072-1142 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 87/7510695CB1/1-496, 1-528, 1-547, 1-764, 1-2415, 4-734, 119-540, 119-547, 119-558, 119-586, 119-677, 119-751, 119-761, 119-845, 119-948, 120-755, 2415 146-899, 150-480, 150-577, 150-590, 150-670, 150-748, 164-785, 192-1080, 193-437, 193-461, 193-552, 193-742, 193-864, 193-986, 193- 1007, 193-1032, 196-924, 226-730, 270-860, 272-964, 297-922, 336-934, 354-1032, 392-761, 421-1064, 441-1386, 453-999, 470-936, 473- 1296, 483-1432, 489-1070, 492-1366, 503-866, 506-1306, 528-1005, 536-787, 556-1183, 557-1341, 563-1284, 612-962, 620-1259, 627- 1101, 646-1101, 649-1227, 681-1174, 719-1356, 730-1185, 741-837, 741-852, 750-1292, 771-1142, 780-1305, 787-1341, 830-976, 877- 1156, 877-1234, 893-1168, 893-1388, 893-1408, 911-1443, 927-1198, 931-1396, 950-1391, 1021-1308, 1038-1430, 1127-1443, 1139-1421, 1203-1441, 1220-1987, 1442-1837, 1442-1953, 1442-1990, 1443-1866, 1478-1944, 1499-1681, 1518-2129, 1521-2052, 1522-1681, 1542- 2071, 1543-2154, 1544-2343, 1553-1681, 1553-1821, 1560-1833, 1567-2222, 1579-2233, 1580-2233, 1581-1842, 1581-1943, 1581-2008, 1581-2012, 1581-2030, 1581-2185, 1583-1917, 1584-2089, 1589-2073, 1607-1881, 1619-1843, 1620-2391, 1644- 2380, 1645-2404, 1685-2289, 1688-2158, 1690-2062, 1699-1952, 1703-1931, 1703-1980, 1713-1973, 1715-1902, 1726-1887, 1726-1924, 1732-2350, 1737-1887, 1743-2363, 1749-2036, 1764-2380, 1809-2081, 1813-2231, 1835-2075, 1843-2364, 1843-2366, 1846-2361, 1848- 2386, 1854-2324, 1857-2193, 1858-2301, 1861-2352, 1861-2415, 1874-2271, 1888-2167, 1898-2415, 1909-2321, 1915-2352, 1916-2415, 1928-2404, 1940-2396, 1949-2255, 1950-2176, 1959-2367, 1963-2406, 1970-2408, 1971-2235, 1974-2407, 1976-2404, 1990-2407, 1996- 2399, 1997-2408, 2023-2415, 2028-2321, 2035-2369, 2043-2415, 2053-2411, 2061-2360, 2076-2398, 2077-2199, 2091-2404, 2092-2325, 2095-2404, 2122-2303, 2124-2395, 2127-2404, 2135-2380, 2175-2201, 2188-2415, 2191-2404, 2195-2415, 2317-2396, 2354-2415 88/7504781CB1/1-163, 73-1916, 93-295, 104-345, 120-357, 122-344, 122-357, 123-357, 125-329, 126-344, 130-270, 141-298, 142-656, 142-962, 142-989, 1980 143-1053, 145-291, 170-313, 190-1053, 222-1058, 350-606, 350-620, 350-631, 350-651, 350-658, 350-898, 350-937, 350-948, 355-475, 361-943, 362-604, 363-563, 363-637, 363-784, 363-791, 363-1053, 364-786, 378-654, 378-667, 379-621, 382-656, 388-952, 392-619, 397- 674, 398-636, 398-648, 398-655, 404-842, 405-675, 408-621, 409-692, 414-967, 416-696, 416-1019, 417-841, 432-696, 432-911, 439-694, 439-733, 443-814, 447-560, 458-726, 458-730, 462-617, 462-730, 465-1019, 471-725, 478-793, 481-1102, 484-714, 487-640, 493-759, 493- 1107, 500-771, 500-799, 500-1078, 503-1064, 509-756, 514-1091, 531-633, 532-784, 555-775, 557-858, 570-1014, 576-1223, 577-995, 580- 730, 582-877, 582-1087, 583-993, 590-1327, 601-756, 607-756, 617-773, 619-1278, 622-890, 630-1094, 640-900, 641-1112, 642-1112, 653- 752, 653-1255, 653-1291, 653-1401, 655-949, 655-1115, 665-1115, 667-1083, 676-898, 676-909, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 676-1005, 676-1121, 676-1165, 682-1023, 682-1109, 686-861, 692-933, 694-911, 694-918, 694-998, 695-1081, 697-1121, 700-1116, 701- 979, 702-942, 704-1116, 706-946, 708-1069, 708-1316, 709-1333, 716-918, 722-983, 722-1025, 725-1005, 729-1014, 732-1194, 732-1249, 733-1072, 736-1300, 736-1530, 744-979, 744-1020, 747-1011, 749-951, 749-1033, 750-1001, 750-1319, 754-1410, 755-1034, 756-1034, 760-1302, 761-907, 761-1042, 761-1065, 761-1112, 765-1306, 767-1183, 770-1021, 773-1389, 776-1039, 777-1212, 780-1112, 781-1112, 782-1028, 782-1076, 782-1698, 785-1027, 785-1401, 787-1039, 787-1390, 788-1010, 788-1027, 788-1068, 789-1098, 789-1544, 790-1457, 791-976, 791-992, 793-1024, 793-1061, 793-1302, 796-1118, 800-1059, 802-1112, 803-1056, 803-1071, 805-1067, 807-986, 809-942, 810- 908, 810-1055, 810-1067, 810-1109, 812-1067, 812-1075, 812-1499, 817-1071, 820-1393, 823-1116, 830-1073, 831-1104, 835-1066, 835- 1357, 835-1389, 838-1079, 844-998, 844-1070, 844-1392, 845-1115, 845-1136, 846-1045, 846-1095, 846-1138, 846-1335, 847-1088, 847-1300, 852-1115, 856-1099, 857-1178, 858-1127, 861-1160, 862-1125, 866-1098, 866-1214, 867-1149, 869-1115, 871-1386, 874-1455, 877-1508, 880-1091, 881-1288, 882-1136, 882-1409, 886-1108, 888-1126, 892-1190, 899-1452, 904-1345, 905-1156, 905-1172, 905-1487, 906-1115, 906-1579, 926-1165, 926-1186, 927-1222, 928-1172, 928-1196, 928-1201, 928-1203, 928-1256, 933-1167, 936-1181, 938-1072, 941-1158, 941-1173, 941-1191, 941-1223, 942-1161, 944-1274, 944-1280, 951-1191, 951-1201, 951-1206, 952-1232, 959-1250, 963-1242, 964-1775, 965-1266, 966-1179, 974-1220, 975-1104, 976-1236, 982-1277, 989-1205, 989-1246, 990-1272, 992-1454, 993-1679, 995-1292, 997-1247, 1000-1645, 1002-1274, 1009-1746, 1014-1316, 1015-1303, 1018-1159, 1018-1319, 1023-1246, 1023-1312, 1024-1303, 1027-1299, 1027-1493, 1029-1285, 1029-1748, 1032-1633, 1033-1253, 1033-1301, 1033-1335, 1033-1341, 1034- 1212, 1034-1279, 1035-1275, 1035-1321, 1036-1267, 1041-1321, 1041-1393, 1043-1513, 1045-1332, 1045-1334, 1046-1295, 1046-1621, 1048-1287, 1048-1302, 1048-1307, 1048-1318, 1050-1326, 1051-1330, 1052-1508, 1053- 1320, 1057-1291, 1057-1645, 1058-1351, 1064-1302, 1065-1315, 1067-1318, 1067-1581, 1067-1760, 1069-1784, 1074-1637, 1075-1172, 1075-1272, 1075-1581, 1078-1510, 1091-1265, 1091-1318, 1091-1365, 1091-1425, 1094-1374, 1096-1321, 1096-1344, 1096-1392, 1096- 1394, 1096-1407, 1096-1549, 1096-1552, 1099-1313, 1099-1358, 1099-1577, 1100-1354, 1103-1383, 1105-1384, 1113-1498, 1115-1383, 1115-1636, 1116-1334, 1116-1352, 1117-1365, 1117-1412, 1118-1375, 1119-1642, 1121-1581, 1126-1379, 1130-1385, 1133-1357, 1133- 1391, 1136-1245, 1136-1299, 1136-1348, 1136-1362, 1136-1394, 1136-1405, 1136-1411, 1138-1821, 1139-1397, 1139-1602, 1139-1621, 1140-1407, 1144-1430, 1146-1662, 1147-1395, 1147-1423, 1148-1391, 1150-1422, 1150-1616, 1152-1614, 1154-1419, 1154-1447, 1155- 1396, 1159-1397, 1159-1398, 1159-1407, 1159-1422, 1159-1423, 1159-1591, 1159-1601, 1159-1620, 1170-1290, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 1170-1445, 1170-1571, 1172-1628, 1177-1443, 1179-1444, 1187-1747, 1193-1403, 1193-1477, 1194-1705, 1196-1649, 1202-1413, 1202- 1442, 1206-1482, 1207-1359, 1208-1865, 1209-1450, 1209-1820, 1210-1444, 1216-1415, 1218-1380, 1222-1526, 1224-1472, 1225-1444, 1225-1872, 1226-1480, 1226-1520, 1226-1880, 1230-1486, 1230-1522, 1231-1502, 1233-1660, 1234-1820, 1236-1497, 1238-1738, 1239- 1496, 1239-1508, 1240-1365, 1243-1819, 1245-1391, 1250-1757, 1252-1488, 1252-1490, 1252-1532, 1253-1880, 1254-1510, 1255-1940, 1256-1503, 1256-1562, 1258-1578, 1259-1880, 1261-1821, 1268-1521, 1281-1870, 1285-1522, 1287-1562, 1287-1782, 1291-1526, 1291- 1617, 1295-1537, 1296-1754, 1297-1730, 1299-1575, 1300-1485, 1300-1563, 1301-1566, 1304-1571, 1305-1558, 1305-1564, 1306-1828, 1309-1576, 1309-1960, 1311-1815, 1311-1909, 1315-1585, 1317-1557, 1317-1608, 1318-1559, 1318-1595, 1320-1882, 1322-1582, 1324- 1600, 1325-1607, 1328-1587, 1328-1621, 1328-1773, 1330-1770, 1335-1822, 1337-1596, 1341-1570, 1341-1587, 1354-1819, 1355-1813, 1356-1604, 1360-1596, 1362-1647, 1363-1528, 1364-1821, 1365-1620, 1365-1819, 1367-1811, 1368-1825, 1368- 1828, 1371-1819, 1373-1607, 1373-1821, 1375-1605, 1375-1647, 1375-1649, 1375-1654, 1375-1816, 1375-1820, 1380-1617, 1380-1688, 1380-1820, 1381-1631, 1382-1795, 1382-1820, 1383-1813, 1386-1635, 1386-1816, 1388-1638, 1389-1657, 1389-1951, 1390-1656, 1390- 1676, 1392-1827, 1392-1866, 1397-1815, 1398-1819, 1399-1817, 1400-1599, 1400-1676, 1406-1819, 1409-1656, 1411-1562, 1411-1672, 1413-1815, 1414-1665, 1414-1669, 1417-1813, 1418-1708, 1418-1806, 1419-1896, 1428-1696, 1432-1708, 1432-1755, 1433-1762, 1433- 1821, 1434-1820, 1436-1682, 1436-1820, 1438-1670, 1440-1820, 1441-1566, 1441-1752, 1441-1820, 1442-1819, 1444-1749, 1444-1803, 1445-1710, 1445-1747, 1446-1745, 1446-1812, 1451-1730, 1451-1883, 1457-1677, 1458-1820, 1462-1725, 1462-1820, 1465-1820, 1468- 1813, 1468-1816, 1469-1789, 1471-1697, 1471-1739, 1471-1816, 1484-1759, 1484-1764, 1485-1780, 1485-1801, 1487-1730, 1494-1748, 1495-1750, 1498-1639, 1498-1756, 1502-1813, 1505-1748, 1514-1872, 1517-1793, 1518-1806, 1518-1820, 1521-1758, 1523- 1792, 1524-1816, 1525-1782, 1525-1788, 1525-1814, 1526-1678, 1526-1784, 1526-1805, 1527-1759, 1527-1780, 1527-1797, 1527-1811, 1528-1777, 1528-1778, 1528-1807, 1532-1784, 1535-1777, 1538-1970, 1544-1799, 1549-1780, 1551-1839, 1552-1798, 1554-1831, 1566- 1831, 1566-1861, 1567-1824, 1569-1862, 1573-1849, 1575-1822, 1575-1832, 1575-1896, 1583-1828, 1584-1845, 1588-1815, 1593-1820, 1596-1820, 1598-1848, 1603-1857, 1605-1816, 1607-1717, 1611-1838, 1614-1856, 1614-1890, 1616-1814, 1616-1830, 1616-1851, 1616- 1903, 1621-1828, 1625-1827, 1625-1908, 1629-1878, 1631-1899, 1633-1893, 1636-1819, 1637-1870, 1639-1820, 1640-1884, 1641-1849, 1641-1850, 1645-1848, 1653-1924, 1655-1871, 1655-1907, 1664-1936, 1667-1907, 1669-1909, 1669-1930, 1672-1904, 1673-1938, 1680- 1906, 1683-1897, 1691-1932, 1693-1813, 1698-1979, 1698-1980, 1699-1905, 1700-1864, 1702-1883, 1737-1921, 1739-1916, 1744-1896 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 89/7504798CB1/1 525, 21-653, 21-662 89/7504798CB1/1-525, 21-653, 21-662, 22-495, 23-656, 32-285, 33-277, 33-676, 33-2354, 34-285, 35-319, 35-323, 36-330, 37-335, 40-170, 40-277, 40-550, 2354 48-283, 50-323, 136-212, 168-323, 170-408, 197-827, 200-841, 318-464, 319-595, 366-627, 431-651, 452-804, 457-1074, 513-593, 513- 642, 513-680, 588-807, 675-952, 675-993, 703-1283, 710-976, 713-1287, 726-1155, 782-1297, 783-1289, 783-1318, 792-1100, 793-1207, 796-1310, 819-1350, 822-1019, 825-1471, 832-993, 841-1448, 847-1104, 854-1296, 866-1229, 881-1206, 882-1535, 893-1391, 897-1139, 923-1133, 941-1274, 972-1354, 979-1159, 980-1551, 986-1436, 1006-1633, 1011-1289, 1023-1266, 1031-1278, 1031-1303, 1031-1507, 1036-1273, 1050-1663, 1075-1500, 1084-1493, 1086-1294, 1104-1383, 1118-1953, 1129-1681, 1136-1546, 1137-1385, 1143-1579, 1150- 1426, 1152-1437, 1152-1596, 1156-1561, 1176-1425, 1180-1498, 1187-1427, 1191-1802, 1200-1958, 1206-1486, 1212-1510, 1213-1653, 1218-1493, 1222-1460, 1224-1809, 1225-1696, 1225-1822, 1233-1491, 1254-1521, 1254-1532, 1255-1823, 1257-1538, 1276-1573, 1277-1549, 1279-1375, 1279-1501, 1281-1689, 1282-1851, 1283-1595, 1284-1420, 1288-1853, 1300-1725, 1304-1515, 1306- 1880, 1310-1562, 1323-1754, 1330-1396, 1330-1421, 1331-1760, 1331-1763, 1343-1565, 1350-1910, 1350-1961, 1355-1769, 1364-1599, 1368-1491, 1371-1602, 1374-1983, 1378-1599, 1381-1520, 1381-2088, 1383-1570, 1383-1637, 1396-1559, 1398-1693, 1400-1816, 1415- 1829, 1424-1998, 1425-1681, 1428-1671, 1435-1692, 1444-1731, 1447-1875, 1448-1725, 1448-2041, 1462-1707, 1464-1906, 1469-1778, 1469-1914, 1483-1746, 1497-1742, 1502-1917, 1502-2301, 1509-1939, 1514-1954, 1519-2136, 1520-1805, 1531-1753, 1531-1979, 1541- 1841, 1549-1986, 1553-1892, 1555-1806, 1568-1820, 1582-1823, 1582-1828, 1587-1868, 1590-2162, 1596-1875, 1609-1867, 1613-1890, 1614-1901, 1621-1995, 1636-2341, 1638-1822, 1641-1908, 1644-2327, 1650-2087, 1651-1909, 1655-2306, 1668-1989, 1712-1901, 1712- 1913, 1716-1896, 1716-2019, 1721-1981, 1722-2139, 1730-2009, 1730-2030, 1730-2243, 1736-1984, 1747-2349, 1776-2032, 1781-2354, 1782-2339, 1792-2089, 1803-2070, 1803-2110, 1805-2258, 1807-2318, 1808-2056, 1808-2257, 1816-2330, 1820-2349, 1839- 2077, 1840-2354, 1841-2354, 1849-2347, 1850-2058, 1855-2080, 1859-2353, 1860-2354, 1865-2303, 1865-2354, 1868-2283, 1879-2354, 1889-2354, 1890-2304, 1898-2148, 1901-2349, 1902-2354, 1903-2166, 1904-2354, 1905-2098, 1908-2354, 1911-2184, 1912-2349, 1921- 2349, 1925-2277, 1928-2347, 1931-2134, 1949-2224, 1950-2170, 1959-2349, 1971-2088, 1974-2246, 1978-2349, 1981-2353, 1986-2354, 1991-2354, 1996-2351, 2019-2353, 2023-2150, 2024-2349, 2027-2307, 2037-2163, 2061-2349, 2064-2331, 2103-2329, 2108-2354, 2133- 2349, 2139-2349, 2151-2311, 2151-2335, 2151-2349, 2151-2354, 2152-2330, 2152-2354, 2172-2354, 2176-2257, 2219-2351, 2229-2349, 2275-2349 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length Length 90/7504800CB1/1-525, 21-653, 21-662, 22-495, 23-656, 32-285, 33-277, 33-701, 33-2348, 34-285, 35-319, 35-323, 36-330, 36-892, 37-335, 40-170, 40-277, 2348 40-550, 48-283, 50-323, 136-212, 168-323, 170-408, 241-753, 306-907, 318-464, 319-595, 366-627, 379-965, 390-974, 431-651, 513-593, 513-642, 513-680, 513-794, 513-889, 513-892, 513-908, 513-1004, 513-1264, 590-1152, 606-716, 638-906, 643-1131, 651-1263, 654- 1089, 670-829, 670-1307, 681-1093, 711-944, 717-1389, 724-852, 769-1048, 799-1379, 806-1072, 809-1383, 822-1251, 878-1393, 879- 1385, 879-1414, 888-1196, 889-1303, 892-1406, 915-1446, 918-1115, 921-1567, 928-1089, 937-1544, 943-1200, 950-1392, 962-1325, 977- 1302, 978-1631, 989-1487, 993-1235, 1019-1229, 1037-1370, 1068-1450, 1075-1255, 1076-1647, 1082-1532, 1102-1710, 1107-1385, 1119- 1363, 1127-1374, 1127-1399, 1127-1603, 1132-1369, 1162-1783, 1171-1596, 1180-1589, 1182-1390, 1182-1811, 1200-1479, 1232-1642, 1233-1481, 1239-1675, 1242-1783, 1246-1522, 1248-1533, 1248-1692, 1252-1657, 1272-1521, 1276-1594, 1283-1523, 1302-1582, 1308-1606, 1309-1710, 1314-1589, 1318-1556, 1321-1909, 1329-1587, 1350-1617, 1350-1628, 1353-1634, 1363- 1863, 1372-1669, 1373-1645, 1375-1471, 1375-1597, 1379-1691, 1380-1516, 1380-1804, 1400-1611, 1406-1658, 1426-1492, 1426-1517, 1439-1661, 1460-1695, 1464-1587, 1467-1698, 1474-1695, 1477-1616, 1479-1666, 1479-1710, 1492-1655, 1651-1801, 1664-1940, 1702- 2013, 1710-1890, 1710-1895, 1710-1902, 1710-1907, 1710-2081, 1710-2300, 1715-1975, 1716-2133, 1724-2003, 1724-2024, 1724-2237, 1730-1978, 1741-2343, 1770-2026, 1775-2348, 1776-2333, 1786-2083, 1797-2064, 1797-2104, 1799-2252, 1801-2312, 1802-2050, 1802- 2251, 1810-2324, 1814-2343, 1833-2071, 1834-2348, 1835-2348, 1843-2341, 1844-2052, 1849-2074, 1853-2347, 1854-2348, 1859-2297, 1859-2348, 1862-2277, 1873-2348, 1883-2348, 1884-2298, 1892-2142, 1895-2343, 1896-2348, 1897-2160, 1898-2348, 1899-2092, 1902- 2348, 1905-2178, 1906-2343, 1915-2343, 1919-2271, 1922-2341, 1925-2128, 1943-2218, 1944-2164, 1953-2343, 1965-2082, 1968-2240, 1972-2343, 1975-2347, 1980-2348, 1985-2348, 1990-2345, 2013-2347, 2017-2144, 2018-2343, 2021-2301, 2031-2157, 2055- 2343, 2058-2325, 2097-2323, 2102-2348, 2127-2343, 2133-2343, 2145-2305, 2145-2329, 2145-2343, 2145-2348, 2146-2324, 2146-2348, 2166-2348, 2170-2251, 2213-2345, 2223-2343, 2269-2343 91/7504902CB1/1-238, 1-282, 1-286, 1-530, 1-591, 1-2448, 22-451, 54-629, 76-361, 85-587, 161-795, 233-638, 237-738, 298-579, 300-625, 301-860, 304- 2918 570, 305-1007, 306-440, 306-560, 306-911, 316-832, 318-595, 318-810, 318-869, 320-491, 323-810, 324-585, 326-443, 338-926, 346-961, 346-1060, 358-492, 358-602, 358-617, 358-648, 377-875, 379-697, 406-610, 406-1079, 410-714, 423-909, 428-921, 454-715, 463-570, 510- 1195, 569-1106, 570-1100, 570-1144, 572-803, 572-816, 588-780, 588-1098, 590-1410, 599-1186, 599-1190, 606-1180, 614-1012, 616- 1314, 627-1257, 632-932, 637-745, 638-1318, 648-1217, 660-909, 661-1248, 663-1037, 680-1169, 709-948, 711-972, 711-992, 711-1206, 720-1336, 721-983, 722-970, 740-1237, 749-991, 749-999, 752-1027, 765-1370, 766-1299, 766-1334, 799-1432, 814-918, 824-1301, 825- 1441, 834-1397, 835-1317, 842-1117, 844-1085, 845-1319, 847-1141, 848-1509, 856-1517, 858-1042, 860-1558, 878-1097, 883-1429, 884- 1448, 891-1527, 897-1598, 921-1179, 924-1234, 957-1582, 958-1106, 987-1499, 1006-1216, 1025-1672, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 1030-1407, 1032-1676, 1039-1488, 1054-1672, 1065-1711, 1076-1612, 1079-1520, 1080-1366, 1082-1344, 1088-1267, 1100-1600, 1109- 1286, 1112-1592, 1124-1430, 1124-1645, 1125-1689, 1129-1596, 1129-1707, 1146-1401, 1146-1423, 1174-1838, 1177-1433, 1181-1830, 1185-1853, 1187-1416, 1191-1672, 1195-1487, 1200-1469, 1200-1852, 1205-1839, 1210-1839, 1211-1490, 1213-1467, 1236-1534, 1240- 1484, 1243-1761, 1246-1529, 1257-1516, 1257-1739, 1263-1547, 1276-1399, 1285-1843, 1295-1427, 1296-1555, 1296-1583, 1314-1487, 1337-1830, 1341-1851, 1349-1783, 1355-1609, 1367-1822, 1386-1618, 1389-1645, 1390-1853, 1411-1633, 1411-1696, 1421-1622, 1423- 1672, 1448-1723, 1450-1688, 1472-1853, 1479-1824, 1488-1746, 1495-1757, 1496-1766, 1512-1948, 1512-2026, 1522-1826, 1538-1786, 1538-1831, 1555-1783, 1567-1701, 1570-1841, 1573-1840, 1582-1821, 1582-1853, 1584-1852, 1587-1853, 1599-1853, 1601-1853, 1816- 2109, 1851-1988, 1851-2065, 1851-2078, 1851-2091, 1851-2092, 1851-2101, 1851-2122, 1851-2370, 1851-2388, 1851-2420, 1851-2429, 1851-2431, 1854-2122, 1855-2428, 1856-2417, 1857-2139, 1860-2166, 1862-2420, 1865-2397, 1867-2114, 1871-2431, 1872- 2431, 1872-2453, 1875-2318, 1875-2429, 1877-2423, 1882-2455, 1887-2169, 1889-2323, 1899-2431, 1908-2420, 1910-2431, 1923-2431, 1927-2455, 1929-2191, 1939-2176, 1939-2430, 1939-2451, 1948-2431, 1951-2428, 1952-2207, 1952-2452, 1958-2431, 1961-2146, 1962- 2428, 1963-2429, 1963-2431, 1964-2224, 1969-2428, 1971-2232, 1971-2431, 1974-2429, 1975-2430, 1978-2224, 1978-2228, 1978-2427, 1978-2431, 1979-2312, 1979-2431, 1983-2226, 1985-2277, 1985-2420, 1985-2431, 1988-2273, 1988-2430, 1990-2431, 1992-2351, 1992- 2430, 1994-2431, 1997-2431, 1998-2430, 1998-2431, 2010-2430, 2013-2453, 2013-2454, 2018-2406, 2018-2429, 2020-2431, 2020-2438, 2021-2431, 2023-2431, 2027-2431, 2028-2430, 2030-2264, 2030-2429, 2036-2429, 2038-2431, 2041-2438, 2044-2251, 2044-2431, 2045- 2437, 2051-2429, 2053-2429, 2055-2435, 2057-2429, 2065-2314, 2072-2431, 2078-2384, 2080-2430, 2084-2427, 2090-2456, 2097-2429, 2099-2347, 2102-2393, 2103-2340, 2103-2416, 2103-2424, 2105-2429, 2115-2346, 2123-2437, 2124-2429, 2125-2272, 2126- 2429, 2131-2452, 2134-2428, 2136-2431, 2139-2406, 2144-2373, 2148-2431, 2155-2431, 2161-2437, 2162-2430, 2162-2507, 2165-2430, 2166-2430, 2168-2431, 2169-2429, 2180-2431, 2190-2463, 2191-2450, 2195-2430, 2200-2423, 2204-2436, 2214-2431, 2214-2532, 2214- 2918, 2215-2451, 2216-2429, 2217-2460, 2227-2431, 2234-2437, 2234-2452, 2247-2416, 2247-2431, 2249-2452, 2257-2503, 2262-2429, 2262-2460, 2262-2482, 2263-2430, 2264-2481, 2285-2431, 2307-2431, 2310-2431, 2352-2435 92/7510792CB1/1-2299, 196-758, 983-1488, 983-1494, 996-1240, 1183-1708, 1206-1893, 1303-1556, 1303-1758, 1364-2285, 1371-2285, 1376-1758, 1376- 2299 1839, 1413-2285, 1414-2285, 1416-2283, 1416-2285, 1417-2285, 1431-2285, 1433-2285, 1482-2285, 1491-2278, 1518-2285, 1520-1798, 1521-1777, 1551-2285, 1553-2285, 1708-2201, 1708-2280, 1709-2283, 1712-2299, 1715-2272, 1716-2003, 1716-2026, 1716-2131, 1716- 2187, 1716-2233, 1716-2243, 1717-2274, 1728-2268, 1742-2271, 1747-2299, 1786-2243, 1876-2231, 1887-2146, 1961-2241, 1973-2288 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 93/7510557CB1/1-688, 3-569, 13-150, 13-275, 13-279, 13-281, 13-758, 13-3741, 15-661, 16-236, 18-266, 19-247, 19-578, 22-312, 32-661, 33-143, 33-300, 3798 33-482, 33-532, 33-587, 34-288, 34-602, 39-275, 39-520, 42-683, 48-435, 53-647, 53-661, 55-296, 55-330, 77-320, 77-370, 103-746, 112- 597, 112-675, 112-704, 112-723, 112-728, 168-363, 201-685, 332-488, 416-533, 501-1105, 556-748, 710-1316, 930-1182, 954-1664, 973- 1470, 1060-1679, 1073-1329, 1081-1616, 1085-1326, 1089-1289, 1104-1325, 1104-1332, 1121-1742, 1142-1422, 1157-1417, 1162-1677, 1175-1802, 1248-1523, 1293-2043, 1309-2044, 1313-1474, 1341-1754, 1352-1975, 1363-2320, 1379-1925, 1410-1535, 1435-1644, 1492- 1588, 1568-1764, 1589-1834, 1603-1721, 1618-2138, 1638-1922, 1638-2063, 1640-1880, 1640-2297, 1646-2200, 1654-1912, 1667-2144, 1708-2084, 1722-1922, 1725-2042, 1732-2341, 1743-2024, 1755-2418, 1782-2347, 1784-2328, 1789-2605, 1806-2407, 1814-1968, 1824- 2271, 1852-2350, 1876-2137, 1877-2210, 1883-2146, 1886-2144, 1899-2176, 1903-2184, 1907-2164, 1909-2232, 1909-2242, 1910-2485, 1915-2210, 1922-2197, 1939-2180, 1946-2406, 1949-2321, 1949-2497, 1953-2216, 1977-2551, 1977-2590, 1988- 2257, 1992-2269, 2002-2282, 2008-2412, 2010-2300, 2019-2328, 2020-2298, 2031-2289, 2045-2379, 2053-2301, 2088-2380, 2088-2395, 2108-2658, 2126-2569, 2128-2291, 2128-2623, 2133-2549, 2147-2425, 2172-2489, 2172-2503, 2178-2882, 2191-2390, 2222-2494, 2237- 2443, 2237-2464, 2261-2549, 2265-2514, 2265-2528, 2265-2585, 2265-2699, 2265-2741, 2267-2453, 2269-2402, 2269-2513, 2269-2551, 2273-2473, 2296-2600, 2326-2630, 2329-2582, 2343-2615, 2343-2621, 2343-2845, 2344-2549, 2345-2601, 2345-2615, 2346-2912, 2347- 2555, 2347-2705, 2368-2852, 2382-2997, 2396-2989, 2397-2633, 2416-2645, 2425-2704, 2434-2796, 2440-2696, 2440-2704, 2452-2890, 2455-2676, 2456-2687, 2456-2696, 2467-2703, 2474-2908, 2475-2767, 2482-2693, 2482-2700, 2482-2774, 2484-2766, 2489-2743, 2502- 2746, 2502-2764, 2504-3378, 2505-3123, 2508-2692, 2517-2783, 2530-2822, 2534-2720, 2552-2814, 2556-2780, 2562-2824, 2563-2816, 2564-2850, 2573-2812, 2573-2848, 2573-2885, 2575-2842, 2578-2810, 2579-2841, 2590-2911, 2595-2810, 2600-2856, 2601- 2898, 2609-2832, 2609-2862, 2609-2884, 2630-2894, 2631-2845, 2631-2908, 2632-2860, 2632-3079, 2653-2921, 2653-3192, 2655-3241, 2676-2963, 2688-2909, 2690-2942, 2692-3134, 2694-2950, 2697-3144, 2697-3146, 2704-3261, 2706-2933, 2719-3425, 2721-3006, 2724- 3000, 2727-3007, 2733-2965, 2738-3389, 2750-3148, 2752-2995, 2752-3065, 2757-3131, 2758-3244, 2768-3010, 2768-3036, 2769-2999, 2786-3009, 2786-3014, 2788-2998, 2789-3204, 2799-3008, 2808-3412, 2809-3107, 2816-3013, 2826-3078, 2841-3048, 2844-3066, 2844- 3070, 2844-3409, 2847-3084, 2852-3054, 2852-3056, 2858-3401, 2874-3159, 2894-3489, 2902-3187, 2905-3133, 2912-3168, 2912-3205, 2912-3504, 2913-3144, 2917-3159, 2917-3177, 2921-3385, 2923-3169, 2929-3313, 2941-3146, 2947-3410, 2951-3242, 2965-3190, 2970- 3175, 2971-3212, 2977-3242, 2977-3257, 2977-3466, 2990-3266, 2995-3262, 2999-3449, 3001-3241, 3005-3249, 3015-3266, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 3015-3275, 3019-3348, 3020-3350, 3028-3282, 3035-3212, 3053-3349, 3056-3318, 3065-3331, 3072-3310, 3072-3322, 3075-3329, 3077- 3274, 3081-3190, 3081-3500, 3082-3369, 3084-3373, 3088-3375, 3094-3360, 3097-3456, 3100-3360, 3102-3343, 3105-3377, 3122-3357, 3122-3377, 3129-3408, 3130-3346, 3130-3373, 3130-3404, 3169-3339, 3186-3459, 3190-3420, 3196-3454, 3197-3444, 3202-3448, 3202- 3454, 3238-3427, 3271-3457, 3351-3622, 3351-3681, 3351-3726, 3366-3500, 3515-3726, 3529-3730, 3588-3715, 3609-3715, 3641-3726, 3661-3798 94/7510649CB1/1-244, 1-1754, 140-257, 140-393, 140-649, 151-531, 242-474, 284-878, 374-1026, 464-954, 496-1184, 557-801, 573-1200, 596-989, 633- 1764 848, 638-902, 646-1198, 663-1247, 723-1408, 772-1332, 822-1256, 854-1049, 863-1074, 910-1305, 924-1121, 953-1164, 990-1445, 1047- 1764, 1065-1582, 1073-1303, 1073-1469, 1079-1764, 1080-1764, 1089-1722, 1095-1654, 1095-1764, 1100-1764, 1105-1763, 1117-1361, 1151-1405, 1168-1435, 1168-1458, 1224-1688, 1254-1753, 1268-1511, 1274-1754, 1283-1527, 1284-1507, 1284-1721, 1284-1751, 1300- 1522, 1304-1610, 1340-1549, 1357-1593, 1362-1600, 1362-1754, 1373-1623, 1385-1754, 1408-1764, 1419-1549, 1601-1754, 1653-1764, 1665-1764 95/7510264CB1/1-599, 1-5243, 30-412, 30-500, 73-373, 73-454, 73-516, 73-623, 75-453, 92-620, 180-910, 267-903, 267-971, 267-976, 267-991, 267-992, 5293 282-992, 283-992, 287-1064, 366-992, 511-992, 697-1298, 697-1343, 755-1383, 808-1273, 915-1273, 972-1273, 1017-1441, 1399-2079, 1420-1858, 1420-2001, 1447-2079, 1492-2032, 1524-2083, 1562-2079, 1592-2238, 1592-2258, 1641-2241, 1671-2184, 1757-1981, 1757- 2102, 1774-2317, 1924-2712, 1978-2650, 2066-2743, 2072-2743, 2124-2743, 2134-2650, 2189-2280, 2250-2611, 2268-2611, 2292-2857, 2459-2753, 2479-3017, 2479-3031, 2583-3395, 2586-3474, 2635-3117, 2635-3297, 2636-2990, 2638-3173, 2663-3173, 2730-3372, 2733- 2990, 2908-3139, 2961-3513, 2990-3633, 3025-3636, 3129-3645, 3167-3603, 3171-3664, 3176-3468, 3264-3943, 3271-4031, 3341-3643, 3341-3791, 3343-3523, 3366-3665, 3446-4009, 3498-3983, 3508-4080, 3508-4127, 3599-4302, 3657-4127, 3719-4384, 3860-4102, 3906- 4549, 4082-4608, 4168-4446, 4240-4538, 4268-4728, 4268-4795, 4294-4796, 4309-4869, 4341-4601, 4358-4625, 4384-4795, 4385-4604, 4420-4663, 4449-4593, 4449-4794, 4449-5002, 4472-4991, 4484-4804, 4504-5125, 4504-5230, 4552-5293, 4563- 4785, 4563-5066, 4568-5064, 4610-4885, 4666-5293, 4683-4934, 4737-5077, 4746-5036, 4764-5280, 4835-5053, 4835-5066, 4884-5185, 4905-5030, 5272-5293 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 96/7506464CB1/1-230, 1-248, 1-255, 1-273, 1-389, 1-405, 1-429, 1-497, 1-506, 3-223, 3-498, 3-1711, 9-265, 11-339, 14-283, 14-295, 14-499, 22-318, 24- 1895 258, 24-281, 24-289, 24-292, 24-297, 24-318, 24-365, 24-469, 24-493, 26-241, 26-302, 26-307, 26-500, 27-241, 28-310, 28-319, 29-242, 29- 292, 34-291, 43-255, 43-315, 43-336, 44-313, 45-341, 46-290, 46-361, 46-506, 48-376, 49-304, 49-327, 50-188, 50-235, 50-294, 50-300, 50- 307, 50-313, 50-318, 50-320, 50-339, 50-344, 50-382, 50-472, 51-253, 51-309, 52-295, 52-317, 54-284, 54-301, 55-279, 56-313, 56-319, 56- 321, 57-319, 58-489, 59-306, 62-310, 62-368, 64-249, 64-281, 64-288, 64-313, 64-314, 64-318, 64-334, 64-336, 64-340, 64-355, 65-309, 65- 327, 66-302, 66-341, 66-500, 67-249, 67-276, 72-320, 74-424, 75-361, 75-422, 76-215, 78-328, 78-331, 79-307, 82-323, 86-457, 87-317, 87- 500, 89-325, 89-326, 89-344, 90-298, 91-264, 91-344, 94-304, 97-305, 98-361, 98-409, 111-393, 113-363, 113-438, 115-705, 115-763, 131- 395, 145-407, 152-386, 152-447, 163-399, 183-461, 206-486, 223-486, 225-506, 233-375, 233-487, 248-471, 248-497, 248-500, 250-434, 279-469, 292-506, 363-506, 495-1337, 501-752, 505-1103, 510-1182, 521-1299, 523-777, 536-1222, 537-832, 548-979, 558-771, 558-1120, 562-1143, 574-1113, 581-1299, 585-855, 585-1148, 586-812, 589-776, 595-839, 595- 1177, 595-1222, 615-1344, 618-869, 618-1047, 628-1299, 633-869, 633-916, 633-1267, 633-1298, 634-924, 634-965, 638-924, 638-1300, 640-936, 645-1161, 645-1182, 674-904, 674-1007, 676-960, 676-1377, 691-965, 692-1222, 693-930, 693-1169, 695-1333, 697-1186, 699- 902, 708-954, 708-1175, 710-992, 712-919, 712-920, 712-928, 712-980, 714-953, 722-954, 725-947, 729-1008, 731-1299, 736-1222, 744- 1004, 744-1041, 744-1332, 750-992, 750-1342, 752-1249, 753-980, 753-1433, 753-1476, 754-1287, 759-1003, 765-1427, 765-1466, 771- 1028, 774-977, 774-979, 776-991, 780-1279, 785-940, 785-1402, 788-1082, 788-1319, 789-1305, 789-1429, 793-1058, 795-1421, 798- 1128, 800-1362, 804-1054, 806-1664, 816-1476, 826-1001, 827-1131, 827-1473, 828-1476, 834-1057, 853-1367, 854-1131, 855-1338, 856-1106, 859-1140, 860-1131, 861-1114, 862-1034, 862-1417, 866-1123, 893-1333, 896-1141, 898-1143, 898-1179, 920-1152, 925-1403, 927-1652, 928-1457, 931-1155, 940-1245, 958-1515, 963-1463, 968-1470, 969-1256, 971-1476, 980-1103, 980-1160, 981-1160, 981-1462, 984-1642, 990-1287, 992-1464, 994-1174, 1000-1650, 1004-1270, 1009-1455, 1025-1588, 1027-1165, 1037-1160, 1039-1251, 1039-1327, 1039-1337, 1040-1204, 1042-1629, 1050-1543, 1054-1160, 1056-1291, 1056-1502, 1058-1707, 1065-1308, 1066- 1284, 1066-1318, 1066-1321, 1066-1328, 1066-1368, 1069-1347, 1069-1667, 1073-1174, 1073-1361, 1073-1693, 1074-1292, 1075-1337, 1075-1690, 1076-1359, 1079-1331, 1079-1343, 1080-1290, 1080-1292, 1080-1312, 1093-1231, 1100-1551, 1100-1591, 1100-1688, 1100- 1715, 1105-1344, 1113-1388, 1113-1394, 1118-1376, 1125-1693, 1166-1628, 1175-1207, 1175-1227, 1176-1208, 1176-1218, 1176-1220, 1176-1227, 1177-1220, 1177-1227, 1181-1218, 1181-1227, 1184-1227, 1197-1227, 1210-1645, 1213-1548, 1224-1895, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 1228-1538, 1228-1715, 1229-1716, 1230-1697, 1232-1716, 1235-1672, 1252-1716, 1255-1633, 1273-1566, 1276-1692, 1288-1716, 1311- 1364, 1312-1354, 1312-1357, 1312-1364, 1313-1357, 1317-1364, 1317-1543, 1317-1561, 1320-1552, 1321-1357, 1333-1357, 1333-1568, 1333-1625, 1333-1716, 1333-1717, 1333-1762, 1335-1581, 1335-1692, 1335-1715, 1342-1621, 1348-1647, 1363-1701, 1363-1716, 1364- 1561, 1370-1602, 1374-1597, 1381-1629, 1398-1624, 1398-1634, 1398-1646, 1398-1658, 1413-1713, 1413-1717, 1418-1716, 1425-1676, 1425-1682, 1432-1627, 1432-1715, 1432-1785, 1436-1676, 1436-1713, 1449-1716, 1452-1669, 1452-1701, 1465-1701, 1468-1701, 1472- 1663, 1472-1695, 1476-1707, 1479-1699, 1479-1701, 1481-1669, 1481-1683, 1481-1701, 1481-1705, 1481-1708, 1484-1661, 1484-1663, 1484-1683, 1484-1699, 1484-1700, 1484-1701, 1484-1702, 1484-1703, 1484-1704, 1484-1706, 1484-1708, 1489-1701, 1489-1716, 1494- 1688, 1494-1701, 1494-1704, 1494-1713, 1494-1716, 1502-1701, 1520-1699, 1530-1716, 1532-1716, 1539-1700, 1541-1717, 1566-1716, 1567-1703, 1568-1716, 1585-1716, 1591-1716, 1611-1714 97/7510101CB 1/964 1-234, 1-255, 1-436, 1-487, 1-502, 1-512, 1-516, 1-560, 1-629, 2-904, 13-655, 63-668, 103-841, 104-841, 105-841, 112-364, 119-361, 120- 342, 128-366, 181-433, 182-464, 190-475, 190-580, 190-778, 190-794, 203-420, 203-529, 204-512, 209-469, 228-344, 228-444, 251-426, 251-480, 255-497, 266-702, 284-392, 301-414, 322-631, 326-588, 330-785, 340-892, 351-876, 354-823, 365-604, 383-842, 385-855, 423- 928, 427-910, 433-893, 434-889, 435-706, 435-889, 438-665, 449-841, 450-894, 451-893, 459-584, 460-855, 461-757, 464-646, 464-889, 469-893, 472-641, 477-893, 482-913, 485-715, 487-737, 489-912, 498-880, 498-909, 515-758, 515-769, 521-892, 521-897, 531-889, 534- 773, 538-781, 539-737, 539-887, 548-889, 551-892, 558-895, 560-895, 569-893, 571-895, 579-890, 581-678, 582-893, 583-895, 590-820, 592-809, 592-893, 611-889, 611-894, 650-891, 676-922, 687-917, 705-908, 708-908, 719-895, 719-911, 731-858, 779-964 98/7510845CB1/1-126, 1-151, 1-154, 3-1069, 9-154, 9-244, 10-124, 10-154, 13-140, 24-154, 27-123, 30-136, 153-363, 153-387, 153-423, 153-542, 153-625, 1132 157-404, 157-410, 157-863, 164-236, 164-373, 168-377, 184-414, 184-445, 184-712, 184-766, 184-805, 190-444, 190-488, 191-830, 195- 463, 195-473, 200-567, 204-492, 206-447, 225-469, 225-478, 229-503, 232-444, 232-516, 233-525, 237-842, 243-522, 250-488, 261-466, 262-637, 265-521, 268-531, 272-524, 272-557, 283-569, 285-711, 287-520, 288-551, 288-553, 289-562, 305-513, 305-563, 317-588, 321- 578, 322-619, 322-906, 323-578, 323-589, 328-575, 328-606, 328-732, 330-549, 332-555, 334-777, 337-1049, 339-574, 344-882, 349-775, 350-620, 350-627, 351-777, 353-638, 355-639, 357-632, 364-571, 364-620, 367-776, 370-673, 380-645, 382-627, 384-1024, 391-682, 392- 768, 392-974, 393-522, 393-682, 394-673, 394-707, 398-719, 408-738, 411-711, 413-664, 413-675, 429-601, 429-634, 429-668, 438-706, 439-727, 451-751, 452-717, 453-601, 454-576, 454-733, 455-1012, 460-1036, 473-747, 473-1071, 478-1068, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 479-741, 479-756, 497-1010, 520-786, 525-703, 531-788, 533-716, 533-804, 533-1065, 534-1069, 537-775, 537-887, 559-830, 560-765, 562-830, 565-751, 565-797, 565-840, 565-846, 570-785, 570-823, 570-1073, 578-1093, 583-842, 583-855, 583-1074, 586-849, 597-832, 598-1045, 599-1056, 605-1049, 606-854, 611-1055, 616-835, 618-1043, 620-875, 622-873, 622-1049, 623-1055, 624-992, 627-1006, 630- 1040, 631-906, 631-907, 634-1016, 634-1051, 636-1063, 639-1053, 640-951, 640-1057, 642-1049, 642-1086, 645-1043, 645-1046, 648- 876, 654-950, 655-887, 655-953, 659-862, 666-921, 667-1055, 672-1052, 673-932, 676-923, 677-923, 677-924, 682-1057, 683-975, 691- 1051, 692-843, 692-879, 693-1055, 693-1061, 694-1038, 701-963, 703-1053, 704-1052, 709-939, 710-1046, 713-1047, 713-1053, 715-957, 715-1073, 716-1073, 717-1053, 719-945, 724-1046, 727-1047, 735-1051, 736-1027, 736-1046, 737-1014, 738-930, 738-940, 742-997, 744- 927, 744-968, 745-1055, 748-1021, 750-1060, 753-1049, 761-1026, 766-1049, 768-1051, 770-1005, 774-950, 783-1033, 785-1013, 799-1049, 816-1055, 831-1069, 834-1049, 840-1045, 840-1051, 842-1065, 845-1057, 856-1039, 869-981, 870-1022, 872-1129, 881-1049, 881-1057, 946-1132, 974-1066, 974-1079, 996-1051 99/7510846CB1/1-296, 1-440, 4-1055, 20-304, 21-309, 57-304, 153-402, 200-396, 272-456, 272-463, 511-721, 511-747, 511-802, 511-883, 512-744, 512- 1130 771, 517-869, 520-743, 522-709, 522-712, 522-748, 522-751, 522-760, 522-761, 522-782, 522-783, 522-787, 522-788, 522-789, 522-796, 522-801, 522-808, 522-817, 522-860, 522-883, 523-700, 523-752, 523-797, 523-815, 523-824, 523-847, 524-742, 524-748, 524-775, 524- 782, 524-785, 524-791, 524-798, 524-802, 524-834, 524-883, 525-744, 525-761, 526-729, 526-768, 526-773, 526-777, 526-784, 526-793, 527-854, 528-747, 528-792, 528-824, 529-755, 529-790, 529-817, 529-825, 529-841, 529-844, 529-883, 530-778, 531-703, 531-713, 531- 715, 531-717, 531-719, 531-728, 531-734, 531-736, 531-743, 531-749, 531-755, 531-758, 531-759, 531-760, 531-762, 531-764, 531-767, 531-770, 531-776, 531-778, 531-779, 531-780, 531-781, 531-783, 531-785, 531-793, 531-794, 531-795, 531-796, 531-797, 531-802, 531- 804, 531-807, 531-808, 531-811, 531-813, 531-815, 531-817, 531-819, 531-822, 531-824, 531-829, 531-830, 531-833, 531-845, 531-855, 531-856, 531-865, 531-867, 532-765, 532-785, 532-791, 532-792, 532-798, 532-871, 533-789, 533-815, 533- 820, 533-847, 534-689, 534-755, 534-759, 534-769, 534-783, 534-788, 534-791, 534-799, 534-817, 535-747, 535-748, 535-774, 535-786, 535-789, 535-790, 535-811, 535-818, 535-836, 536-662, 536-766, 536-791, 536-824, 536-827, 536-829, 536-832, 536-835, 536-851, 537- 781, 537-804, 537-821, 539-778, 539-808, 539-809, 539-830, 539-857, 541-756, 541-777, 541-781, 541-798, 541-802, 542-713, 543-715, 543-717, 543-762, 543-773, 543-785, 543-808, 543-813, 543-815, 543-818, 543-824, 544-679, 544-730, 544-746, 544-752, 544-759, 544- 765, 544-789, 544-798, 544-805, 544-820, 544-826, 544-843, 545-669, 545-770, 545-774, 545-792, 545-797, 545-812, 546-780, 546-791, 546-799, 546-806, 546-822, 546-862, 547-883, 549-796, 549-818, 550-732, 551-779, 551-783, 551-785, 551-792, 551-800, 551-802, 551- 808, 551-813, 551-827, 551-830, 551-854, 551-876, 551-883, 552-739, 552-791, 553-785, 553-793, Table 4 Fotynucteotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 553-800, 553-809, 553-817, 553-818, 553-829, 553-833, 553-846, 553-852, 553-883, 554-815, 554-819, 554-847, 555-748, 555-805, 555- 807, 555-836, 555-856, 556-810, 556-831, 558-837, 559-752, 559-778, 559-786, 559-788, 559-807, 559-808, 559-812, 559-813, 559-814, 559-816, 559-817, 559-820, 560-672, 560-769, 560-770, 560-771, 560-788, 560-792, 560-802, 560-824, 560-825, 560-855, 560-856, 560- 860, 560-861, 561-797, 561-831, 561-883, 562-775, 562-825, 563-802, 563-827, 564-822, 564-833, 564-840, 565-814, 565-883, 566-825, 569-773, 569-824, 570-834, 571-782, 571-810, 571-811, 571-820, 571-834, 571-837, 571-842, 571-846, 571-861, 571-872, 572-790, 572- 856, 572-877, 572-880, 572-881, 573-819, 573-861, 574-760, 574-781, 574-830, 574-856, 574-857, 574-861, 574-883, 575-856, 575-875, 575-883, 576-679, 576-828, 576-853, 576-866, 578-760, 578-879, 579-792, 579-817, 579-851, 579-860, 579-883, 580-881, 582-818, 582- 823, 582-835, 582-874, 582-877, 584-848, 584-862, 586-835, 588-805, 590-763, 590-826, 590-883, 592-826, 592-851, 592-853, 599-854, 600-818, 601-802, 602-745, 602-811, 602-817, 602-854, 602-858, 603-835, 604-855, 604-865, 608- 794, 610-883, 611-832, 612-851, 613-850, 614-784, 614-799, 614-846, 614-847, 620-883, 621-883, 623-881, 626-849, 626-883, 628-883, 630-883, 631-821, 631-879, 632-883, 712-883, 739-962, 878-1042, 878-1060, 878-1063, 878-1069, 878-1080, 878-1081, 878-1082, 878- 1083, 886-1064, 889-1016, 891-1065, 891-1068, 896-1049, 896-1055, 913-1067, 925-1064, 926-1078, 935-1104, 935-1122, 940-1084, 947- 1067, 973-1130 100i7510921CB1/1-253, 1-257, 13-235, 13-277, 14-220, 16-282, 18-258, 18-285, 22-289, 23-215, 23-228, 23-246, 23-251, 23-254, 23-259, 23-270, 23-274, 762 23-275, 23-277, 23-280, 23-281, 23-296, 23-300, 23-301, 23-304, 23-307, 23-308, 23-314, 23-324, 23-325, 24-243, 24-252, 24-257, 24-265, 24-276, 24-277, 24-278, 24-281, 24-284, 24-286, 24-288, 24-289, 24-294, 24-298, 24-304, 24-305, 24-306, 24-371, 24-426, 24-447, 24-456, 24-459, 24-477, 24-491, 24-516, 25-297, 26-272, 26-278, 26-297, 26-299, 26-307, 26-318, 26-344, 26-384, 26-447, 26-458, 26-460, 26-469, 26-503, 26-504, 26-506, 26-516, 26-526, 26-527, 27-216, 27-249, 27-258, 27-267, 27-272, 27-278, 27-285, 27-288, 27-301, 27-312, 27-313, 27-314, 27-321, 28-177, 28-289, 28-304, 28-386, 28-397, 29-290, 30-271, 30-319, 31-264, 31-287, 31-302, 31-321, 32-264, 32-281, 33-279, 34-218, 34-278, 34-284, 34-297, 34-317, 35-295, 36-312, 36-409, 37-289, 41-298, 41-302, 41-327, 43-235, 43-321, 43-323, 44-307, 44-327, 45-241, 45-297, 45-350, 46-323, 47-297, 47-320, 53-331, 55-327, 57-292, 57-303, 57-333, 57-334, 57-344, 60-268, 60-270, 62-330, 62-342, 65-330, 67-236, 67-312, 68-289, 68-301, 68-316, 68-321, 69-195, 70-507, 75-282, 78-277, 78-278, 78-280, 78-376, 82-346, 89-352, 91-340, 96-272, 96-315, 113-303, 113-304, 121-411, 127-363, 133-389, 142-426, 142- 430, 148-426, 149-258, 165-446, 181-264, 195-445, 201-423, 210-357, 229-330, 237-372, 267-504, 267-546, 289-397, 310-437, 323-561, 374-646, 415-648, 439-749, 448-751, 480-743, 506-745, 563-762, 582-762, 583-762, 598-762, 602-762, 606-746, 613-762, 636-760, 658- 750 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 101/7505097CB1/1-176, 1-200, 1-230, 1-233, 1-235, 1-242, 1-246, 1-248, 1-255, 1-261, 1-268, 1-273, 1-274, 1-276, 1-278, 1-281, 1-283, 1-285, 1-292, 1-306, 1481 1-307, 1-327, 1-545, 1-702, 2-133, 2-169, 2-183, 2-188, 2-212, 2-215, 2-217, 2-224, 2-232, 2-235, 2-236, 2-237, 2-238, 2-239, 2-240, 2-241, 2-243, 2-244, 2-245, 2-247, 2-250, 2-254, 2-255, 2-256, 2-260, 2-261, 2-262, 2-266, 2-268, 2-271, 2-275, 2-277, 2-281, 2-284, 2-291, 2-293, 2-302, 2-305, 2-310, 2-311, 2-315, 2-319, 2-431, 2-442, 2-465, 2-481, 2-530, 2-577, 2-725, 2-825, 3-113, 3-213, 3-220, 3-228, 3-230, 3-231, 3-232, 3-234, 3-237, 3-239, 3-241, 3-243, 3-245, 3-248, 3-249, 3-251, 3-254, 3-256, 3-258, 3-260, 3-264, 3-265, 3-268, 3-279, 3-283, 3-284, 3-286, 3-287, 3-293, 3-294, 3-297, 3-318, 3-321, 3-438, 3-594, 3-623, 3-656, 3-679, 4-172, 4-228, 4-247, 4-252, 4-261, 4-268, 4-272, 4-286, 4-291, 4-331, 4-475, 4-492, 4-535, 4-595, 4-612, 5-198, 5-241, 5-250, 5-256, 5-262, 5-263, 5-280, 5-295, 5-673, 5-706, 5-724, 5-823, 6-216, 6-238, 6-242, 6-306, 6-502, 6-649, 7-191, 7-219, 7-239, 7-253, 7-254, 7-261, 7-263, 7-268, 7-285, 7-525, 7-576, 7-653, 7-659, 7-821, 8-242, 8-245, 8-264, 8-274, 8-281, 8-288, 8-296, 8-336, 8-388, 8-714, 9-148, 9-251, 9-252, 9-263, 9-265, 9-290, 9-291, 9-304, 9-310, 9-571, 9-634, 9-651, 9-757, 10-206, 10-238, 10-243, 10-252, 10-254, 10-262, 10-299, 10-310, 10-461, 10-532, 10-535, 10-868, 11-255, 11-276, 11-439, 12-300, 12-351, 13-236, 13-255, 13-276, 13-278, 13-432, 13-434, 15-202, 15-510, 15-558, 15-586, 15-620, 16-128, 16-236, 17-241, 18-309, 18-566, 19-371, 19-518, 19-823, 20-569, 20-840, 21-224, 21-233, 21-267, 21-285, 21-304, 22-407, 23-225, 23-255, 23-263, 23-266, 23-272, 23-286, 23-296, 23-580, 23-609, 24-185, 24-191, 24-229, 24-233, 24-240, 24-243, 24-254, 24-255, 24-264, 24-265, 24-266, 24-267, 24-268, 24-269, 24-272, 24-278, 24-284, 24-291, 24-292, 24-294, 24-299, 24-302, 24-314, 24-317, 24-322, 24-324, 24-326, 24-580, 24-615, 24-688, 24-729, 25-225, 25-261, 25-462, 26-250, 26-322, 26-353, 26-354, 26-502, 26-622, 26-676, 27-316, 28-271, 28-286, 28-330, 28-443, 28-461, 28-462, 29-255, 29-318, 29-348, 29-605, 31-258, 31-270, 31-283, 31-481, 31-522, 31-604, 31-725, 31-730, 31-835, 32-265, 32-302, 32-790, 32-848, 33-312, 33-346, 33-356, 33-700, 35-475, 35-638, 36-218, 36-249, 36-531, 37-295, 37-440, 37-579, 38-280, 38-287, 38-357, 38-599, 39-256, 39-274, 39-283, 39-338, 39-542, 39-714, 39-961, 40-313, 41-326, 41-471, 42-266, 42-298, 42-487, 42-633, 43-762, 44-409, 45-434, 46-545, 46-564, 47-337, 47-486, 47-578, 47-633, 47-714, 50-339, 51-542, 52-620, 53-292, 54-303, 56-438, 56-446, 56-702, 57-746, 60-448, 63-438, 65-487, 69-671, 77-801, 81-362, 83-690, 84-373, 84-560, 86-363, 89-622, 92-372, 97-504, 97-616, 109-703, 120-682, 125-666, 125-675, 130-734, 134-893, 135-369, 135- 585, 137-663, 138-399, 143-848, 145-398, 145-729, 146-333, 147-852, 150-446, 150-737, 151-428, 152-418, 152-419, 153-384, 153-428, 155-457, 155-737, 156-423, 157-398, 157-748, 160-373, 163-468, 166-476, 169-435, 171-428, 171-468, 177-434, 178-894, 179-701, 183- 436, 183-448, 185-492, 187-415, 187-769, 188-468, 189-853, 192-446, 193-843, 196-816, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 199-468, 200-283, 202-812, 203-453, 203-852, 204-509, 205-468, 207-870, 208-408, 208-771, 212-232, 214-447, 217-842, 218-478, 219- 838, 220-1016, 221-858, 223-461, 223-526, 224-468, 224-567, 224-625, 224-784, 228-482, 232-894, 234-425, 235-471, 236-491, 238-624, 238-853, 240-484, 240-501, 241-952, 243-448, 244-506, 244-763, 247-823, 250-712, 251-456, 252-870, 256-544, 257-700, 259-531, 261- 565, 262-860, 265-957, 266-954, 268-480, 268-554, 269-530, 270-863, 271-596, 272-619, 272-937, 274-870, 275-552, 276-518, 277-496, 277-549, 277-895, 277-904, 279-526, 280-395, 280-472, 280-480, 280-482, 282-954, 282-967, 289-919, 290-719, 297-552, 297-853, 298- 971, 299-423, 301-502, 301-573, 303-999, 305-972, 306-549, 306-578, 307-562, 309-530, 309-853, 311-590, 312-777, 316-896, 319-871, 320-436, 322-580, 322-842, 326-621, 326-860, 330-895, 331-1154, 332-562, 332-576, 332-617, 333-622, 333-632, 336-894, 336-936, 341- 585, 345-612, 345-791, 346-675, 358-533, 359-577, 363-639, 367-926, 370-617, 373-643, 373-940, 375-898, 380-648, 382-661, 383-636, 383-651, 386-635, 387-655, 388-1129, 389-798, 391-907, 396-633, 396-654, 397-1112, 399-702, 399- 718, 410-664, 410-671, 410-793, 416-653, 418-610, 418-691, 418-957, 419-681, 420-627, 422-674, 422-715, 424-856, 426-704, 428-662, 428-963, 430-720, 432-954, 433-823, 434-1097, 439-1004, 442-1006, 444-736, 446-718, 446-732, 448-1083, 451-731, 455-1064, 456-695, 456-761, 456-765, 465-725, 465-736, 465-757, 466-682, 468-766, 471-776, 473-660, 475-1027, 475-1067, 475-1148, 478-900, 482-755, 488-1028, 489-935, 493-907, 493-1126, 498-1105, 501-801, 501-1131, 503-759, 505-936, 507-1129, 511-808, 513-753, 517-786, 517- 1043, 518-804, 519-653, 519-771, 521-1129, 522-732, 522-758, 524-1078, 525-803, 526-795, 526-809, 526-821, 526-822, 526-1139, 527- 761, 527-767, 527-786, 527-1146, 528-1121, 529-1121, 531-732, 537-784, 537-805, 537-957, 539-708, 539-812, 539-1121, 541-853, 541- 1126, 542-768, 542-853, 545-729, 546-803, 547-795, 552-1154, 555-818, 557-817, 561-796, 561-960, 562-860, 563-860, 564-828, 567-1095, 569-1031, 571-802, 581-888, 581-889, 582-870, 583-781, 583-1116, 584-726, 584-954, 585-870, 590-784, 591-876, 593-867, 594-1080, 595-925, 595-1078, 597-1096, 598-864, 598-869, 600-868, 603-860, 613-1121, 615-892, 619-890, 621-878, 624-870, 626-1121, 628-1131, 629-954, 637-1132, 638-882, 638-1094, 639-832, 639-902, 639-1111, 641-866, 641-904, 641-906, 643-892, 643- 1108, 652-933, 659-1134, 662-911, 662-939, 664-890, 666-1331, 667-956, 680-901, 680-1035, 682-887, 684-1154, 685-957, 687-954, 690- 839, 690-1009, 690-1037, 691-995, 692-961, 694-1089, 696-879, 697-955, 697-958, 697-979, 697-980, 698-902, 701-963, 703-1121, 704- 1021, 717-969, 717-978, 717-983, 717-999, 717-1007, 718-1001, 720-992, 724-1047, 725-969, 725-1072, 726-867, 726-999, 726-1010, 730- 1334, 737-891, 737-1105, 750-1034, 799-1102, 807-1125, 811-1068, 811-1079, 812-1048, 813-1043, 818-1116, 819-1070, 819-1083, 821- 1138, 823-1086, 824-1015, 826-1106, 826-1120, 827-1097, 831-1077, 833-1083, 834-1143, 837-1078, 837-1124, 838-1087, 847-1094, 850-1073, 851-1122, 863-1052, 866-1130, 868-1092, 869-1115, 869-1138, 879-1096, 879-1107, 880-1114, 881-1123, 885-1094, 885-1119, 885-1139, 885-1148, 885-1153, 896-1147, 898-1144, 898-1153, 919-1111, 920-1138, 926-1144, 938-1017, 941-1154, 954-1139, 959-1110, 1005-1115, 1007-1077, 1009-1108, 1015-1144, 1032-1124, 1052-1134, 1162-1380, 1211-1315, 1248-1481, 1269-1408, 1270-1406 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 102/7506527CB 1/1-238, 1-282, 1-286, 1-530, 1-2544, 22-451, 25-65, 76-361, 180-917, 306-440, 320-491, 326-443, 328-599, 328-955, 328-966, 358-492, 535- 3031 1072, 536-1066, 536-1110, 538-769, 538-782, 554-746, 554-1064, 556-1376, 565-1152, 565-1156, 572-1146, 574-1208, 574-1214, 580- 978, 582-1280, 593-1223, 598-898, 603-711, 604-1284, 614-1183, 626-875, 627-1214, 629-1003, 646-1135, 675-914, 677-938, 677-958, 677-1172, 686-1302, 687-949, 688-936, 706-1203, 715-957, 715-965, 718-993, 731-1336, 732-1265, 732-1300, 765-1398, 780-884, 790- 1267, 791-1407, 800-1363, 801-1283, 808-1083, 810-1051, 811-1285, 813-1107, 814-1475, 822-1483, 824-1008, 826-1524, 844-1063, 849- 1395, 850-1414, 857-1493, 863-1564, 887-1145, 890-1200, 923-1548, 924-1072, 953-1465, 972-1182, 991-1638, 996-1373, 998-1642, 1005-1454, 1020-1638, 1031-1677, 1042-1578, 1045-1486, 1046-1332, 1048-1310, 1054-1233, 1066-1566, 1075-1252, 1078-1558, 1090- 1396, 1090-1611, 1091-1655, 1095-1562, 1095-1673, 1112-1367, 1112-1389, 1140-1804, 1143-1399, 1147-1796, 1151-1826, 1153-1382, 1157-1638, 1161-1453, 1166-1435, 1166-1818, 1171-1805, 1176-1805, 1177-1456, 1179-1433, 1202- 1500, 1206-1450, 1209-1727, 1212-1495, 1217-1388, 1223-1482, 1223-1705, 1229-1513, 1232-1918, 1242-1365, 1251-1809, 1261-1393, 1262-1521, 1262-1549, 1280-1453, 1285-1884, 1294-1934, 1303-1796, 1307-1817, 1315-1749, 1321-1575, 1333-1788, 1349-1948, 1352- 1584, 1353-1924, 1355-1611, 1356-1858, 1356-1872, 1356-1904, 1356-1916, 1360-1916, 1377-1599, 1377-1662, 1387-1588, 1389-1638, 1395-2066, 1397-2095, 1398-1891, 1414-1689, 1416-1654, 1416-2114, 1423-1982, 1431-2027, 1431-2048, 1432-2128, 1438-1885, 1445- 1790, 1448-1969, 1454-1712, 1454-2061, 1456-2169, 1461-1723, 1462-1732, 1467-2006, 1476-1608, 1476-2158, 1486-2147, 1488-1792, 1488-1988, 1491-2006, 1500-1990, 1502-2053, 1504-1752, 1504-1797, 1504-2099, 1504-2117, 1510-2059, 1518-2091, 1521-1749, 1522- 2171, 1529-1985, 1530-2157, 1533-1667, 1536-1807, 1539-1806, 1547-2062, 1547-2172, 1548-1787, 1548-1823, 1550-1818, 1553-1832, 1555-2168, 1559-2072, 1561-1854, 1565-1837, 1565-2259, 1567-1835, 1599-2080, 1599-2223, 1599- 2243, 1603-1863, 1603-1885, 1605-1912, 1605-2159, 1607-2313, 1621-2418, 1622-1860, 1644-1861, 1645-2235, 1646-1933, 1647-2227, 1653-1714, 1654-2076, 1654-2158, 1655-2147, 1656-1958, 1668-2235, 1673-2271, 1679-2235, 1679-2268, 1683-2235, 1687-2238, 1689- 1961, 1701-1894, 1702-1968, 1702-1976, 1702-2317, 1703-2296, 1703-2396, 1704-1982, 1709-1993, 1712-1819, 1712-2235, 1715-2235, 1724-2390, 1730-2018, 1730-2050, 1741-1951, 1741-2054, 1750-2032, 1754-2456, 1756-2394, 1760-2177, 1761-2025, 1762-2031, 1764- 2369, 1765-2021, 1765-2348, 1768-2001, 1768-2331, 1773-2060, 1773-2474, 1775-2300, 1775-2443, 1775-2464, 1778-2498, 1782-2001, 1782-2403, 1782-2488, 1784-1993, 1789-2364, 1800-2439, 1802-2235, 1803-2021, 1803-2430, 1807-2456, 1813-2052, 1821-2235, 1833- 2124, 1839-2285, 1842-2106, 1843-2526, 1861-2515, 1862-2533, 1869-2138, 1869-2463, 1871-2542, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 1872-2113, 1872-2114, 1872-2119, 1872-2128, 1883-2154, 1884-2128, 1884-2463, 1885-2531, 1885-2533, 1886-2120, 1887-2146, 1887- 2178, 1887-2539, 1895-2227, 1901-2383, 1902-2240, 1910-2360, 1920-2553, 1921-2047, 1921-2182, 1921-2193, 1924-2053, 1924-2189, 1924-2290, 1925-2178, 1928-2235, 1930-2554, 1931-2052, 1931-2199, 1931-2200, 1931-2225, 1931-2235, 1936-2483, 1939-2101, 1940- 2501, 1944-2191, 1944-2214, 1944-2245, 1948-2205, 1949-2204, 1954-2178, 1968-2541, 1969-2530, 1970-2252, 1973-2279, 1978-2510, 1980-2227, 1984-2558, 1985-2561, 1985-2566, 1988-2431, 1988-2555, 1990-2536, 1995-2568, 2000-2282, 2002-2436, 2012-2556, 2021- 2533, 2023-2560, 2036-2553, 2040-2568, 2042-2304, 2052-2289, 2052-2543, 2052-2544, 2061-2560, 2064-2547, 2065-2320, 2065-2565, 2071-2556, 2071-2560, 2074-2259, 2075-2547, 2076-2542, 2076-2547, 2077-2337, 2082-2541, 2084-2345, 2084-2546, 2087-2542, 2088- 2543, 2091-2337, 2091-2341, 2091-2540, 2091-2544, 2092-2425, 2092-2547, 2096-2339, 2098-2390, 2098-2533, 2098-2554, 2101-2386, 2101-2543, 2103-2556, 2105-2464, 2105-2543, 2107-2546, 2110-2545, 2111-2543, 2111-2547, 2123-2543, 2126- 2566, 2126-2567, 2131-2519, 2131-2542, 2133-2544, 2134-2544, 2136-2561, 2140-2546, 2141-2543, 2143-2377, 2143-2542, 2149-2542, 2151-2544, 2154-2544, 2157-2364, 2157-2546, 2158-2544, 2164-2542, 2166-2542, 2168-2544, 2170-2542, 2178-2427, 2185-2545, 2191- 2497, 2193-2543, 2197-2540, 2203-2569, 2210-2542, 2212-2460, 2215-2506, 2216-2453, 2216-2537, 2216-2556, 2218-2542, 2228-2459, 2236-2544, 2237-2542, 2238-2385, 2239-2542, 2244-2565, 2247-2541, 2249-2560, 2252-2519, 2257-2486, 2261-2557, 2268-2545, 2274- 2544, 2275-2548, 2275-2620, 2278-2543, 2279-2543, 2281-2556, 2282-2542, 2293-2559, 2303-2576, 2304-2563, 2308-2543, 2313-2536, 2317-2544, 2320-2557, 2320-2561, 2327-2550, 2327-2645, 2327-3031, 2328-2544, 2329-2542, 2330-2573, 2340-2545, 2347-2544, 2347- 2565, 2360-2529, 2360-2554, 2360-2556, 2362-2565, 2370-2616, 2375-2542, 2375-2573, 2375-2595, 2376-2543, 2377-2594, 2398-2557, 2399-2560, 2420-2546, 2423-2545, 2465-2544 103/7504894CB1/276, 3-285, 5-249, 5-596, 5-618, 6-618, 8- 3120 217, 8-221, 8-270, 10-314, 12-261, 16-258, 17-617, 18-248, 43-256, 46-253, 46-281, 57-578, 59-481, 69-345, 69-586, 85-312, 114-389, 128- 257, 353-919, 369-952, 616-1151, 650-769, 650-1063, 650-1076, 661-1071, 665-895, 674-1021, 679-1268, 682-1191, 694-978, 720-1149, 795-917, 803-1067, 817-1182, 858-1183, 872-1491, 885-1251, 885-1411, 885-1473, 885-1488, 885-1496, 885-1520, 885-1559, 885-1642, 885-1673, 894-1160, 894-1510, 920-1071, 923-1176, 945-1585, 982-1076, 982-1615, 983-1256, 1031-1794, 1033-1663, 1176-1904, 1179- 1499, 1180-1485, 1203-1698, 1226-1355, 1226-1362, 1241-1951, 1265-1953, 1270-1971, 1275-1551, 1286-1951, 1296-1930, 1311-1854, 1368-2098, 1371-1999, 1453-1952, 1460-1846, 1466-1706, 1466-1911, 1484-2014, 1501-1786, 1511-1730, 1514-2148, 1520-2079, 1582- 1952, 1616-1872, 1631-2010, 1667-1930, 1691-2215, 1710-2169, 1735-1982, 1736-2525, 1742-1991, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 1764-2040, 1783-1944, 1785-2076, 1791-2054, 1827-2029, 1861-2337, 1879-2072, 1884-2279, 1884-2476, 1893-2097, 1912-2178, 1912- 2182, 1912-2209, 1913-2118, 1913-2181, 1939-2166, 1942-2240, 1948-2503, 1960-2207, 1990-2267, 1990-2792, 1998-2276, 2030-2268, 2038-2513, 2041-2497, 2048-2298, 2072-2339, 2076-2815, 2094-2496, 2108-2384, 2121-2383, 2121-2583, 2128-2359, 2128-2364, 2128- 2372, 2130-2414, 2133-2402, 2137-2436, 2148-2362, 2148-2419, 2153-2779, 2159-2396, 2161-2586, 2165-2882, 2168-2401, 2179-2391, 2181-2421, 2201-2467, 2220-2738, 2223-2442, 2223-2776, 2223-2800, 2225-2532, 2225-2710, 2226-2439, 2230-2351, 2230-2481, 2230- 2486, 2230-2497, 2231-2900, 2232-2468, 2235-2637, 2240-2770, 2246-2428, 2246-2476, 2257-2484, 2265-2503, 2267-2500, 2280-2755, 2281-2669, 2281-2938, 2286-2544, 2286-2579, 2288-2773, 2297-2560, 2307-2763, 2307-2813, 2309-3023, 2345-2966, 2346-2527, 2346- 2779, 2354-2563, 2356-2758, 2356-2873, 2358-2618, 2363-2654, 2368-2730, 2370-3120, 2371-2615, 2382-2656, 2382-2887, 2386-2934, 2388-3062, 2396-3107, 2408-2886, 2408-3097, 2412-2658, 2437-2571, 2444-3118, 2447-3036, 2451-2910, 2455- 2710, 2455-2713, 2455-3120, 2469-2654, 2473-3007, 2477-3120, 2486-3120, 2492-2724, 2498-2736, 2499-2746, 2501-2735, 2511-3054, 2516-2708, 2520-2820, 2529-2840, 2533-3118, 2536-3085, 2547-2774, 2548-2811, 2549-3120, 2555-2838, 2555-2839, 2556-3095, 2564- 2864, 2565-2945, 2565-2967, 2567-2778, 2567-2823, 2580-2813, 2587-3022, 2603-2863, 2606-3118, 2606-3120, 2607-2861, 2611-2914, 2613-2852, 2613-3120, 2623-3120, 2626-2795, 2627-2906, 2635-3120, 2645-3069, 2658-3120, 2672-3120, 2679-2934, 2685-2919, 2685- 3009, 2689-2942, 2702-3120, 2721-3059, 2722-3115, 2724-3120, 2725-2999, 2729-3033, 2733-3120, 2742-3120, 2744-3120, 2746-3120, 2748-2971, 2748-3004, 2748-3120, 2749-2996, 2750-3120, 2751-3120, 2757-2874, 2757-3009, 2757-3015, 2769-3051, 2776-3120, 2777- 3120, 2781-3011, 2783-3120, 2784-3120, 2785-3120, 2790-3120, 2793-3120, 2795-3120, 2797-3120, 2798-3120, 2799-3120, 2800-3120, 2801-3120, 2822-3024, 2836-3120, 2840-3120, 2842-3047, 2843-3120, 2852-3120, 2857-3120, 2858-3120, 2871- 3120, 2880-3064, 2892-3120, 2897-3120, 2934-3120, 2938-3120, 2954-3120, 2956-3120, 2970-3120, 2976-3120, 2981-3120, 3036-3120 104/7510529CB1/1-250, 1-281, 2-293, 2-300, 3-246, 4-137, 4-246, 8-161, 8-254, 8-343, 11-249, 12-269, 12-274, 12-290, 12-293, 12-324, 13-322, 15-253, 15- 814 273, 15-276, 15-324, 15-422, 17-134, 17-251, 18-278, 18-309, 19-262, 19-299, 21-814, 22-251, 24-271, 24-289, 24-334, 26-277, 27-191, 27- 560, 28-270, 28-294, 28-307, 28-379, 30-295, 31-274, 33-143, 34-157, 34-247, 34-280, 35-201, 38-262, 39-266, 39-274, 40-232, 40-290, 43- 263, 43-274, 44-282, 45-288, 45-305, 46-328, 47-361, 49-397, 51-214, 57-406, 64-311, 90-414, 92-416, 103-247, 103-443, 135-387, 144- 398, 162-385, 169-461, 205-453, 244-514, 244-539, 248-484, 262-546, 289-536, 289-547, 296-563, 313-556, 313-574, 349-601, 352-578, 376-805, 600-803, 628-732, 636-814 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 105/7510581CB 1/X 5 105/751058ICBI/1-384, 4-293, 7-293, 7-308, 14-326, 14-584, 15-698, 21-572, 21-2512, 23-328, 24-378, 24-637, 24-646, 25-265, 25-674, 26-397, 26-589, 33- 2512 268, 50-514, 104-348, 105-348, 186-634, 271-583, 324-711, 353-522, 376-646, 693-1078, 1016-1605, 1113-1351, 1134-1434, 1135-1419, 1138-1394, 1142-1377, 1142-1385, 1142-1466, 1142-1473, 1160-1405, 1211-1641, 1229-1764, 1233-1498, 1244-1528, 1313-1580, 1314- 1867, 1316-1740, 1317-1860, 1319-1519, 1326-1897, 1349-1627, 1354-1737, 1355-1769, 1368-1631, 1373-1639, 1374-2240, 1390-1523, 1407-1664, 1407-1861, 1426-1721, 1429-2052, 1454-1736, 1464-1639, 1465-1811, 1470-1771, 1472-2095, 1479-1730, 1479-1732, 1496- 1740, 1511-1797, 1522-1855, 1526-1800, 1529-1788, 1544-1834, 1552-1795, 1576-1785, 1616-1965, 1616-2207, 1618-2426, 1633-1972, 1642-2180, 1665-1900, 1676-2128, 1686-1832, 1687-1883, 1687-2156, 1690-2316, 1705-1973, 1705-2098, 1705-2121, 1705-2272, 1709- 2263, 1745-2506, 1767-2229, 1794-2035, 1806-2056, 1837-2126, 1839-2470, 1841-2459, 1844-2132, 1844-2134, 1848-2097, 1851-2105, 1857-2425, 1889-2505, 1890-2276, 1892-2130, 1907-2498, 1907-2507, 1908-2135, 1909-2182, 1910- 2212, 1921-2148, 1922-2207, 1928-2453, 1931-2323, 1931-2453, 1932-2238, 1951-2220, 1951-2510, 1952-2215, 1961-2238, 1962-2483, 1964-2255, 1968-2293, 1983-2512, 1986-2512, 1990-2448, 1995-2243, 2017-2512, 2034-2288, 2037-2510, 2053-2467, 2055-2213, 2066- 2313, 2070-2510, 2076-2369, 2077-2512, 2081-2510, 2086-2348, 2086-2512, 2090-2500, 2090-2512, 2092-2510, 2093-2510, 2096-2497, 2096-2502, 2096-2511, 2097-2502, 2099-2510, 2105-2510, 2109-2512, 2117-2512, 2119-2391, 2120-2502, 2126-2499, 2135-2502, 2145- 2502, 2153-2510, 2155-2368, 2155-2447, 2155-2502, 2157-2510, 2157-2512, 2162-2510, 2163-2510, 2183-2502, 2188-2511, 2200-2510, 2202-2500, 2207-2512, 2212-2510, 2217-2473, 2221-2510, 2224-2495, 2235-2501, 2247-2501, 2247-2512, 2268-2501, 2285-2512, 2303- 2512, 2323-2500, 2341-2512, 2362-2512, 2414-2510, 2437-2502 106/7510582CB1/1-384, 4-293, 7-293, 7-308, 14-326, 14-584, 15-698, 21-572, 21-2683, 23-328, 24-378, 24-637, 24-646, 25-265, 25-674, 26-397, 26-589, 33- 2683 268, 50-514, 104-348, 105-348, 186-415, 186-421, 186-634, 271-583, 324-711, 353-522, 376-646, 716-1291, 722-1527, 772-1366, 792- 1069, 856-1089, 881-1458, 903-1194, 918-1197, 948-1172, 970-1228, 970-1250, 979-1385, 983-1438, 1003-1652, 1017-1249, 1054-1315, 1054-1336, 1054-1342, 1065-1690, 1077-1205, 1093-1333, 1098-1659, 1108-1381, 1110-1652, 1116-1393, 1117-1529, 1158-1417, 1164- 1285, 1174-1491, 1194-1455, 1194-1591, 1217-1489, 1244-1503, 1250-1849, 1277-1762, 1325-1535, 1325-1547, 1348-1659, 1354-1690, 1366-1635, 1377-1603, 1512-1750, 1533-1833, 1534-1818, 1537-1793, 1541-1776, 1541-1784, 1541-1851, 1559-1804, 1688-1931, 1852- 2071, 1852-2596, 1853-2298, 1857-2003, 1858-2054, 1858-2326, 1861-2486, 1876-2141, 1876-2142, 1876-2143, 1876-2149, 1876-2212, 1876-2268, 1876-2291, 1876-2442, 1880-2433, 1916-2676, 1938-2399, 1953-2297, 1965-2205, 1977-2226, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 2008-2296, 2010-2640, 2012-2297, 2012-2629, 2015-2302, 2015-2304, 2019-2267, 2022-2275, 2028-2595, 2060-2675, 2061-2446, 2063- 2300, 2074-2668, 2075-2305, 2078-2677, 2079-2352, 2080-2382, 2091-2318, 2092-2377, 2098-2623, 2101-2493, 2101-2623, 2102-2297, 2102-2408, 2121-2297, 2121-2390, 2121-2680, 2122-2385, 2131-2408, 2132-2653, 2134-2425, 2138-2463, 2153-2683, 2156-2683, 2160- 2618, 2165-2413, 2187-2683, 2204-2458, 2207-2680, 2223-2637, 2225-2383, 2236-2483, 2240-2680, 2246-2539, 2247-2683, 2251-2680, 2256-2518, 2256-2683, 2260-2670, 2260-2683, 2262-2680, 2263-2680, 2266-2667, 2266-2672, 2266-2681, 2267-2672, 2269-2680, 2275- 2680, 2279-2683, 2287-2683, 2289-2561, 2290-2672, 2296-2669, 2305-2672, 2315-2672, 2323-2680, 2325-2538, 2325-2617, 2325-2672, 2327-2680, 2327-2683, 2332-2680, 2333-2680, 2353-2672, 2358-2681, 2370-2680, 2372-2670, 2377-2683, 2382-2680, 2385-2444, 2385- 2625, 2385-2633, 2387-2643, 2391-2680, 2394-2665, 2405-2671, 2417-2671, 2417-2683, 2438-2671, 2455-2683, 2473-2683, 2493-2670, 2511-2683, 2532-2683, 2584-2680, 2607-2672 107/7510583CB1/1-384, 4-293, 7-293, 7-308, 14-326, 14-584, 15-698, 21-572, 21-2523, 23-328, 24-378, 24-637, 24-646, 25-265, 25-674, 26-397, 26-589, 33- 2523 268, 50-514, 104-348, 105-348, 186-415, 186-421, 186-634, 271-583, 324-711, 353-522, 376-646, 789-1285, 1031-1620, 1128-1366, 1149- 1449, 1150-1434, 1153-1409, 1157-1392, 1157-1400, 1157-1481, 1157-1488, 1175-1420, 1226-1656, 1244-1779, 1248-1513, 1259-1543, 1328-1595, 1329-1882, 1331-1755, 1332-1875, 1334-1534, 1341-1912, 1364-1642, 1369-1752, 1370-1784, 1383-1646, 1388-1654, 1389- 2254, 1405-1538, 1422-1679, 1422-1876, 1441-1736, 1444-2066, 1469-1751, 1479-1654, 1480-1826, 1485-1786, 1487-2109, 1494-1745, 1494-1747, 1511-1755, 1526-1812, 1537-1870, 1541-1815, 1544-1803, 1559-1849, 1567-1810, 1591-1800, 1631-1979, 1631-2221, 1633- 2440, 1648-1858, 1648-1986, 1657-2194, 1680-1915, 1691-2142, 1701-1847, 1702-1898, 1702-2170, 1705-2330, 1720-1987, 1720-2112, 1720-2135, 1720-2286, 1724-2277, 1760-2520, 1782-2243, 1809-2049, 1821-2070, 1852-2140, 1854-2484, 1856-2473, 1859-2146, 1859-2148, 1863-2111, 1866-2119, 1872-2439, 1904-2519, 1905-2290, 1907-2144, 1921-2149, 1922-2512, 1922- 2521, 1923-2196, 1924-2226, 1935-2162, 1936-2221, 1942-2467, 1945-2337, 1945-2467, 1946-2252, 1965-2141, 1965-2234, 1965-2523, 1966-2229, 1975-2252, 1976-2497, 1978-2269, 1982-2307, 1997-2523, 2000-2523, 2004-2462, 2009-2257, 2031-2523, 2048-2302, 2051- 2523, 2067-2481, 2069-2227, 2080-2327, 2084-2523, 2090-2383, 2091-2523, 2095-2523, 2100-2362, 2100-2523, 2104-2514, 2104-2523, 2106-2523, 2107-2523, 2110-2511, 2110-2516, 2110-2523, 2111-2516, 2113-2523, 2119-2523, 2123-2523, 2131-2523, 2133-2405, 2134- 2516, 2140-2513, 2149-2516, 2159-2516, 2167-2523, 2169-2382, 2169-2461, 2169-2516, 2171-2520, 2171-2523, 2176-2523, 2177-2523, 2197-2516, 2202-2523, 2214-2523, 2216-2514, 2221-2523, 2226-2523, 2231-2487, 2235-2523, 2238-2509, 2249-2515, 2261-2515, 2261- 2523, 2282-2515, 2299-2523, 2317-2523, 2337-2514, 2355-2523, 2376-2523, 2428-2523, 2451-2516 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 108/7510596CB 1/1-531, 19-273, 19-317, 19-367, 20-171, 20-262, 20-315, 20-329, 20-340, 20-999, 24-248, 30-442, 35-565, 40-260, 43-406, 49-319, 50-352, 1050 57-441, 57-453, 57-465, 57-512, 61-557, 68-369, 68-484, 69-300, 69-321, 69-332, 69-374, 69-495, 69-556, 70-157, 70-170, 70-217, 70-245, 70-254, 70-262, 70-298, 70-302, 70-306, 70-307, 70-309, 70-310, 70-311, 70-313, 70-314, 70-320, 70-322, 70-323, 70-324, 70-325, 70-326, 70-328, 70-329, 70-331, 70-335, 70-342, 70-343, 70-347, 70-348, 70-349, 70-350, 70-359, 70-368, 70-373, 70-384, 70-402, 70-433, 70-435, 70-491, 70-494, 70-503, 70-514, 70-565, 71-293, 71-485, 71-500, 71-506, 72-299, 72-321, 72-517, 72-525, 73-290, 73-296, 73-301, 73-306, 73-310, 73-312, 73-314, 73-315, 73-316, 73-319, 73-320, 73-323, 73-325, 73-326, 73-329, 73-330, 73-333, 73-337, 73-338, 73-342, 73-344, 73-352, 73-365, 73-368, 73-369, 73-376, 73-487, 73-526, 73-543, 74-195, 74-204, 74-267, 74-294, 74-321, 74-360, 74-371, 74-381, 74-513, 74-542, 74-565, 75-223, 75-306, 75-308, 75-312, 75-315, 75-328, 75-329, 75-330, 75-331, 75-339, 75-348, 75-357, 75-358, 75-364, 75-379, 75-395, 75-482, 75-495, 75-527, 75-565, 76-231, 76-385, 76-425, 77-297, 77-347, 77-372, 77-395, 77-437, 77-512, 77-554, 77-556, 78-210, 78-285, 78-287, 78-304, 78-306, 78-307, 78-311, 78-312, 78-313, 78-317, 78-318, 78-319, 78-322, 78-324, 78-325, 78-326, 78-328, 78-332, 78-337, 78-339, 78-340, 78-344, 78-345, 78-346, 78-347, 78-350, 78-355, 78-356, 78-357, 78-358, 78-370, 78-372, 78-374, 78-377, 78-380, 78-381, 78-385, 78-392, 78-559, 78-565, 79-232, 79-239, 79-260, 79-290, 79-299, 79-305, 79-306, 79-308, 79-314, 79-315, 79-316, 79-317, 79-318, 79-319, 79-325, 79-331, 79-332, 79-339, 79-344, 79-345, 79-356, 79-362, 79-369, 79-387, 79-392, 79-396, 79-560, 79-565, 80-267, 80-352, 80-363, 80-383, 80-384, 80-422, 80-454, 81-340, 81-342, 81-344, 81-354, 81-360, 81-366, 81-371, 82-296, 82-300, 82-302, 82-305, 82-316, 82-322, 82-323, 82-327, 82-328, 82-332, 82-337, 82-341, 82-342, 82-344, 82-351, 82-352, 82-362, 82-363, 82-365, 82-367, 82-397, 82-578, 83-328, 83-333, 83-336, 83-341, 83-342, 83-343, 83-356, 83-372, 83-412, 84-280, 84-337, 84-366, 84-372, 84-464, 85-281, 85-305, 85-316, 85-352, 85-357, 85-371, 85-554, 86-274, 86-302, 86-305, 86-307, 86-310, 86-312, 86-318, 86-323, 86-328, 86-333, 86-336, 86-338, 86-339, 86-345, 86-349, 86-350, 86-351, 86-357, 86-358, 86-360, 86-361, 86-362, 86-366, 86-370, 86-375, 86-385, 86-390, 86-392, 86-394, 86-398, 86-415, 86-419, 86-435, 86-436, 87-212, 87-321, 87-333, 87-334, 87-336, 87-345, 87-360, 87-445, 87-536, 88-281, 88-306, 88-307, 88-314, 88-324, 88-326, 88-327, 88-331, 88-332, 88-342, 88-344, 88-345, 88-347, 88-351, 88-352, 88-357, 88-362, 88-368, 88-369, 88-374, 88-565, 89-216, 89-297, 89-321, 89-345, 89-365, 90-320, 90-326, 90-370, 90-372, 90-386, 90-393, 90-397, 90-562, 90-565, 91-320, 91-341, 91-352, 91-359, 92-222, 92-325, 92-329, 92-336, 92-342, 92-551, 93-447, 94-366, 95-289, 95-316, 96-371, 96-412, 96-565, 98-333, 99-221, 99-278, 99-296, 99-334, 99-352, 99-354, 99-355, 99-362, 99-363, 99-364, 99-365, 99-366, 99-369, 99-410, 100-284, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 100-343, 100-350, 100-435, 100-565, 101-352, 101-422, 101-537, 102-381, 102-482, 103-476, 103-553, 107-367, 107-377, 108-347, 108- 353, 108-365, 108-406, 112-343, 112-363, 117-352, 118-312, 119-402, 121-534, 124-329, 124-342, 125-389, 127-565, 128-399, 134-364, 134-373, 134-400, 135-421, 137-427, 137-564, 139-407, 141-459, 144-435, 144-440, 146-565, 151-292, 151-395, 154-309, 162-565, 170- 463, 172-459, 174-292, 176-418, 185-432, 185-480, 186-437, 192-565, 201-438, 202-493, 207-511, 208-426, 212-499, 213-463, 215-448, 218-443, 218-526, 222-502, 231-467, 231-470, 232-563, 235-529, 236-505, 246-454, 266-489, 268-421, 268-511, 268-512, 268-531, 270- 545, 283-537, 293-527, 299-533, 301-452, 312-558, 312-578, 313-554, 322-557, 327-578, 365-578, 423-675, 573-787, 573-1003, 583-805, 907-1050 109/7510643CB1/1-452, 1-562, 11-281, 16-538, 28-197, 28-340, 28-420, 28-493, 28-601, 30-293, 30-316, 31-759, 32-385, 32-395, 32-466, 32-2636, 33-155, 2965 33-168, 33-195, 33-245, 33-466, 33-631, 33-678, 34-760, 35-321, 35-685, 36-291, 36-308, 36-658, 36-664, 36-853, 39-250, 39-274, 39-300, 39-304, 39-332, 39-357, 39-500, 39-509, 39-527, 39-540, 39-564, 39-587, 39-593, 39-601, 39-610, 39-635, 39-725, 40-303, 40-557, 40-590, 41-259, 41-308, 41-672, 42-678, 42-881, 43-281, 43-322, 43-325, 43-333, 43-461, 43-504, 43-609, 43-651, 43-658, 43-934, 44-293, 45-143, 45-295, 45-604, 45-612, 45-680, 45-792, 45-829, 45-881, 46-442, 46-445, 46-544, 46-648, 47-664, 49-527, 50-217, 50-280, 50-295, 50-306, 50-310, 50-313, 50-597, 50-607, 50-904, 51-552, 52-748, 53-308, 53-319, 53-552, 53-585, 54-282, 57-361, 61-478, 62-487, 62-816, 66-881, 72-881, 76-932, 89-370, 95-249, 95-266, 95-276, 95-280, 95-302, 95-311, 95-352, 95-372, 95-458, 95-525, 96-336, 97-344, 109-838, 112- 881, 115-881, 117-881, 165-619, 169-748, 187-879, 190-881, 196-746, 225-1020, 251-800, 276-748, 276-907, 277-765, 278-716, 279-784, 284-558, 284-909, 290-526, 291-437, 313-984, 314-792, 328-1042, 343-965, 344- 579, 344-908, 346-625, 348-752, 355-759, 370-1006, 382-803, 401-966, 402-1015, 416-919, 419-991, 421-666, 422-884, 430-672, 430- 874, 441-652, 441-744, 441-827, 441-956, 441-977, 441-983, 441-987, 455-998, 460-686, 461-996, 493-699, 493-962, 496-938, 500-768, 507-1184, 521-1143, 528-944, 537-1207, 545-1141, 549-775, 549-1214, 566-1219, 568-1214, 576-1082, 577-1039, 590-1233, 596-853, 611- 989, 620-1122, 622-1001, 624-1003, 630-1162, 637-1125, 637-1257, 637-1305, 639-898, 663-1222, 665-789, 673-999, 684-1292, 686-929, 702-953, 704-995, 704-1334, 714-1260, 736-1433, 745-1257, 747-1021, 748-930, 750-1037, 752-987, 758-1017, 759-1007, 763-1026, 766- 1290, 777-1396, 779-1180, 779-1259, 779-1324, 779-1387, 779-1544, 791-1060, 791-1084, 792-1285, 793-1366, 794-1279, 794-1284, 833- 957, 838-1091, 838-1479, 845-1560, 856-1438, 862-1444, 866-1423, 877-1139, 879-1349, 879-1493, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 880-1179, 883-1348, 883-1440, 895-1435, 900-1435, 901-1166, 905-1384, 910-1533, 919-1409, 920-1128, 921-1255, 921-1401, 932-1496, 948-1539, 951-1347, 952-1287, 953-1344, 959-1545, 961-1475, 962-1229, 974-1106, 975-1535, 976-1252, 980-1117, 987-1252, 991-1541, 1006-1254, 1006-1483, 1006-1548, 1035-1160, 1036-1594, 1038-1238, 1077-1630, 1078-1211, 1092-1333, 1098-1630, 1102-1394, 1141- 1385, 1143-1407, 1154-1618, 1163-1433, 1163-1496, 1205-1481, 1205-1495, 1206-1421, 1206-1452, 1214-1289, 1226-1510, 1231-1630, 1248-1594, 1283-1545, 1284-1582, 1323-1590, 1325-1591, 1344-1512, 1344-1564, 1348-1621, 1351-1618, 1358-1483, 1361-1602, 1362- 1518, 1383-1630, 1396-1630, 1403-1677, 1410-1630, 1420-1551, 1432-1537, 1437-1630, 1631-1823, 1631-1826, 1631-1877, 1631-1884, 1631-1886, 1631-1979, 1631-2117, 1631-2131, 1631-2169, 1631-2180, 1631-2353, 1631-2357, 1631-2370, 1631-2371, 1631-2442, 1631- 2469, 1632-2244, 1634-2204, 1634-2293, 1643-2102, 1643-2281, 1645-1883, 1647-1896, 1647-2319, 1649-1911, 1664-1890, 1664-2339, 1666-2054, 1672-1967, 1673-1920, 1673-1927, 1673-1935, 1675-1927, 1680-2206, 1681-1818, 1681- 1947, 1682-1905, 1691-2323, 1693-2314, 1694-1940, 1694-2202, 1699-2028, 1699-2029, 1700-2208, 1703-2549, 1704-2037, 1706-1967, 1706-2297, 1710-2172, 1713-2185, 1720-2542, 1721-1998, 1721-2198, 1723-1998, 1726-2003, 1735-2162, 1735-2281, 1735-2318, 1739- 1985, 1739-2132, 1739-2192, 1741-2430, 1747-2469, 1751-2034, 1752-2469, 1759-1995, 1767-2265, 1768-2207, 1772-2551, 1772-2570, 1774-2570, 1777-2381, 1781-1991, 1783-2039, 1783-2448, 1789-2042, 1794-2037, 1794-2056, 1794-2070, 1794-2182, 1796-2097, 1796- 2209, 1803-2415, 1805-2067, 1809-2095, 1812-2463, 1817-2573, 1834-2288, 1851-2230, 1852-2300, 1853-2361, 1865-2523, 1869-2471, 1877-2577, 1878-2448, 1880-2129, 1886-2124, 1888-2530, 1891-2145, 1892-2513, 1896-2133, 1901-2556, 1905-2542, 1906-2640, 1911- 2485, 1913-2406, 1920-2170, 1925-2242, 1926-2197, 1928-2169, 1929-2225, 1943-2637, 1951-2142, 1951-2180, 1958-2158, 1962-2577, 1967-2185, 1969-2226, 1970-2242, 1979-2525, 1980-2400, 1983-2639, 1986-2222, 1989-2191, 1991-2135, 1992- 2251, 1996-2232, 2001-2554, 2003-2232, 2004-2261, 2005-2442, 2009-2638, 2015-2438, 2019-2313, 2021-2196, 2026-2372, 2027-2578, 2028-2558, 2039-2641, 2044-2324, 2044-2605, 2044-2638, 2045-2281, 2053-2573, 2053-2639, 2055-2640, 2067-2508, 2072-2330, 2072- 2624, 2076-2640, 2076-2641, 2077-2640, 2080-2347, 2082-2641, 2083-2640, 2084-2639, 2084-2641, 2086-2549, 2087-2339, 2087-2640, 2088-2238, 2088-2640, 2093-2335, 2093-2352, 2098-2218, 2099-2421, 2100-2261, 2101-2638, 2102-2521, 2103-2624, 2106-2657, 2108- 2639, 2108-2640, 2111-2401, 2112-2639, 2114-2398, 2118-2327, 2118-2359, 2119-2403, 2120-2657, 2121-2639, 2124-2639, 2127-2356, 2127-2553, 2127-2559, 2127-2569, 2127-2579, 2134-2385, 2136-2425, 2136-2639, 2137-2620, 2141-2584, 2142-2640, 2144-2631, 2144- 2641, 2147-2407, 2147-2640, 2148-2641, 2151-2618, 2153-2627, 2155-2640, 2156-2560, 2157-2587, 2157-2629, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length < 2170-2638, 2172-2640, 2175- 2160-2640, 2162-2631, 2163-2626, 2163-2629, 2164-2578, 2164-2609, 2164-2639, 2168-2381, 2169-2640, 2170-2638, 2172-2640, 2175- 2640, 2176-2623, 2176-2624, 2176-2639, 2181-2406, 2182-2624, 2182-2640, 2184-2430, 2184-2641, 2185-2640, 2187-2623, 2187-2640, 2187-2641, 2191-2624, 2194-2635, 2195-2624, 2197-2625, 2199-2451, 2199-2459, 2199-2497, 2199-2623, 2200-2624, 2200-2640, 2201- 2428, 2204-2639, 2204-2640, 2204-2641, 2205-2492, 2205-2625, 2206-2625, 2208-2623, 2208-2626, 2208-2640, 2209-2625, 2211-2624, 2214-2624, 2215-2624, 2217-2622, 2219-2353, 2219-2624, 2219-2625, 2219-2626, 2220-2640, 2227-2460, 2228-2627, 2230-2502, 2231- 2482, 2231-2491, 2232-2478, 2232-2514, 2235-2469, 2235-2625, 2239-2581, 2241-2623, 2247-2636, 2250-2639, 2252-2641, 2254-2624, 2256-2640, 2258-2515, 2258-2542, 2259-2630, 2262-2622, 2264-2517, 2265-2640, 2267-2639, 2268-2621, 2269-2639, 2271-2639, 2272- 2560, 2272-2625, 2273-2636, 2277-2626, 2278-2620, 2282-2626, 2285-2532, 2286-2639, 2297-2535, 2297-2580, 2301-2569, 2303-2521, 2303-2583, 2310-2620, 2312-2747, 2314-2529, 2317-2573, 2330-2624, 2333-2616, 2333-2653, 2336-2563, 2336- 2624, 2337-2584, 2338-2623, 2339-2625, 2340-2620, 2340-2624, 2344-2627, 2345-2639, 2348-2611, 2348-2627, 2349-2599, 2351-2623, 2356-2593, 2356-2668, 2357-2621, 2357-2965, 2368-2548, 2374-2658, 2377-2623, 2377-2658, 2381-2552, 2384-2627, 2384-2650, 2390- 2624, 2398-2578, 2402-2617, 2402-2638, 2404-2639, 2408-2624, 2409-2624, 2414-2918, 2417-2624, 2429-2915, 2434-2631, 2440-2623, 2442-2623, 2443-2615, 2447-2624, 2449-2862, 2450-2619, 2454-2620, 2455-2660, 2464-2624, 2467-2624, 2533-2810, 2567-2624 110/7506671CB1/1-353, 1-474, 1-542, 1-558, 1-570, 1-571, 1-593, 1-595, 1-628, 1-651, 1-756, 1-1468, 65-787, 72-273, 72-331, 72-457, 74-226, 84-733, 84- 1468 763, 93-675, 94-300, 94-360, 94-580, 95-381, 95-450, 95-609, 95-719, 97-350, 101-771, 103-391, 110-392, 112-391, 113-409, 114-445, 115-476, 126-703, 126-786, 134-476, 140-345, 141-821, 146-708, 148-331, 148-418, 148-556, 148-590, 148-612, 148-633, 148-634, 148- 654, 148-703, 148-708, 162-426, 175-820, 185-599, 185-614, 185-728, 185-730, 202-796, 213-813, 239-722, 375-700, 396-518, 478-812, 481-1185, 520-789, 522-801, 544-1151, 587-1185, 666-1185, 674-1185, 745-1184, 746-1185, 771-1185, 821-1194, 821-1374, 821-1376, 821-1390, 975-1177, 975-1468, 1039-1314, 1179-1403 111/7510518CB1/l1-253, 1-1074, 109 714, 201-416, 201-672, 389-858, 413-715, 426-1008, 554-767, 877-1062, 886-1062 1074 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 112/7510585 CB l/< w 112/7510585CBI/1-206, 1-278, 1-287, 1-2466, 42-259, 44-246, 44-294, 72-218, 72-236, 75-679, 107-320, 126-287, 184-323, 189-286, 321-603, 321-650, 321- 2612 732, 321-755, 321-775, 321-843, 324-959, 324-997, 327-843, 345-692, 347-843, 353-901, 379-838, 385-623, 391-832, 395-644, 400-851, 407-823, 411-888, 412-870, 414-659, 414-864, 422-653, 454-1061, 454-1067, 473-875, 473-1172, 477-933, 482-843, 486-827, 491-650, 491-1179, 498-667, 500-740, 540-841, 543-1057, 556-769, 563-986, 567-1086, 575-1143, 575-1145, 587-1145, 592-1162, 598-843, 604- 1040, 604-1152, 605-965, 605-1134, 608-1241, 622-884, 625-851, 629-811, 629-1032, 629-1182, 667-938, 696-1321, 699-1361, 737-1277, 738-967, 787-1285, 788-990, 806-1467, 808-1100, 817-1309, 817-1565, 817-1580, 817-1720, 818-1040, 819-1341, 825-1516, 844-1123, 844-1208, 845-1369, 874-1570, 874-1592, 884-1160, 884-1407, 892-1792, 898-1469, 903-1123, 906-1347, 936-1491, 937-1644, 939-1481, 961-1255, 966-1153, 966-1333, 966-1341, 973-1612, 974-1634, 989-1570, 993-1602, 997-1704, 1004-1492, 1013-1530, 1015-1792, 1022-1608, 1024-1715, 1027-1249, 1028-1426, 1030-1314, 1032-1149, 1032-1300, 1041-1208, 1041- 1394, 1042-1153, 1043-1463, 1062-1570, 1064-1591, 1074-1748, 1087-1320, 1089-1533, 1090-1699, 1091-1777, 1092-1695, 1095-1680, 1101-1716, 1103-1783, 1105-1611, 1109-1496, 1114-1792, 1124-1394, 1124-1563, 1124-1564, 1124-1877, 1127-1825, 1129-1748, 1131- 1612, 1135-1657, 1145-1645, 1147-1431, 1155-1565, 1158-1797, 1164-1611, 1175-1588, 1176-1443, 1179-1657, 1184-1619, 1186-1350, 1186-1356, 1205-1867, 1209-1394, 1209-1565, 1210-1580, 1211-1475, 1225-1476, 1226-1938, 1228-1495, 1228-1713, 1234-1502, 1266- 1815, 1280-1904, 1282-1537, 1307-1820, 1310-1689, 1322-1798, 1326-1838, 1338-1727, 1342-1640, 1342-1788, 1345-1974, 1346-1610, 1351-1621, 1352-1605, 1352-1977, 1362-1612, 1363-1900, 1369-1536, 1369-1616, 1371-1564, 1382-1645, 1387-1819, 1394-1616, 1395- 1891, 1415-2038, 1442-1691, 1442-1708, 1442-1722, 1442-1731, 1444-1722, 1444-1738, 1445-1879, 1466-1677, 1466-1701, 1471-1749, 1492-1748, 1493-1720, 1494-1838, 1500-1767, 1510-1738, 1513-1708, 1514-1793, 1516-1736, 1516-1768, 1516- 1814, 1530-1946, 1541-1733, 1554-1810, 1554-2378, 1554-2382, 1555-1810, 1555-1844, 1557-1810, 1566-1971, 1570-2213, 1574-1971, 1577-2056, 1578-1971, 1580-2086, 1583-1835, 1590-1862, 1615-1837, 1615-1880, 1621-1829, 1641-2143, 1648-2136, 1650-2082, 1655- 2273, 1656-2137, 1692-2450, 1693-2336, 1694-1947, 1695-2137, 1699-1941, 1707-2142, 1736-1901, 1738-2449, 1746-2063, 1746-2256, 1759-2450, 1761-2394, 1768-2020, 1771-2023, 1776-2073, 1777-2008, 1777-2066, 1777-2070, 1777-2403, 1779-2023, 1780-2042, 1781- 2433, 1789-2137, 1790-2137, 1791-2439, 1801-2449, 1802-2062, 1806-2285, 1806-2415, 1818-2327, 1826-2061, 1830-2075, 1840-2355, 1844-2456, 1845-2138, 1846-2303, 1851-2101, 1852-2465, 1853-2466, 1857-2146, 1860-2018, 1860-2120, 1870-2402, 1872-2038, 1872- 2394, 1878-2347, 1879-2346, 1888-2037, 1888-2094, 1895-2467, 1896-2437, 1896-2465, 1896-2466, 1901-2466, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 1902-2166, 1909-2434, 1917-2450, 1917-2467, 1918-2273, 1920-2464, 1927-2472, 1929-2406, 1931-2471, 1951-2465, 1951-2466, 1953- 2468, 1955-2200, 1955-2217, 1955-2226, 1958-2137, 1958-2222, 1963-2490, 1965-2464, 1966-2078, 1966-2200, 1966-2410, 1966-2464, 1967-2216, 1967-2223, 1967-2293, 1968-2345, 1969-2220, 1969-2456, 1969-2483, 1973-2137, 1974-2451, 1975-2474, 1977-2410, 1984- 2450, 1990-2464, 1991-2454, 1994-2463, 1994-2469, 1998-2414, 1999-2143, 2000-2450, 2001-2414, 2006-2471, 2008-2449, 2010-2446, 2017-2457, 2018-2224, 2018-2321, 2021-2451, 2024-2449, 2025-2455, 2028-2497, 2036-2451, 2036-2458, 2042-2454, 2043-2449, 2044- 2464, 2055-2451, 2056-2449, 2061-2451, 2065-2451, 2072-2452, 2079-2451, 2083-2332, 2087-2205, 2100-2451, 2102-2451, 2105-2458, 2113-2449, 2117-2451, 2120-2449, 2121-2451, 2123-2452, 2128-2451, 2166-2451, 2167-2398, 2167-2452, 2172-2450, 2186-2471, 2187- 2450, 2189-2449, 2191-2463, 2205-2451, 2207-2451, 2221-2465, 2237-2473, 2238-2466, 2253-2460, 2263-2451, 2273-2451, 2277-2451, 2286-2450, 2303-2451, 2312-2511, 2314-2416, 2328-2457, 2334-2460, 2337-2451, 2379-2612, 2566-2612 113/7510590CB /1-266, 17-255, 17-259, 17-298, 17-306, 17-308, 17-312, 21-227, 22-313, 22-332, 24-282, 24-626, 25-266, 25-1279, 30-249, 30-285, 30-299, 1735 30-301, 30-302, 30-313, 30-321, 32-319, 33-277, 33-304, 33-309, 34-191, 34-295, 34-309, 34-329, 34-343, 35-265, 39-239, 39-277, 39-278, 39-288, 39-292, 39-329, 39-337, 39-650, 40-307, 42-290, 42-301, 42-318, 42-331, 43-343, 46-309, 48-333, 49-276, 49-286, 50-318, 51-299, 51-301, 51-304, 51-305, 51-308, 51-321, 51-339, 52-294, 52-325, 53-176, 53-254, 53-290, 53-308, 53-335, 54-275, 54-314, 55-289, 55-304, 55-326, 55-343, 56-305, 58-274, 58-343, 60-256, 60-339, 60-341, 61-189, 62-306, 62-323, 62-343, 63-304, 63-343, 64-239, 64-304, 64-337, 64-339, 64-340, 64-343, 65-289, 65-300, 65-320, 65-333, 65-335, 65-343, 66-285, 66-340, 67-272, 67-301, 67-315, 67-334, 67-340, 67-343, 68-285, 68-326, 69-328, 71-314, 72-333, 72-343, 73-206, 73-269, 73-277, 73-281, 73-342, 74-295, 74-342, 79-320, 79-340, 79-343, 80-232, 80-324, 80-334, 80-343, 81-343, 83-325, 83-333, 84-343, 85-324, 87-316, 89-333, 97-340, 98-343, 100-343, 105-298, 105-343, 117-289, 118-343, 127-286, 159-343, 171-342, 342-447, 342-546, 342-550, 342-581, 342-584, 342-585, 342-618, 342-625, 342-674, 342-819, 342-912, 342-978, 348-853, 348-981, 349-588, 350-591, 351-647, 352-606, 360-973, 361- 600, 368-493, 368-627, 368-926, 377-629, 378-628, 378-646, 378-762, 383-973, 400-657, 402-524, 407-674, 408-670, 413-765, 415-987, 416-762, 419-687, 423-984, 429-681, 429-688, 440-642, 440-654, 440-757, 442-677, 443-688, 443-778, 443-992, 449-1026, 449-1042, 457- 690, 457-717, 460-717, 469-689, 470-719, 476-694, 477-1146, 479-778, 480-783, 489-678, 492-599, 496-612, 496-733, 496-1127, 497- 751, 497-753, 497-765, 497-778, 497-1109, 502-1032, 503-848, 503-1283, 505-1101, 511-775, 513-757, 513-811, 518-791, 519-776, 524- 717, 527-717, 527-785, 542-773, 554-796, 554-805, 557-671, 557-1035, 559-1195, 561-829, 562-760, 562-798, 563-1179, 571-969, 571- 1199, 572-837, 579-892, 579-1171, 583-815, 583-872, 587-1070, 602-849, 607-843, 609-1160, 610-893, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length R 614-832, 614-1200, 615-935, 621-816, 621-866, 621-884, 622-908, 626-1166, 626-1274, 630-912, 631-1190, 632-780, 639-1108, 649-851, 650-931, 650-940, 657-1038, 659-1187, 660-909, 665-913, 668-933, 668-1051, 674-933, 675-1190, 678-1022, 680-1214, 683-949, 684- 1285, 689-827, 689-1306, 695-963, 695-988, 700-944, 701-948, 701-1142, 702-960, 703-894, 703-977, 705-945, 705-1043, 712-1314, 716- 915, 719-1007, 719-1088, 723-935, 726-1310, 727-1251, 728-1349, 730-989, 735-1299, 738-979, 740-987, 744-993, 744-1308, 745-990, 756-1275, 757-1016, 758-985, 763-888, 765-979, 765-1305, 765-1312, 766-1017, 767-791, 768-1043, 769-1283, 771-1041, 772-1071, 772- 1160, 772-1250, 772-1273, 773-1263, 775-1298, 775-1304, 775-1308, 778-987, 782-1328, 788-1034, 788-1043, 789-1248, 791-1253, 801- 1077, 803-1064, 805-1086, 805-1179, 805-1313, 808-1026, 810-1055, 811-1210, 814-1054, 815-1056, 818-1291, 820-1074, 820-1091, 821- 1321, 823-1289, 828-1121, 829-1149, 831-1115, 838-1115, 838-1128, 838-1292, 839-1054, 839-1295, 839-1297, 841-1103, 841-1108, 842-1225, 843-1058, 846-1291, 849-1296, 850-1213, 851-1099, 852-1291, 853-1296, 855-1291, 858-1288, 860-1286, 861-1006, 866-1288, 866-1297, 867-1286, 873-1288, 874-1065, 874-1288, 875-1089, 876-1105, 879-1065, 880-1009, 882-1291, 883-1324, 884-1062, 885-1286, 886-1065, 888-1065, 888-1137, 889-1065, 890-1305, 893-1288, 894-1062, 894-1294, 894-1305, 897-1065, 898-1191, 898-1291, 899-1065, 899-1298, 902-1158, 909-1263, 909-1295, 910-1291, 912-1106, 913-1263, 920-1203, 921-1130, 921-1151, 921-1158, 923-1151, 923-1240, 926-1179, 932-1187, 934-1123, 935-1203, 943-1065, 947-1065, 947-1308, 952-1211, 953-1232, 955-1263, 957-1183, 958-1132, 959-1258, 959-1263, 960-1252, 961-1065, 962-1291, 962-1297, 963-1062, 969-1290, 973-1269, 974-1253, 974-1291, 975-1291, 976-1278, 986-1238, 986-1243, 987-1202, 991-1178, 991-1239, 996-1205, 999-1300, 1001-1236, 1002-1290, 1008-1244, 1008- 1277, 1011-1289, 1013-1286, 1014-1115, 1017-1297, 1029-1209, 1031-1277, 1032-1269, 1050-1289, 1056-1289, 1058-1296, 1064-1293, 1068-1287, 1078-1313, 1078-1328, 1079-1288, 1079-1296, 1083-1286, 1089-1286, 1090- 1362, 1090-1735, 1097-1286, 1101-1295, 1108-1305, 1108-1380, 1140-1297, 1152-1379, 1170-1305, 1192-1299 114/7510617CB1/1-239, 1-271, 2-272, 2-551, 2-700, 10-536, 11-1934, 14-644, 19-212, 20-524, 27-537, 28-634, 29-169, 29-275, 29-369, 29-627, 30-316, 32- 2073 172, 32-605, 32-663, 32-771, 34-189, 34-195, 34-375, 35-329, 37-300, 38-707, 39-200, 41-280, 41-286, 41-290, 41-299, 41-513, 41-721, 41- 722, 43-296, 44-558, 45-271, 46-315, 46-317, 47-285, 47-330, 47-588, 48-331, 49-287, 52-331, 52-380, 52-712, 53-329, 54-765, 56-663, 56- 726, 56-851, 60-617, 73-343, 84-301, 96-722, 100-665, 118-304, 120-897, 120-915, 120-1013, 120-1019, 124-722, 133-735, 134-603, 134- 751, 135-474, 136-555, 137-393, 138-391, 139-369, 139-415, 139-427, 139-873, 141-727, 148-380, 148-693, 148-742, 148-789, 148-857, 148-861, 148-913, 148-1022, 148-1043, 148-1082, 149-316, 150-1020, 162-408, 163-393, 163-459, 163-701, 163-738, 168-793, 170-689, 173-507, 182-843, 209-241, 223-433, 233-513, 234-826, 243-510, 243-530, 249-507, 251-523, 251-655, 251-1127, 251-1131, 251-1132, 251-1258, 260-507, 265-482, 266-505, 267-916, 276-791, 281-510, 283-767, 296-851, 303-941, 305-806, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length v 306-839, 311-868, 312-922, 317-628, 317-870, 318-825, 320-601, 321-552, 321-591, 325-916, 331-1261, 334-605, 352-654, 352-682, 352- 853, 359-1291, 363-938, 367-572, 368-658, 370-931, 370-1095, 381-1088, 391-664, 401-690, 401-951, 402-567, 404-846, 409-1045, 411- 608, 415-1009, 418-602, 418-652, 418-1159, 422-669, 422-786, 427-781, 427-1043, 429-695, 431-695, 431-710, 437-709, 447-698, 447- 984, 447-1359, 448-1066, 455-731, 457-1199, 457-1359, 457-1360, 457-1367, 464-1159, 470-667, 473-1374, 475-644, 476-1359, 480-752, 480-1079, 481-885, 484-1359, 491-795, 492-1020, 499-683, 499-1258, 504-1046, 507-768, 507-1098, 515-839, 524-803, 531-706, 532- 787, 533-736, 534-1157, 537-656, 537-1183, 540-1175, 542-870, 543-1068, 543-1076, 554-1183, 555-1369, 556-777, 564-1362, 565-1166, 566-1048, 568-1049, 572-1133, 575-762, 578-1117, 584-870, 591-1037, 593-829, 593-883, 601-1034, 603-1226, 604-824, 608-1223, 610- 1063, 613-1122, 620-915, 625-911, 625-1001, 627-890, 627-1089, 628-931, 633-882, 633-899, 633-936, 633-1148, 633-1272, 635-931, 638-1238, 641-806, 641-898, 641-1236, 643-919, 645-1373, 646-1250, 652-1258, 653-1295, 655-1264, 657- 1043, 657-1091, 657-1218, 658-1233, 659-1244, 660-904, 667-1126, 668-1330, 675-1030, 675-1293, 679-953, 679-1216, 680-1295, 685- 946, 686-948, 687-978, 689-1010, 693-1266, 699-1129, 699-1202, 707-987, 707-1280, 708-1153, 708-1345, 709-992, 712-1368, 713-1238, 717-1285, 720-939, 720-956, 720-979, 720-991, 720-1005, 721-928, 723-1166, 724-1267, 725-978, 726-961, 726-971, 727-1168, 732- 1024, 732-1268, 737-1185, 737-1256, 741-1075, 746-1000, 748-916, 748-1372, 749-1030, 751-946, 751-998, 753-1012, 755-1103, 759- 1063, 759-1372, 761-1310, 762-1007, 763-1013, 763-1052, 763-1314, 763-1327, 763-1328, 763-1347, 764-981, 766-942, 769-1276, 770- 1001, 770-1002, 792-1015, 797-1123, 797-1329, 799-1104, 800-1069, 804-1087, 805-1134, 806-1278, 806-1279, 807-1011, 807-1057, 808- 920, 810-1369, 811-1063, 811-1101, 811-1102, 815-1231, 816-1088, 817-1018, 817-1053, 819-1062, 823-1065, 827-1372, 829-1069, 829-1070, 832-1075, 832-1113, 832-1285, 832-1296, 837-1024, 837-1099, 841-1306, 845-1055, 845-1096, 845-1306, 847-1026, 847-1139, 848-1091, 848-1128, 848-1314, 849-1005, 851-1244, 855-1110, 868-1141, 868-1297, 869-1118, 872-1044, 881-1372, 886-1027, 888-1081, 888-1188, 888-1197, 894-1307, 894-1338, 894-1342, 894-1372, 896-1137, 896-1140, 896-1149, 896-1220, 899-1150, 901-1166, 903-1137, 903-1245, 910-1174, 917-1283, 919-1197, 921-1101, 924-1151, 924-1203, 924-1208, 925-1214, 926-1227, 934-1173, 935-1197, 937-1235, 938-1205, 938-1207, 940-1224, 940-1356, 941-1201, 943-1195, 947-1236, 949-1259, 952-1242, 957-1182, 957-1224, 958-1234, 960-1252, 960-1268, 969-1232, 973-1225, 973-1229, 973-1244, 974-1166, 975-1235, 980-1194, 985-1333, 989-1197, 989-1267, 990-1208, 997-1372, 998-1372, 999-1227, 1001-1206, 1001-1276, 1005-1199, 1006-1248, 1009-1208, 1012-1227, 1014-1275, 1015-1248, 1016-1335, 1017-1261, 1024-1244, 1024-1301, 1027-1230, 1027-1265, 1027-1295, 1027-1296, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 1033-1257, 1037-1297, 1039-1242, 1040-1280, 1043-1212, 1043-1337, 1053-1291, 1058-1285, 1059-1353, 1065-1333, 1066-1338, 1069- 1289, 1074-1351, 1076-1350, 1080-1333, 1084-1314, 1084-1347, 1085-1329, 1091-1344, 1093-1372, 1098-1298, 1098-1353, 1098-1363, 1101-1349, 1104-1341, 1104-1358, 1107-1303, 1108-1360, 1109-1364, 1110-1325, 1110-1372, 1115-1368, 1115-1372, 1125-1372, 1138- 1338, 1139-1372, 1148-1372, 1164-1363, 1177-1372, 1203-1372, 1206-1412, 1216-1327, 1262-1507, 1266-1372, 1369-1884, 1369-1935, 1369-1939, 1371-1610, 1372-1499, 1372-1519, 1372-1602, 1372-1633, 1372-1647, 1372-1654, 1372-1661, 1372-1674, 1372-1678, 1372- 1791, 1372-1808, 1372-1810, 1372-1880, 1372-1915, 1374-1651, 1374-1841, 1375-1882, 1377-1593, 1378-1883, 1382-1620, 1382-1626, 1384-1641, 1385-1666, 1388-1635, 1388-1661, 1398-1521, 1400-1912, 1406-1674, 1408-1618, 1410-1668, 1414-1633, 1414-1688, 1415- 1919, 1420-1665, 1422-1645, 1424-1614, 1424-1625, 1425-1838, 1429-1728, 1429-1731, 1430-1697, 1432-1662, 1434-1886, 1436-1675, 1437-1653, 1440-1886, 1442-1878, 1443-1854, 1444-1937, 1446-1937, 1447-1755, 1447-1886, 1447-1922, 1447- 1927, 1447-1928, 1447-1930, 1447-1931, 1447-1933, 1447-1934, 1447-1935, 1447-1936, 1447-1937, 1447-1938, 1447-1939, 1447-1944, 1447-1945, 1447-1965, 1447-2073, 1449-2028, 1450-1696, 1450-1886, 1451-1650, 1452-1883, 1454-1922, 1456-1752, 1458-1936, 1459- 1937, 1460-1698, 1463-1937, 1464-1937, 1467-1924, 1472-1657, 1474-1721, 1476-1904, 1478-1937, 1479-1760, 1479-1919, 1480-1925, 1481-1751, 1482-1912, 1482-1937, 1483-1892, 1485-1924, 1486-1930, 1487-1749, 1488-1720, 1488-1915, 1488-1926, 1489-1923, 1489- 1931, 1491-1738, 1491-1937, 1492-1746, 1492-1755, 1492-1763, 1493-1923, 1493-1925, 1494-1922, 1496-1777, 1497-1917, 1498-1915, 1500-1937, 1501-1914, 1501-1931, 1502-1922, 1503-1924, 1504-1925, 1505-1922, 1505-1924, 1506-1838, 1506-1922, 1506-1924, 1507- 1922, 1507-1923, 1507-1925, 1508-1922, 1508-1925, 1509-1917, 1509-1922, 1510-1919, 1510-1922, 1510-1924, 1510-1937, 1511-1922, 1512-1922, 1513-1796, 1513-1922, 1515-1923, 1516-1917, 1516-1941, 1516-1942, 1517-1928, 1522-1895, 1522- 1917, 1522-1922, 1522-1928, 1523-1922, 1523-1937, 1524-1807, 1526-1742, 1526-1925, 1528-1916, 1529-1917, 1529-1922, 1530-1922, 1531-1897, 1532-1931, 1535-1917, 1535-1929, 1536-1923, 1536-1925, 1536-1937, 1539-1927, 1545-1922, 1549-1917, 1549-1922, 1554- 1923, 1554-1937, 1555-1897, 1557-1928, 1560-1916, 1561-1925, 1564-1916, 1569-1917, 1573-1922, 1574-1931, 1576-1926, 1579-1922, 1580-1925, 1588-1817, 1589-1922, 1589-1930, 1590-1925, 1591-1922, 1591-1925, 1592-1922, 1593-1916, 1593-1922, 1593-1927, 1593- 1929, 1595-1880, 1596-1927, 1597-1922, 1597-1947, 1598-1922, 1599-1866, 1606-1837, 1606-1852, 1607-1868, 1607-1930, 1608-1924, 1610-1930, 1615-1919, 1615-1922, 1615-1923, 1615-1927, 1616-1913, 1617-1920, 1622-1929, 1623-1675, 1625-1922, 1626-1894, 1626- 1918, 1628-1826, 1628-1850, 1628-1883, 1628-1897, 1628-1917, 1629-1889, 1631-1873, 1632-1923, 1635-1863, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length Length 1635-1922, 1635-1937, 1636-1923, 1637-1922, 1638-1877, 1641-1922, 1642-1802, 1646-1925, 1648-1922, 1650-1858, 1650-1893, 1650- 1917, 1650-1930, 1655-1860, 1655-1922, 1656-1919, 1656-1930, 1660-1922, 1661-1922, 1662-1922, 1665-1922, 1668-1922, 1669-1922, 1669-1930, 1670-1925, 1671-1922, 1677-1922, 1679-1894, 1680-1919, 1688-1922, 1692-1923, 1710-1923, 1711-1922, 1711-1923, 1714- 1926, 1715-1919, 1716-1931, 1722-1935, 1752-1929, 1753-1917, 1753-1922, 1756-1917, 1757-1936, 1762-1906, 1778-1922, 1782-1922, 1783-1929, 1796-1939, 1825-1927, 1829-1922, 1851-1922 115/7510618CB1/1-239, 1-271, 2-272, 11-1061, 19-212, 27-502, 29-169, 29-275, 29-369, 30-316, 32-172, 34-189, 34-195, 34-375, 35-329, 37-300, 39-200, 1062 41-280, 41-286, 41-290, 41-299, 41-502, 43-296, 45-271, 46-315, 46-317, 47-285, 47-330, 48-331, 49-287, 52-331, 52-380, 53-329, 73-343, 84-301, 96-502, 118-304, 135-474, 137-393, 138-391, 139-369, 139-415, 139-427, 148-920, 153-919, 162-408, 163-393, 233-502, 243-502, 251-497, 251-502, 260-502, 265-482, 266-502, 498-626, 498-646, 498-729, 498-760, 498-774, 498-781, 498-788, 498-801, 498-805, 498- 918, 498-937, 498-1007, 498-1042, 499-737, 500-1011, 501-778, 501-968, 502-1009, 504-720, 504-935, 504-1062, 505-1010, 505-1042, 509-747, 509-753, 511-768, 512-793, 515-762, 515-788, 525-648, 527-1039, 533-801, 535-745, 537-795, 541-760, 541-815, 542-1046, 547- 792, 549-772, 551-741, 551-752, 552-965, 555-701, 556-855, 556-858, 557-824, 559-789, 561-1013, 563-802, 564-780, 567-1013, 569- 1005, 570-981, 574-882, 574-946, 574-1013, 574-1049, 574-1054, 574-1055, 574-1057, 574-1058, 574-1060, 574-1061, 574-1062, 576-1062, 577-823, 577-1013, 578-777, 579-1010, 580-819, 581-1049, 583-879, 585-809, 585-868, 585-1062, 586- 1062, 587-825, 590-1062, 591-1062, 594-1051, 599-784, 601-848, 603-1031, 606-887, 606-1046, 607-1052, 608-878, 609-1039, 609-1062, 610-1019, 612-1051, 613-1057, 614-876, 615-847, 615-1042, 615-1053, 616-1050, 616-1058, 618-865, 618-1062, 619-873, 619-882, 619- 890, 620-1050, 621-1049, 623-904, 624-1044, 625-980, 625-1042, 628-1058, 629-1049, 630-1051, 631-1052, 632-1049, 632-1051, 633- 965, 633-1049, 633-1051, 634-1049, 634-1050, 634-1052, 635-1049, 635-1052, 636-1044, 636-1049, 637-1046, 637-1049, 637-1051, 637- 1062, 638-1049, 639-1049, 640-923, 640-1049, 642-1050, 643-1044, 643-1062, 644-1055, 649-1022, 649-1044, 649-1049, 649-1055, 650- 1049, 650-1062, 651-934, 653-869, 653-1052, 655-1043, 656-1044, 656-1049, 657-1049, 658-1024, 659-1058, 662-1044, 662-1056, 663- 1050, 663-1052, 666-1054, 672-1049, 673-915, 676-1044, 676-1049, 681-1050, 681-1062, 682-1024, 682-1062, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length _-1049, 684-1055, 687-1043, 691-1043, 696-1044, 700-1049, 701-1058, 703-1052, 703-1053, 703-1062, 706-1049, 707-1052, 715-944, 716-1049, 716-1057, 717-1052, 718-1049, 719-1049, 720-1043, 720-1049, 720-1054, 720-1056, 722-1007, 723-1054, 724-1049, 724-1062, 725-1049, 726-993, 727-1060, 727-1062, 728-1050, 728-1062, 733-964, 733-979, 733-1041, 733-1050, 734-995, 734-1057, 735-1051, 737-1057, 742- 1046, 742-1049, 742-1050, 742-1054, 743-1040, 749-1056, 752-1049, 753-1021, 753-1045, 755-953, 755-977, 755-1010, 755-1024, 755- 1044, 756-1016, 758-1000, 759-1050, 762-990, 762-1049, 762-1062, 763-1050, 764-1049, 765-1004, 768-1049, 769-929, 773-1052, 775- 1049, 777-985, 777-1020, 777-1044, 777-1057, 782-987, 782-1049, 783-1046, 783-1057, 787-1049, 788-1049, 789-1049, 792-1049, 795- 1049, 796-1049, 796-1057, 797-1052, 802-1049, 804-1049, 806-1021, 807-1046, 810-1062, 815-1049, 819-1050, 820-1062, 836-1032, 837- 1050, 838-1049, 838-1050, 841-1053, 842-1046, 843-1058, 849-1062, 880-1044, 880-1049, 883-1044, 884-1062, 889-1033, 891-1050, 905- 1049, 909-1049, 910-1056, 923-1062, 952-1054, 956-1049 116/7510620CB1/1-264, 11-206, 14-314, 14-320, 14-1271, 14-1281, 22-296, 22-303, 22-608, 23-146, 23-282, 29-285, 31-299, 31-316, 31-317, 31-322, 31- 1339 323, 40-286, 40-321, 43-307, 46-272, 47-286, 47-302, 47-314, 48-256, 48-293, 48-294, 48-322, 50-336, 50-337, 51-178, 51-239, 51-260, 51- 284, 51-292, 51-305, 51-337, 51-344, 53-326, 53-335, 54-208, 54-229, 54-246, 54-262, 54-274, 54-286, 54-290, 54-297, 54-301, 54-302, 54- 304, 54-305, 54-307, 54-313, 54-315, 54-320, 54-321, 54-329, 54-331, 54-333, 54-335, 54-337, 54-340, 54-341, 54-343, 54-344, 55-296, 55- 313, 55-322, 55-332, 55-336, 55-338, 55-342, 55-344, 56-273, 56-290, 56-317, 56-325, 56-344, 57-192, 57-209, 57-297, 57-303, 57-306, 57- 312, 57-314, 57-315, 57-318, 57-326, 57-329, 57-330, 57-343, 57-344, 58-219, 58-303, 58-309, 58-313, 58-318, 58-336, 58-340, 59-291, 59- 304, 59-323, 59-327, 59-337, 60-289, 60-310, 60-333, 60-336, 60-338, 60-342, 60-344, 61-344, 62-344, 62-608, 63-280, 63-316, 63-328, 63- 333, 64-327, 64-344, 67-316, 67-336, 67-344, 68-222, 69-243, 69-332, 70-327, 75-343, 76-277, 76-284, 76-286, 76-325, 76-344, 77-305, 77-324, 77-341, 77-343, 77-344, 78-344, 107-343, 111-293, 116-229, 125-344, 131-279, 131-291, 133-330, 133-337, 135-336, 135-337, 188-272, 192-313, 193-344, 343-591, 343-924, 343-934, 343-936, 366-512, 366-898, 369- 1076, 369-1221, 369-1243, 388-651, 388-884, 393-591, 398-668, 403-926, 404-987, 427-693, 427-1056, 459-1268, 464-992, 464-1011, 490- 1218, 499-766, 499-773, 512-1013, 517-789, 536-797, 540-1079, 551-1228, 562-836, 562-1059, 562-1273, 563-839, 563-861, 563-928, 564- 1257, 564-1266, 564-1271, 564-1273, 567-821, 570-807, 571-818, 571-835, 572-799, 572-806, 575-804, 576-1222, 577-839, 580-1096, 589- 805, 590-1273, 595-1157, 596-874, 599-880, 605-870, 605-1096, 612-1182, 613-1166, 615-1188, 616-1189, 621-1272, 623-966, 630-1161, 634-1214, 639-943, 639-1220, 641-1229, 647-911, 653-832, 653-904, 654-1159, 657-1187, 659-1156, 660-873, 665-813, 665-936, 667- 911, 667-1007, 668-865, 668-927, 669-941, 669-1166, 670-1143, 671-925, 671-951, 672-848, 673-935, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 691-849, 691-911, 693-857, 693-1152, 701-914, 711-920, 711-961, 712-973, 713-941, 713-962, 716-995, 717-1283, 723-1006, 726-978, 738-1011, 745-1222, 745-1268, 748-1016, 750-1027, 758-1009, 763-1012, 777-969, 777-971, 777-1266, 780-1226, 788-983, 794-1295, 796- 1073, 796-1091, 797-987, 798-1156, 798-1252, 799-1038, 803-1287, 805-1082, 813-1047, 813-1268, 815-1232, 816-1119, 817-1094, 817- 1170, 818-1076, 821-1290, 823-1053, 825-1051, 832-1002, 839-1084, 841-1138, 844-1135, 847-1098, 848-1127, 849-1064, 849-1116, 849- 1121, 849-1125, 849-1168, 849-1187, 849-1264, 849-1268, 850-1142, 850-1244, 850-1277, 851-1083, 853-1272, 854-1273, 855-1068, 857- 1129, 860-1190, 860-1276, 860-1336, 878-1221, 879-1021, 879-1151, 880-1115, 880-1139, 883-1126, 886-1138, 887-1172, 889-1212, 893- 1152, 893-1191, 894-1122, 895-1110, 901-1130, 911-1155, 915-1173, 920-1178, 922-1336, 926-1181, 926-1290, 927-1294, 933-1155, 935- 1167, 935-1197, 944-1075, 949-1266, 954-1157, 954-1207, 954-1228, 965-1207, 972-1256, 980-1252, 981-1280, 986-1292, 995-1227, 1008-1263, 1012-1279, 1015-1218, 1015-1271, 1017-1176, 1017-1306, 1019-1249, 1019-1266, 1019-1271, 1022-1261, 1037-1262, 1038-1255, 1047-1282, 1050-1271, 1052-1279, 1053-1282, 1053-1287, 1053-1310, 1053-1335, 1056- 1289, 1061-1294, 1067-1172, 1070-1167, 1071-1219, 1077-1273, 1079-1265, 1079-1290, 1082-1274, 1084-1266, 1085-1278, 1088-1268, 1101-1289, 1101-1307, 1102-1291, 1103-1279, 1103-1292, 1103-1317, 1103-1339, 1105-1273, 1107-1268, 1109-1282, 1109-1325, 1113- 1211, 1113-1300, 1114-1314, 1118-1318, 1124-1285, 1140-1309, 1142-1286, 1151-1245, 1164-1313, 1166-1278, 1169-1331, 1176-1268, 1204-1311 117/7510628CB1/1-240, 1-436, 1-1357, 23-254, 29-260, 35-312, 52-261, 80-228, 96-261, 100-261, 107-258, 259-520, 259-687, 259-780, 259-850, 259-874, 1360 266-759, 270-563, 273-703, 274-651, 274-703, 275-541, 275-567, 286-973, 292-537, 293-837, 300-576, 306-1148, 313-567, 316-973, 334- 585, 336-918, 342-860, 345-837, 347-599, 355-646, 366-673, 368-632, 369-740, 375-608, 376-661, 383-616, 383-619, 392-708, 394-626, 394-652, 409-1138, 417-524, 417-634, 429-650, 433-883, 437-1305, 439-631, 444-1045, 445-1097, 452-1306, 456-621, 462-868, 464-950, 477-1356, 486-946, 487-839, 493-1228, 494-1067, 498-742, 518-1058, 520-1199, 521-631, 526-964, 527-855, 527-1312, 545-1111, 554- 1087, 559-931, 559-1216, 561-1072, 563-828, 563-838, 563-1104, 568-1241, 570-810, 570-817, 573-1360, 580-890, 582-1236, 585-815, 585-1116, 591-1095, 592-846, 592-875, 606-1248, 608-1257, 610-1062, 610-1162, 611-1239, 621-876, 622-1337, 630-879, 638-1320, 639- 1083, 647-1358, 652-916, 655-897, 657-1202, 657-1273, 657-1290, 667-953, 676-952, 676-1355, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 679-1259, 684-881, 685-908, 693-1044, 696-1095, 699-1316, 700-1356, 706-1360, 709-949, 709-955, 714-894, 725-988, 725-1284, 733- 946, 741-983, 741-1168, 742-1023, 752-1356, 755-1324, 764-1002, 767-1356, 778-1101, 778-1322, 801-1252, 801-1306, 806-1360, 808- 1249, 811-1052, 820-1355, 823-1100, 823-1319, 826-1291, 830-1078, 831-1102, 831-1107, 846-1344, 847-1360, 850-995, 853-966, 853- 1285, 855-1360, 858-1133, 859-1350, 865-1119, 867-1354, 873-1360, 874-1356, 888-1147, 888-1346, 891-1312, 891-1341, 893-1341, 896- 1090, 902-1321, 908-1359 ; 908-1360, 912-1322, 915-1343, 915-1344, 920-1360, 925-1109, 925-1342, 926-1360, 927-1343, 929-1357, 929- 1360, 933-1341, 933-1342, 941-1344, 948-1342, 950-1190, 953-1342, 955-1331, 959-1214, 962-1360, 976-1135, 977-1163, 978-1322, 985- 1348, 997-1227, 997-1340, 1007-1346, 1012-1340, 1018-1313, 1020-1277, 1023-1340, 1028-1360, 1029-1322, 1043-1340, 1045-1342, 1055-1344, 1061-1342, 1066-1285, 1068-1344, 1068-1360, 1069-1354, 1073-1320, 1075-1337, 1080-1303, 1081-1275, 1083-1344, 1096-1277, 1104-1336, 1108-1347, 1109-1339, 1115-1322, 1117-1339, 1120-1344, 1127-1344, 1144-1336, 1153- 1342, 1155-1332, 1177-1346, 1184-1344, 1186-1341, 1190-1345, 1203-1339, 1233-1346, 1234-1303 118/7510650CB1/1-280, 1-1469, 419-580, 419-636, 419-692, 419-818, 419-886, 419-923, 450-961, 452-644, 489-1092, 531-791, 548-791, 616-1093, 646- 1474 848, 646-852, 692-808, 699-962, 754-959, 834-1121, 887-1474, 933-1474, 975-1154, 975-1359, 975-1425, 981-1474, 1003-1282, 1101- 1472, 1101-1473, 1102-1474, 1123-1464, 1133-1463, 1158-1452, 1162-1390, 1162-1466, 1172-1401, 1191-1466, 1249-1474, 1256-1474, 1261-1464, 1268-1474, 1338-1467, 1351-1474, 1392-1474 119/7506644CB1/1-175, 1-177, 1-842, 1-879, 2-1471, 6-789, 20-177, 31-177, 47-177, 47-243, 49-135, 56-254, 57-246, 60-177, 63-177, 66-308, 70-177, 74- 1473 177, 81-188, 81-285, 81-422, 86-313, 88-177, 89-177, 92-364, 93-177, 96-177, 101-292, 102-177, 112-270, 116-370, 117-175, 117-177, 125-406, 139-282, 139-355, 159-1023, 423-574, 423-861, 423-890, 423-902, 423-1037, 423-1099, 423-1305, 445-1294, 489-1032, 502- 1325, 559-640, 567-1167, 606-1308, 633-1466, 639-1473, 667-1285, 670-1472, 687-1472, 699-1473, 705-1309, 711-1470, 713-1243, 713- 1472, 731-1470, 737-1390, 747-1305, 800-1059, 835-1155, 849-1448, 862-1457, 878-1100, 878-1234, 878-1413, 878-1426, 878-1428, 878- 1429, 878-1431, 878-1434, 878-1449, 878-1454, 878-1460, 878-1465, 878-1473, 906-1146, 910-1242, 910-1243, 933-1391, 935-1253, 947- 1390, 1011-1455, 1066-1327, 1082-1317 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 120/7506692CB 1/1-98, 1-99, 1-264, 1-270, 1-365, 1-389, 1-400, 1-517, 1-534, 1-536, 1-551, 1-618, 1-630, 1-634, 1-674, 1-724, 1-865, 1-883, 1-2388, 2-274, 2400 2-476, 3-277, 3-849, 4-527, 4-771, 5-856, 10-594, 11-559, 11-603, 19-676, 19-677, 21-262, 35-645, 78-633, 118-816, 120-675, 120-686, 120-722, 120-740, 122-587, 123-847, 127-164, 128-457, 134-634, 137-524, 137-774, 141-782, 153-776, 155-681, 164-625, 175-835, 188- 752, 188-800, 188-816, 188-834, 191-744, 199-792, 209-761, 229-826, 239-690, 250-573, 267-794, 277-487, 277-527, 277-542, 277-787, 324-879, 344-614, 346-632, 371-630, 375-888, 376-534, 388-795, 400-602, 408-674, 408-692, 422-840, 424-667, 432-930, 463-879, 470- 719, 490-811, 502-921, 517-780, 535-661, 555-930, 577-777, 584-856, 585-856, 591-735, 668-855, 687-885, 725-886, 739-923, 769-928, 774-930, 774-1104, 830-930, 904-1068, 928-1087, 928-1100, 928-1168, 931-1062, 932-1342, 935-1110, 938-1362, 946-1191, 950-1407, 957-1596, 968-1239, 977-1517, 986-1604, 990-1489, 995-1205, 997-1253, 1001-1213, 1002-1587, 1005-1417, 1010-1484, 1013-1594, 1016-1208, 1017-1903, 1022-1213, 1029-1483, 1030-1379, 1046-1623, 1053-1521, 1057-1517, 1060-1242, 1061- 1588, 1061-1689, 1064-1359, 1065-1249, 1071-1252, 1071-1295, 1071-1338, 1071-1595, 1071-1626, 1071-1696, 1072-1961, 1084-1236, 1088-1353, 1092-1279, 1092-2008, 1094-1625, 1094-1691, 1103-1769, 1106-1769, 1107-1306, 1107-1905, 1108-1371, 1112-1749, 1115- 1423, 1119-1739, 1125-1375, 1126-1411, 1127-1313, 1129-1308, 1132-1403, 1134-1394, 1136-1324, 1153-1412, 1159-1653, 1161-1376, 1164-1814, 1168-1871, 1170-1761, 1174-1432, 1175-1485, 1176-1787, 1182-1922, 1189-1579, 1190-1597, 1190-1711, 1196-1821, 1197- 1983, 1210-1414, 1221-1694, 1223-1576, 1231-1477, 1239-2010, 1240-1588, 1241-1494, 1241-1849, 1245-1461, 1248-1511, 1250-1521, 1255-1700, 1255-1902, 1257-1384, 1263-1411, 1271-1505, 1272-1874, 1275-1526, 1275-1528, 1275-1780, 1276-1854, 1280-1712, 1281- 1776, 1283-1754, 1287-1945, 1289-1539, 1290-1452, 1291-1863, 1292-1534, 1292-1548, 1292-2139, 1293-1633, 1294-1502, 1296-2239, 1298-1784, 1302-1914, 1308-1886, 1312-1938, 1313-1901, 1316-1599, 1320-1949, 1321-1589, 1321-1842, 1322- 1890, 1324-1651, 1325-1514, 1326-1543, 1330-1934, 1344-1983, 1349-1502, 1349-2233, 1354-1534, 1354-1611, 1358-1907, 1359-1941, 1360-1854, 1363-1651, 1363-1827, 1369-1551, 1373-1544, 1373-1955, 1373-1976, 1374-1489, 1383-1909, 1385-1739, 1389-2039, 1389- 2104, 1391-1651, 1394-2091, 1397-1683, 1397-1932, 1400-1659, 1400-1675, 1401-1880, 1405-2266, 1406-1651, 1406-1682, 1406-1692, 1412-1694, 1412-1903, 1413-1957, 1415-2117, 1419-1935, 1420-1729, 1425-1889, 1426-2010, 1428-2072, 1431-1771, 1431-1965, 1431- 2076, 1463-2008, 1464-1693, 1465-1949, 1466-2047, 1471-2023, 1472-1751, 1474-2131, 1476-1741, 1478-1764, 1479-1795, 1479-2041, 1480-1875, 1491-2146, 1492-1742, 1492-1768, 1494-2186, 1496-1888, 1520-1769, 1522-1870, 1534-1654, 1534-1741, 1538-2046, 1538- 2310, 1549-1785, 1551-1763, 1551-1851, 1551-1862, 1552-1996, 1554-1855, 1561-1836, 1562-2146, 1567-1820, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 1567-2016, 1567-2256, 1567-2272, 1582-1919, 1582-2092, 1583-2243, 1588-2028, 1588-2171, 1589-1883, 1589-2134, 1591-2119, 1594- 1826, 1596-1842, 1598-1826, 1598-2082, 1600-1731, 1600-1816, 1601-2247, 1605-1852, 1605-1871, 1606-1814, 1609-1833, 1610-2322, 1611-1994, 1611-2000, 1614-2334, 1619-1845, 1620-1902, 1622-1886, 1625-1870, 1625-2361, 1632-2233, 1634-1922, 1635-1900, 1656- 2257, 1658-1919, 1658-2142, 1662-1821, 1666-1809, 1666-1942, 1668-1872, 1674-1779, 1674-1993, 1674-2214, 1676-1755, 1678-2109, 1679-2330, 1684-2112, 1685-2157, 1689-1904, 1689-1929, 1689-1932, 1692-2323, 1692-2372, 1694-1933, 1694-2007, 1694-2011, 1694- 2113, 1695-1976, 1695-1990, 1695-1992, 1695-1996, 1695-1998, 1695-2001, 1695-2018, 1695-2019, 1695-2026, 1695-2307, 1695-2399, 1696-1992, 1697-2144, 1701-1945, 1702-2314, 1706-2311, 1709-1966, 1713-2000, 1724-1993, 1724-2256, 1728-2351, 1730-2171, 1731- 1904, 1731-1911, 1733-1970, 1734-2117, 1742-2385, 1747-2325, 1754-2002, 1754-2295, 1755-2020, 1759-1973, 1759-2010, 1764-2366, 1776-2199, 1776-2400, 1779-2109, 1780-2312, 1782-2077, 1782-2163, 1784-2103, 1785-2003, 1785-2060, 1787- 2022, 1787-2324, 1791-2115, 1791-2400, 1794-2041, 1794-2064, 1796-2369, 1798-2350, 1802-2314, 1802-2394, 1802-2400, 1803-2311, 1805-2120, 1813-1994, 1815-2400, 1816-2051, 1816-2081, 1818-2019, 1827-2151, 1829-2382, 1830-2061, 1834-2371, 1836-2381, 1844- 2171, 1850-2390, 1856-2116, 1861-2135, 1862-2400, 1865-2120, 1865-2136, 1869-2146, 1870-2068, 1870-2122, 1872-2145, 1879-2040, 1883-2162, 1887-2138, 1894-2400, 1895-2149, 1903-2294, 1904-2398, 1912-2233, 1915-2394, 1917-2046, 1923-2146, 1923-2368, 1923- 2384, 1923-2400, 1924-2171, 1924-2383, 1927-2172, 1928-2151, 1928-2380, 1933-2387, 1935-2400, 1938-2170, 1939-2156, 1939-2400, 1941-2380, 1943-2379, 1944-2400, 1948-2121, 1951-2380, 1956-2121, 1956-2197, 1959-2400, 1962-2398, 1966-2224, 1966-2242, 1968- 2380, 1973-2383, 1974-2380, 1975-2380, 1976-2361, 1977-2241, 1979-2380, 1980-2379, 1985-2209, 1985-2380, 1986-2122, 1987-2221, 1987-2249, 1987-2380, 1990-2192, 1990-2380, 1999-2387, 2006-2373, 2024-2381, 2030-2270, 2030-2284, 2031- 2400, 2032-2380, 2033-2394, 2034-2380, 2040-2317, 2042-2387, 2044-2376, 2047-2379, 2047-2380, 2052-2309, 2052-2399, 2055-2323, 2062-2400, 2071-2400, 2075-2335, 2075-2380, 2075-2400, 2079-2388, 2084-2363, 2087-2337, 2087-2380, 2095-2380, 2098-2399, 2103- 2371, 2105-2394, 2110-2380, 2111-2380, 2112-2380, 2120-2380, 2124-2277, 2126-2388, 2140-2378, 2151-2380, 2158-2373, 2159-2342, 2159-2400, 2166-2394, 2169-2369, 2169-2400, 2170-2294, 2171-2400, 2181-2280, 2184-2400, 2186-2391, 2187-2398, 2187-2400, 2189- 2398, 2202-2380, 2205-2369, 2205-2376, 2206-2367, 2210-2377, 2223-2379, 2225-2380, 2226-2400, 2238-2383, 2242-2379, 2256-2400, 2257-2392, 2309-2380, 2315-2380 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 121/7504938CB /1-262, 1-1658, 24-248, 224-456, 263-459, 263-461, 263-488, 263-797, 263-807, 263-868, 267-791, 267-803, 269-710, 269-983, 279-613, 1658 282-573, 283-534, 283-571, 295-769, 300-906, 308-988, 310-570, 318-555, 325-701, 325-833, 325-881, 327-946, 329-634, 333-878, 340- 951, 342-850, 378-667, 378-1035, 379-571, 379-582, 379-611, 379-916, 385-656, 411-654, 415-691, 417-663, 441-1057, 447-854, 452- 670, 459-719, 471-1102, 500-762, 500-1027, 500-1038, 501-912, 502-739, 508-1041, 526-923, 529-765, 539-1054, 552-723, 554-820, 557- 1054, 576-868, 578-863, 584-831, 584-1052, 585-836, 586-1050, 589-1115, 591-816, 591-1035, 591-1054, 596-1054, 598-1050, 605-1107, 607-1054, 614-882, 614-1054, 617-1192, 633-1050, 635-1054, 642-1250, 649-936, 653-1054, 660-1048, 663-1048, 669-1051, 672-933, 693- 961, 693-1349, 705-938, 706-1203, 720-1318, 726-1051, 731-1126, 732-1050, 743-1017, 743-1053, 745-1031, 749-1017, 749-1028, 777- 978, 778-1197, 779-1050, 782-1048, 795-1037, 816-1051, 817-1054, 818-1076, 828-1106, 828-1124, 828-1127, 833-1054, 835-1051, 852-1050, 854-1458, 858-1051, 861-1052, 865-1541, 877-1095, 882-1051, 883-1149, 886-1095, 889-1482, 891-1367, 895-1521, 909-1051, 921-1496, 921-1497, 932-1168, 936-1052, 936-1593, 942-1190, 967-1229, 974-1189, 977-1266, 993-1437, 1023-1658, 1033-1303, 1067-1287, 1067-1315, 1067-1339, 1067-1651, 1075-1646, 1078-1362, 1082-1374, 1100-1651, 1103-1651, 1105- 1658, 1114-1361, 1114-1419, 1120-1600, 1128-1658, 1134-1658, 1135-1433, 1143-1404, 1160-1658, 1169-1658, 1170-1643, 1175-1611, 1185-1450, 1185-1627, 1185-1655, 1188-1658, 1191-1649, 1193-1646, 1193-1653, 1194-1658, 1198-1649, 1198-1658, 1199-1650, 1200- 1490, 1208-1278, 1209-1481, 1210-1654, 1212-1646, 1214-1658, 1221-1444, 1235-1656, 1239-1605, 1276-1533, 1276-1542, 1280-1646, 1289-1646, 1291-1646, 1292-1648, 1292-1649, 1294-1586, 1319-1650, 1331-1542, 1333-1649, 1338-1646, 1341-1446, 1369-1651, 1370- 1649, 1372-1646, 1387-1622, 1401-1658, 1404-1650, 1432-1651, 1438-1649, 1440-1658, 1441-1658, 1459-1652, 1463-1649, 1469-1622, 11473-1646, 1477-1658, 1492-1658, 1575-1646 122/7505625CB 1/1-264, 1-275, 28-282, 28-3327, 32-294, 35-430, 36-236, 48-430, 51-293, 295-795, 295-832, 295-876, 295-891, 295-901, 295-1117, 306- 3343 913, 313-891, 316-599, 317-903, 319-949, 320-898, 322-848, 328-996, 328-1011, 330-867, 339-909, 342-599, 356-1010, 356-1071, 356- 1117, 356-1131, 356-1136, 356-1211, 356-1214, 360-990, 361-950, 365-934, 376-1015, 383-1040, 385-625, 392-1043, 393-1056, 397-667, 400-713, 404-508, 408-1073, 420-900, 426-1046, 431-996, 438-983, 438-1059, 445-807, 459-1055, 460-1078, 464-1156, 478-638, 482- 1194, 482-1325, 486-996, 486-1063, 495-909, 500-846, 506-959, 518-962, 523-1084, 524-1052, 525-1146, 525-1207, 527-1156, 528-1090, 529-1100, 536-784, 536-918, 536-928, 541-797, 547-735, 548-1037, 549-923, 549-1206, 551-1012, 560-1133, 563-997, 565-1070, 574- 1023, 581-998, 581-1310, 586-1273, 588-1104, 591-1048, 594-830, 594-877, 595-1012, 595-1266, 596-1237, 602-1048, 604-1401, 608- 1215, 618-887, 618-1431, 629-1325, 635-1294, 636-897, 647-1225, 654-1202, 661-913, 675-834, 678-1078, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length v 683-1278, 684-1394, 695-932, 701-1092, 703-1287, 705-1356, 714-1397, 720-927, 724-977, 724-1276, 724-1562, 729-1058, 729-1207, 734- 1370, 736-1295, 737-992, 740-1340, 740-1388, 743-1440, 751-951, 757-1224, 759-1221, 764-1177, 764-1305, 766-1385, 766-1434, 772- 1314, 774-1197, 778-1519, 780-1426, 784-1710, 786-1710, 791-1039, 791-1048, 791-1182, 791-1609, 798-1210, 799-1438, 807-1076, 813- 1257, 814-1440, 814-1710, 816-1399, 817-1119, 822-1119, 824-1402, 825-1402, 831-1498, 833-1112, 837-1594, 841-1393, 842-1458, 845- 1063, 845-1187, 847-1352, 847-1658, 849-1455, 854-1011, 856-1468, 859-1080, 861-1439, 864-1055, 868-1726, 872-1710, 873-1679, 877- 1107, 877-1138, 879-1195, 882-1035, 886-1148, 886-1413, 893-1348, 896-1186, 900-1151, 901-1220, 902-1674, 905-1087, 918-1710, 925- 1580, 935-1260, 936-1442, 939-1470, 942-1366, 950-1470, 950-1493, 952-1199, 952-1478, 954-1303, 960-1189, 960-1549, 964-1574, 971- 1624, 975-1496, 976-1478, 976-1584, 980-1563, 992-1678, 995-1289, 1019-1574, 1020-1779, 1026-1261, 1028-1283, 1036-1648, 1037-1624, 1042-1596, 1043-1659, 1044-1293, 1046-1375, 1047-1622, 1047-1671, 1047- 1707, 1050-1197, 1052-1319, 1055-1552, 1060-1530, 1061-1337, 1068-1731, 1084-1367, 1084-1784, 1088-1653, 1092-1710, 1093-1270, 1095-1613, 1096-1720, 1098-1383, 1098-1783, 1098-1878, 1100-1718, 1105-1636, 1108-1661, 1108-1791, 1116-1403, 1117-1829, 1125- 1926, 1130-1806, 1131-1647, 1141-1373, 1141-1633, 1153-1792, 1153-1926, 1154-1533, 1161-1435, 1161-1586, 1161-1646, 1162-1408, 1164-1473, 1166-1536, 1168-1440, 1168-1749, 1171-1288, 1174-1781, 1177-1500, 1177-1526, 1178-1508, 1180-1715, 1182-1437, 1184- 1603, 1185-1792, 1187-1808, 1189-1787, 1190-1448, 1190-1542, 1197-1440, 1198-1668, 1204-1582, 1205-1707, 1209-1840, 1211-1811, 1213-1864, 1214-1683, 1215-1800, 1221-1706, 1223-1480, 1224-1455, 1224-1507, 1228-1881, 1228-1908, 1235-1798, 1242-1543, 1246- 1785, 1247-1485, 1248-1819, 1251-1497, 1252-1499, 1254-1522, 1255-1898, 1256-1866, 1258-1645, 1260-1867, 1263-1789, 1264-1502, 1273-1877, 1279-1824, 1279-1910, 1279-1934, 1281-1594, 1291-1836, 1295-1890, 1296-1901, 1301- 1541, 1301-1974, 1302-1837, 1302-1897, 1305-1568, 1307-2118, 1311-1526, 1312-1635, 1315-1589, 1315-1590, 1315-1847, 1319-1836, 1320-1834, 1321-1955, 1326-1934, 1332-1955, 1335-1606, 1339-1553, 1339-1592, 1353-1646, 1353-1870, 1354-1871, 1357-1940, 1373- 1610, 1376-1632, 1379-1617, 1379-1974, 1387-1867, 1391-1693, 1397-2083, 1398-1600, 1398-2091, 1403-1896, 1407-1671, 1415-1882, 1417-1667, 1417-1689, 1423-2217, 1426-1662, 1427-1610, 1436-2137, 1437-1999, 1441-2102, 1448-1910, 1450-1686, 1451-1975, 1452- 1665, 1455-2046, 1457-1697, 1457-1721, 1457-1844, 1462-2002, 1464-1684, 1467-1656, 1470-1675, 1472-1712, 1472-1734, 1472-1964, 1473-1727, 1473-1792, 1475-1821, 1475-1829, 1479-1732, 1479-1745, 1479-1755, 1481-2166, 1485-1771, 1486-1919, 1491-1745, 1494- 2143, 1495-1934, 1497-1783, 1497-2071, 1501-1784, 1502-1760, 1502-1767, 1502-2219, 1504-2196, 1509-2002, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 1512-2052, 1514-2180, 1516-1714, 1516-1814, 1516-1855, 1521-2111, 1522-2200, 1523-1796, 1523-1813, 1526-2049, 1527-1826, 1528- 1946, 1531-2065, 1531-2218, 1539-2060, 1546-1812, 1550-2114, 1555-1808, 1555-1916, 1557-2152, 1563-1848, 1569-2030, 1571-2014, 1571-2027, 1573-2220, 1586-2156, 1586-2248, 1589-2151, 1589-2203, 1596-2111, 1601-1929, 1604-2299, 1606-2227, 1608-2099, 1620- 2258, 1620-2296, 1622-2211, 1622-2311, 1623-1644, 1629-2247, 1640-2341, 1652-2264, 1656-2220, 1657-1898, 1657-1916, 1657-1919, 1658-2249, 1659-1919, 1662-1902, 1662-1944, 1662-2206, 1672-1915, 1672-2212, 1673-2267, 1675-1918, 1676-1941, 1680-1943, 1688- 1994, 1688-2340, 1689-2131, 1690-2240, 1693-2229, 1703-1958, 1704-2174, 1705-1977, 1707-2009, 1708-2037, 1711-2310, 1722-1941, 1722-2035, 1722-2393, 1723-2394, 1724-2017, 1730-2339, 1733-2059, 1734-1827, 1735-1827, 1735-2251, 1736-2223, 1739-2251, 1740- 2059, 1741-1953, 1744-2044, 1745-2387, 1748-2009, 1751-2147, 1752-2391, 1758-2067, 1773-2253, 1774-2057, 1775-2213, 1781-2300, 1781-2362, 1783-2338, 1783-2467, 1800-2338, 1801-2421, 1819-2484, 1843-2254, 1854-2012, 1899-2531, 1900- 2486, 1904-2529, 1906-2183, 1918-2107, 1921-2255, 1921-2567, 1922-2202, 1925-2385, 1936-2207, 1943-2479, 1943-2487, 1951-2219, 1952-2633, 1959-2242, 1960-2440, 1960-2718, 1963-2546, 1966-2202, 1966-2216, 1970-2226, 1971-2223, 1977-2504, 1979-2440, 1984- 2499, 1987-2556, 1990-2188, 1990-2515, 1992-2600, 1993-2251, 1993-2599, 1994-2249, 2003-2539, 2007-2677, 2009-2601, 2015-2517, 2027-2332, 2028-2623, 2041-2296, 2042-2294, 2042-2543, 2043-2606, 2044-2527, 2046-2580, 2051-2664, 2054-2682, 2059-2240, 2062- 2334, 2066-2572, 2067-2479, 2068-2746, 2072-2337, 2074-2531, 2075-2680, 2079-2625, 2080-2574, 2080-2625, 2081-2325, 2086-2620, 2090-2363, 2090-2385, 2096-2353, 2096-2705, 2099-2349, 2102-2693, 2103-2576, 2104-2639, 2104-2721, 2109-2361, 2109-2643, 2117- 2690, 2117-2794, 2118-2616, 2120-2593, 2124-2645, 2128-2377, 2128-2385, 2129-2401, 2129-2541, 2132-2288, 2133-2756, 2135-2805, 2140-2646, 2142-2407, 2142-3089, 2145-2419, 2146-2356, 2146-2413, 2149-2247, 2149-2396, 2149-2696, 2151- 2356, 2151-2400, 2152-2406, 2152-2871, 2156-2782, 2164-2896, 2168-2675, 2170-2774, 2179-2555, 2180-2447, 2185-2787, 2186-2352, 2189-2441, 2192-2590, 2195-2739, 2195-2771, 2198-2853, 2199-2574, 2205-2451, 2208-2472, 2209-2727, 2212-2774, 2215-2449, 2215- 2472, 2215-2771, 2217-2500, 2217-2503, 2219-2894, 2224-2759, 2225-2784, 2225-2789, 2232-2539, 2235-2478, 2235-2517, 2241-2720, 2242-2498, 2242-2520, 2248-2508, 2248-2513, 2249-2567, 2249-2617, 2251-2454, 2251-2488, 2255-2923, 2256-2477, 2256-2706, 2256- 2828, 2256-2860, 2259-2490, 2262-2483, 2262-2489, 2262-2513, 2263-2528, 2268-2847, 2279-2538, 2279-2567, 2280-2629, 2280-2974, 2281-2862, 2284-2566, 2285-2493, 2285-2499, 2285-2540, 2285-2646, 2285-2820, 2285-2852, 2285-2911, 2285-2951, 2289-2586, 2289- 2851, 2293-2569, 2293-2581, 2293-2820, 2301-2612, 2302-2455, 2302-2563, 2302-2616, 2302-2971, 2303-2554, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 2305-2822, 2311-2856, 2312-2440, 2318-2603, 2320-2610, 2320-2917, 2322-3013, 2325-2580, 2327-2600, 2331-2745, 2334-2770, 2334- 2798, 2334-2926, 2335-2459, 2338-2587, 2338-2627, 2339-2569, 2340-2622, 2340-2652, 2340-2842, 2341-2837, 2343-2551, 2345-2463, 2345-2619, 2350-2603, 2350-2611, 2350-2625, 2351-2856, 2351-2913, 2351-2926, 2355-2626, 2355-2632, 2357-2472, 2357-2662, 2362- 2742, 2363-2678, 2364-2531, 2364-2554, 2364-2563, 2364-2864, 2372-2776, 2372-2911, 2373-2973, 2374-2647, 2374-2648, 2374-2656, 2374-2815, 2374-2862, 2382-3072, 2389-2657, 2390-2467, 2392-2674, 2392-2678, 2392-2943, 2396-2582, 2397-2590, 2397-2685, 2397- 2976, 2400-2644, 2400-2701, 2400-2773, 2400-2859, 2400-2869, 2400-2879, 2400-2897, 2400-2908, 2400-2959, 2400-2994, 2403-2632, 2404-2648, 2408-2944, 2409-2697, 2410-2660, 2413-2676, 2415-2900, 2417-2697, 2418-2688, 2420-2677, 2423-2815, 2423-2987, 2429- 2633, 2433-2681, 2435-2987, 2436-2655, 2436-2695, 2436-2740, 2436-2976, 2437-2699, 2442-2891, 2447-3089, 2450-3280, 2451-2968, 2453-2687, 2456-3167, 2457-3190, 2460-2689, 2462-3284, 2466-3262, 2468-3073, 2474-2886, 2474-3031, 2474- 3032, 2476-2682, 2480-2842, 2482-3071, 2485-2813, 2485-3229, 2488-2649, 2488-2692, 2488-2729, 2488-2731, 2488-2780, 2489-2747, 2489-2762, 2492-2753, 2492-2755, 2494-2750, 2494-2771, 2495-3227, 2498-2702, 2498-2719, 2501-2756, 2501-2758, 2504-2738, 2504- 3026, 2504-3033, 2506-2784, 2506-2786, 2506-2983, 2507-2743, 2507-2791, 2508-2630, 2509-2748, 2511-2774, 2512-2708, 2512-2737, 2513-2769, 2513-2798, 2514-2805, 2514-3333, 2515-2744, 2515-3185, 2517-2809, 2526-3081, 2527-2745, 2528-3068, 2535-2886, 2535- 3097, 2535-3150, 2537-2804, 2539-2747, 2539-2766, 2539-2773, 2540-2760, 2541-2815, 2543-3080, 2543-3290, 2544-2749, 2544-2908, 2545-3083, 2546-2795, 2546-2966, 2547-2787, 2547-2823, 2547-2835, 2547-3263, 2551-2815, 2551-2886, 2553-2779, 2553-2829, 2560- 2753, 2560-2800, 2560-2814, 2560-2981, 2560-3032, 2562-3296, 2567-2791, 2569-3328, 2572-2840, 2572-2842, 2572-3162, 2572-3163, 2572-3174, 2574-2813, 2576-2821, 2576-2862, 2576-3083, 2580-3331, 2581-2811, 2581-2816, 2581-2825, 2581- 2859, 2581-2985, 2581-3048, 2581-3280, 2581-3333, 2582-2670, 2582-3291, 2584-2719, 2586-2932, 2586-3168, 2587-2856, 2588-2849, 2589-3252, 2590-2931, 2592-3314, 2594-3333, 2595-2849, 2596-2838, 2597-2837, 2598-2798, 2598-2849, 2600-2815, 2601-2818, 2601- 2860, 2601-2862, 2601-3042, 2602-2833, 2602-3209, 2603-2895, 2603-3047, 2606-2787, 2607-3343, 2609-3333, 2611-2870, 2611-3288, 2612-2870, 2612-2894, 2613-3206, 2616-2844, 2617-2858, 2618-3263, 2621-2905, 2622-2715, 2622-2884, 2623-2888, 2623-3329, 2624- 2908, 2626-2899, 2632-2835, 2632-2880, 2632-2882, 2632-2898, 2632-2905, 2632-2942, 2634-2881, 2634-2938, 2636-2831, 2637-2893, 2645-2934, 2646-2861, 2646-2909, 2646-2921, 2646-2926, 2648-3324, 2648-3333, 2653-3260, 2655-3261, 2657-3254, 2661-3282, 2662- 2917, 2663-3343, 2664-2931, 2666-2922, 2666-2950, 2666-3270, 2668-2928, 2671-3232, 2671-3281, 2673-2901, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 2676-2909, 2679-2940, 2679-3343, 2684-3280, 2684-3285, 2685-2952, 2686-3082, 2687-3343, 2693-2922, 2693-2950, 2693-2963, 2693- 3340, 2694-3292, 2696-2893, 2697-2849, 2700-3097, 2701-2865, 2701-3343, 2702-3318, 2704-2989, 2705-3343, 2706-3330, 2710-2948, 2715-2978, 2717-2963, 2718-3282, 2720-2904, 2721-2882, 2721-3280, 2722-2974, 2724-2943, 2728-2938, 2728-2953, 2728-2975, 2728- 2979, 2728-2988, 2728-3007, 2728-3252, 2729-3004, 2729-3009, 2729-3292, 2730-2957, 2730-2965, 2732-3320, 2733-2938, 2733-2978, 2733-3003, 2733-3324, 2734-3288, 2734-3343, 2737-2991, 2737-3249, 2739-3341, 2739-3343, 2741-3005, 2742-3005, 2744-3048, 2748- 3324, 2749-2999, 2750-3343, 2753-3002, 2754-2960, 2754-2961, 2759-2927, 2759-3002, 2759-3003, 2761-3219, 2761-3244, 2761-3335, 2763-3072, 2763-3318, 2766-3033, 2768-3343, 2772-3343, 2773-2999, 2775-3343, 2776-2884, 2779-2985, 2780-2930, 2780-3018, 2782- 3343, 2783-3343, 2784-2991, 2784-3018, 2785-3209, 2787-3039, 2792-3030, 2796-3333, 2797-3069, 2797-3077, 2799-2957, 2799-3343, 2802-3026, 2802-3332, 2804-3035, 2804-3044, 2804-3338, 2804-3343, 2811-2888, 2811-2955, 2811-3059, 2811- 3097, 2813-3170, 2813-3331, 2814-3335, 2814-3341, 2815-3139, 2816-3033, 2816-3089, 2816-3138, 2819-3343, 2820-3065, 2820-3080, 2820-3089, 2820-3343, 2822-3343, 2823-3322, 2825-3343, 2830-2942, 2831-3320, 2832-3089, 2832-3215, 2833-2939, 2833-3089, 2833- 3281, 2834-3080, 2835-3343, 2837-3343, 2838-3141, 2838-3323, 2839-3343, 2840-3343, 2841-3073, 2841-3096, 2841-3097, 2842-3317, 2842-3343, 2843-3067, 2843-3233, 2843-3333, 2846-3343, 2850-3343, 2851-3263, 2851-3275, 2852-3343, 2853-3138, 2855-3086, 2855- 3146, 2856-3343, 2857-3334, 2857-3341, 2857-3343, 2858-3147, 2858-3343, 2861-3271, 2862-3244, 2862-3328, 2862-3335, 2862-3339, 2862-3343, 2864-3343, 2866-3317, 2869-3333, 2870-3333, 2870-3343, 2871-3149, 2871-3337, 2871-3343, 2872-3318, 2872-3334, 2873- 3343, 2874-3097, 2874-3339, 2875-3336, 2875-3338, 2877-3320, 2878-3038, 2879-3331, 2879-3343, 2880-3075, 2882-3146, 2883-3332, 2885-3318, 2885-3343, 2886-3333, 2886-3343, 2887-3343, 2891-3332, 2892-3343, 2894-3343, 2896-3085, 2896- 3188, 2896-3200, 2896-3343, 2897-3097, 2898-3148, 2898-3157, 2898-3174, 2898-3337, 2899-3177, 2899-3343, 2900-3333, 2901-3097, 2901-3138, 2901-3160, 2901-3169, 2901-3335, 2902-3333, 2902-3334, 2902-3343, 2903-3173, 2903-3333, 2903-3343, 2904-3343, 2905- 3333, 2906-3343, 2907-3158, 2907-3333, 2907-3334, 2908-3333, 2908-3334, 2908-3343, 2909-3334, 2911-3334, 2912-3164, 2912-3259, 2912-3333, 2913-3238, 2913-3333, 2913-3335, 2914-3174, 2914-3334, 2914-3337, 2915-3089, 2915-3335, 2915-3343, 2916-3323, 2916- 3329, 2916-3343, 2917-3333, 2918-3172, 2918-3330, 2918-3333, 2919-3333, 2919-3336, 2919-3339, 2921-3170, 2921-3333, 2921-3334, 2922-3343, 2923-3334, 2923-3336, 2923-3343, 2924-3337, 2926-3089, 2926-3190, 2926-3205, 2926-3343, 2927-3288, 2927-3335, 2929- 3343, 2931-3160, 2931-3333, 2933-3212, 2933-3343, 2934-3231, 2935-3333, 2937-3246, 2938-3333, 2940-3334, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 2941-3333, 2942-3334, 2942-3336, 2943-3333, 2943-3334, 2944-3339, 2946-3333, 2949-3097, 2949-3219, 2950-3319, 2950-3333, 2952- 3097, 2952-3333, 2954-3333, 2955-3263, 2956-3333, 2956-3337, 2957-3338, 2958-3333, 2958-3337, 2959-3333, 2959-3334, 2959-3340, 2961-3333, 2961-3336, 2962-3332, 2965-3179, 2965-3327, 2968-3262, 2968-3335, 2969-3337, 2971-3331, 2971-3333, 2971-3334, 2975- 3326, 2977-3207, 2979-3207, 2979-3269, 2980-3275, 2982-3269, 2983-3343, 2988-3232, 2988-3273, 2990-3236, 2990-3258, 2990-3273, 2991-3245, 2994-3263, 2995-3282, 2996-3304, 2998-3334, 2998-3342, 3001-3222, 3004-3257, 3005-3290, 3007-3333, 3011-3288, 3012- 3337, 3013-3340, 3015-3147, 3015-3279, 3015-3287, 3018-3333, 3019-3335, 3021-3290, 3022-3333, 3023-3333, 3024-3335, 3028-3332, 3028-3343, 3030-3237, 3036-3328, 3037-3267, 3040-3279, 3041-3333, 3042-3328, 3044-3333, 3045-3331, 3046-3325, 3048-3333, 3051- 3343, 3052-3218, 3052-3327, 3055-3080, 3090-3262, 3090-3263, 3090-3308, 3090-3332, 3090-3333, 3090-3335, 3090-3337, 3090-3340, 3090-3343, 3093-3300, 3093-3332, 3093-3343, 3098-3332, 3100-3316, 3102-3339, 3106-3337, 3107-3128, 3107- 3332, 3109-3336, 3113-3343, 3116-3300, 3117-3332, 3117-3334, 3121-3333, 3127-3333, 3129-3332, 3130-3339, 3130-3343, 3133-3330, 3135-3341, 3138-3317, 3139-3332, 3151-3343, 3155-3343, 3156-3343, 3160-3333, 3162-3333, 3167-3333, 3171-3333, 3172-3334, 3172- 3343, 3175-3335, 3178-3333, 3178-3336, 3179-3343, 3180-3343, 3186-3332, 3188-3343, 3189-3343, 3197-3279, 3200-3334, 3200-3343, 3201-3343, 3204-3343, 3206-3343, 3209-3296, 3210-3333, 3217-3343, 3218-3343, 3219-3343, 3222-3343, 3247-3343 123/7506468CB1/1-338, 43-298, 53-342, 56-258, 56-939, 69-648, 69-713, 75-923, 83-342, 87-342, 92-280, 98-342, 217-923, 338-906, 338-933, 343-922, 344- 962 744, 351-860, 353-613, 353-929, 353-947, 373-602, 385-929, 386-807, 392-851, 399-860, 400-852, 402-615, 402-838, 402-903, 402-940, 402-941, 402-962, 409-871, 412-852, 420-807, 420-843, 420-867, 425-928, 431-687, 445-675, 448-864, 453-930, 487-941, 499-940, 515- 941, 533-935, 536-933, 553-935, 568-940, 594-852, 638-940, 649-852, 651-940, 653-940, 657-940, 691-940, 697-907, 723-941, 725-940, 730-941, 738-932, 834-864, 834-865, 834-870, 864-890, 864-894 124/7510682CB1/1-242, 1-247, 1-291, 1-1093, 38-265, 147-371, 147-387, 147-403, 160-422, 185-406, 406-679, 406-775, 406-801, 406-827, 406-877, 411- 1113 758, 414-988, 415-1032, 418-995, 425-1083, 433-955, 442-1108, 449-638, 451-722, 467-1109, 472-1110, 486-712, 493-995, 494-793, 494- 848, 494-911, 494-946, 494-985, 494-995, 494-998, 494-1004, 494-1015, 494-1041, 494-1046, 494-1050, 494-1064, 494-1070, 494-1074, 494-1075, 494-1084, 494-1086, 494-1087, 494-1091, 494-1094, 494-1098, 494-1101, 494-1102, 494-1103, 494-1104, 494-1105, 494-1106, 494-1111, 495-773, 495-1105, 496-1027, 497-1011, 497-1086, 509-1047, 514-1113, 523-1009, 529-1111, 538-1092, 538-1113, 553-875, 553-995, 554-1111, 557-1023, 567-926, 572-1104, 577-836, 581-1111, 585-830, 585-992, 588-806, 589-835, 590-1050, 604-1001, 604- 1056, 605-1111, 618-1092, 633-1092, 633-1111, 638-1092, 651-1113, 653-1110, 654-1041, 658-1056, 668-1089, 675-1094, 700-1092, 713- 1086, 715-1092, 718-1100, 719-1105, 723-1050, 728-1093, 734-1095, 745-1094, 752-951, 801-1087, 807-932, 809-1092, 813-1092, 823-929, 875-1106, 905-1086 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 125/7505420CB1/1-159, 1-188, 1-225, 1-227, 1-240, 1-249, 1-253, 1-282, 1-303, 1-345, 1-495, 1-499, 1-508, 1-526, 1-529, 1-551, 1-554, 1-606, 1-644, 1- 2475 2358, 3-227, 5-319, 6-253, 7-256, 10-250, 10-800, 14-618, 15-271, 15-617, 25-608, 25-623, 25-659, 25-681, 25-795, 29-535, 29-614, 30- 538, 30-709, 31-293, 31-326, 32-607, 32-612, 33-611, 34-106, 34-357, 37-287, 37-308, 38-261, 38-263, 38-298, 38-300, 38-302, 38-304, 38- 308, 38-309, 39-273, 39-404, 39-657, 40-270, 40-276, 40-289, 40-301, 40-426, 41-339, 41-638, 42-290, 42-300, 43-302, 43-309, 43-595, 43- 729, 44-396, 44-400, 44-414, 44-561, 44-584, 44-593, 48-629, 49-293, 50-318, 52-299, 54-684, 58-629, 62-276, 62-360, 62-799, 67-622, 68- 320, 71-332, 71-373, 71-621, 71-765, 72-296, 72-610, 72-683, 73-252, 73-659, 79-799, 81-397, 83-385, 84-336, 86-377, 88-453, 92-544, 97- 359, 97-365, 101-335, 108-353, 113-792, 113-875, 123-729, 126-402, 126-418, 126-754, 128-379, 128-401, 128-587, 128-723, 131-374, 133-599, 163-323, 163-468, 163-504, 163-522, 165-716, 166-690, 178-680, 190-797, 191-299, 222-797, 247-502, 251-780, 257-488, 268-551, 270-512, 283-463, 283-797, 298-799, 308-799, 328-532, 331-650, 338-570, 346-615, 393-645, 394- 657, 402-662, 402-709, 421-699, 437-714, 437-729, 444-646, 489-773, 499-774, 522-797, 526-693, 526-751, 526-799, 538-629, 538-719, 538-799, 554-799, 560-665, 619-799, 630-720, 635-797, 642-738, 700-973, 798-1034, 798-1039, 798-1054, 798-1082, 798-1344, 798- 1388, 799-1171, 799-1262, 799-1265, 804-1040, 805-1401, 808-1416, 811-1082, 820-1202, 822-1056, 822-1337, 829-1107, 836-1098, 838- 1460, 842-1431, 843-1078, 843-1085, 843-1279, 850-1363, 851-1086, 855-1459, 857-1063, 857-1067, 861-1111, 862-1461, 865-1250, 870- 1112, 870-1189, 871-1431, 873-1461, 873-1528, 877-1230, 877-1275, 877-1409, 879-1104, 881-1125, 894-1223, 902-1311, 903-1461, 907- 1078, 908-1520, 914-1461, 921-1399, 921-1515, 923-1020, 926-1174, 926-1446, 926-1458, 927-1414, 927-1449, 928-1192, 928-1195, 929- 1149, 934-1199, 934-1225, 936-1188, 938-1627, 940-1403, 943-1398, 944-1602, 946-1188, 948-1198, 950-1637, 954-1208, 954-1249, 954-1417, 958-1083, 967-1219, 978-1225, 989-1240, 991-1461, 992-1382, 993-1461, 993-1620, 994-1630, 1001-1533, 1002-1258, 1002-1564, 1003-1559, 1003-1629, 1003-1632, 1004-1413, 1005-1560, 1006-1415, 1011-1300, 1013- 1461, 1015-1612, 1019-1701, 1021-1295, 1021-1839, 1023-1630, 1024-1344, 1026-1365, 1032-1297, 1033-1589, 1035-1270, 1036-1461, 1038-1314, 1039-1631, 1042-1682, 1042-1736, 1049-1313, 1049-1321, 1050-1650, 1052-1661, 1053-1303, 1053-1351, 1053-1759, 1057- 1461, 1057-1589, 1058-1461, 1060-1131, 1062-1354, 1063-1557, 1064-1353, 1065-1539, 1066-1428, 1069-1503, 1073-1755, 1077-1659, 1080-1372, 1082-1295, 1082-1648, 1085-1383, 1092-1826, 1095-1678, 1096-1585, 1100-1285, 1100-1303, 1101-1375, 1101-1420, 1102- 1401, 1104-1634, 1104-1753, 1107-1786, 1109-1365, 1109-1376, 1110-1372, 1110-1374, 1111-1747, 1111-1760, 1111-1817, 1113-1536, 1114-1611, 1114-1668, 1118-1667, 1120-1387, 1121-1553, 1122-1661, 1142-1724, 1150-1839, 1155-1459, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length w 1155-1841, 1160-1683, 1161-1378, 1162-1906, 1164-1637, 1180-1905, 1181-1772, 1200-1439, 1200-1723, 1200-1807, 1201-1461, 1202- 1459, 1204-1636, 1204-1757, 1204-1781, 1209-1461, 1211-1702, 1223-1895, 1227-1764, 1227-1831, 1230-1517, 1230-1532, 1233-1721, 1233-1912, 1234-1911, 1235-1526, 1236-1461, 1242-1883, 1243-1392, 1251-1775, 1254-1556, 1255-1567, 1256-1865, 1256-1870, 1257- 1902, 1258-1899, 1266-1894, 1267-1684, 1271-1557, 1275-1863, 1278-1894, 1280-1521, 1280-1937, 1282-1867, 1286-1898, 1298-1724, 1305-1912, 1306-1912, 1309-1817, 1311-1733, 1314-1780, 1317-1779, 1318-1884, 1319-1865, 1321-1899, 1322-1910, 1322-1912, 1323- 1956, 1325-1574, 1325-1912, 1326-1606, 1329-1912, 1336-1772, 1341-1781, 1342-1888, 1342-1912, 1347-1672, 1347-1894, 1348-1661, 1348-1877, 1350-1829, 1352-1912, 1366-1912, 1370-1909, 1377-1879, 1381-1637, 1382-1692, 1384-1619, 1388-1872, 1390-2055, 1400- 1603, 1400-1815, 1401-1796, 1401-1839, 1405-1909, 1418-1524, 1418-1564, 1418-1632, 1418-1698, 1418-1963, 1419-1849, 1424-1454, 1434-1454, 1465-1757, 1465-1874, 1465-1911, 1465-2022, 1465-2030, 1465-2055, 1469-1493, 1472-1492, 1472- 1496, 1472-1498, 1472-1500, 1472-1506, 1472-1507, 1473-1911, 1474-1871, 1475-1896, 1487-1912, 1494-1911, 1498-1644, 1498-1725, 1500-1911, 1502-1909, 1502-2047, 1503-1912, 1507-1783, 1508-1910, 1509-1783, 1510-1911, 1511-1764, 1512-2045, 1513-2045, 1514- 1912, 1515-1737, 1515-1873, 1517-1802, 1524-2042, 1526-2022, 1527-1777, 1527-1903, 1535-1784, 1538-1912, 1541-2138, 1549-1683, 1557-1787, 1566-2092, 1578-1906, 1581-1771, 1591-1840, 1591-1894, 1607-1911, 1610-1912, 1617-1909, 1621-1807, 1622-2062, 1634- 1911, 1653-1872, 1653-1900, 1655-1937, 1679-2338, 1680-1996, 1681-2323, 1688-1907, 1693-1911, 1693-1912, 1697-1975, 1699-1908, 1700-1771, 1706-2315, 1712-2348, 1717-1909, 1768-2363, 1774-2027, 1776-2283, 1777-2299, 1788-1911, 1788-2382, 1796-1911, 1804- 2008, 1804-2315, 1804-2327, 1822-2333, 1840-2386, 1853-2391, 1858-2396, 1860-2327, 1869-2475, 1878-2039, 1878-2201, 1878-2313, 1880-2350, 1883-2132, 1883-2314, 1930-2351, 1960-2336, 2045-2272, 2082-2350, 2171-2350 126/7505604CB1/1-266, 1-334, 1-373, 1-385, 1-453, 1-479, 1-494, 1-495, 1-514, 1-521, 1-538, 1-580, 1-585, 1-608, 1-615, 1-665, 1-666, 1-687, 1-2147, 832- 2151 1655, 1363-2079, 1448-2147, 1687-2151, 1783-2151, 1788-2147, 1789-2146, 1865-2151, 1952-2146 127/7505606CB1/1-226, 1-229, 1-251, 1-254, 1-299, 1-411, 1-430, 1-449, 1-480, 1-491, 1-493, 1-501, 1-506, 1-507, 1-515, 1-518, 1-539, 1-543, 1-548, 1-553, 2565 1-575, 1-576, 1-632, 1-640, 1-655, 1-661, 1-699, 1-728, 1-2565, 3-233, 3-245, 3-256, 3-334, 28-792, 31-562, 56-717, 59-554, 93-618, 159- 728, 217-522, 233-760, 233-911, 249-464, 257-795, 290-464, 334-840, 366-875, 370-794, 384-869, 386-799, 386-909, 425-1037, 456-989, 457-975, 463-748, 465-756, 530-1025, 710-805, 727-984, 826-983, 994-1709, 994-1769, 995-1782, 996-1381, 996-1602, 996-1810, 998- 1571, 1000-1764, 1059-1515, 1059-1551, 1059-1559, 1059-1695, 1067-1609, 1072-1538, 1073-1659, 1109-1686, 1113-1667, 1145-1662, 1153-1623, 1156-1390, 1156-1394, 1156-1396, 1156-1404, 1156-1408, 1156-1419, 1156-1708, 1166-1415, 1191-1786, 1194-1718, 1222- 1788, 1230-1872, 1238-1681, 1253-1830, 1258-2009, 1270-1796, 1290-1824, 1320-1920, 1323-1581, 1336-1968, 1375-2085, 1399-2016, 1400-1884, 1438-2152, 1445-1535, 1451-1975, 1452-1930, 1484-1771, 1508-1781, 1526-2280, 1532-1620, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 1539-2196, 1547-1792, 1553-1708, 1560-2139, 1573-1877, 1573-2213, 1587-2096, 1589-1792, 1630-2123, 1630-2143, 1637-1923, 1645- 2062, 1650-2049, 1666-2196, 1682-2196, 1706-2221, 1728-2218, 1729-2196, 1741-1930, 1759-2479, 1767-1963, 1831-2364, 1832-2339, 1884-2471, 1900-2479, 1903-2536, 1936-2426, 1981-2376, 1994-2146, 2057-2334, 2074-2341, 2261-2565 128/7511044CB1/1-781, 210-821, 292-781, 347-768, 598-2094, 601-1139, 647-768, 852-906, 934-1088, 934-1278, 934-1286, 934-1350, 977-1646, 1289- 8957 1824, 1289-1933, 1289-2113, 1289-2126, 1289-2128, 1289-2220, 1297-2087, 1565-2325, 1643-2363, 1645-2244, 1698-2566, 1700-2566, 1703-2566, 1716-2566, 1726-2566, 1743-1826, 1875-2565, 1898-2566, 1971-2566, 2066-2566, 2134-2302, 2134-2305, 2134-2352, 2134- 2371, 2134-2376, 2134-2456, 2134-2464, 2134-2504, 2134-2506, 2134-2515, 2134-2537, 2134-2578, 2134-2585, 2134-2635, 2134-2650, 2134-2654, 2134-2665, 2134-2670, 2134-2672, 2134-2686, 2134-2691, 2134-2715, 2134-2718, 2134-2739, 2134-2751, 2134-2764, 2134- 2766, 2134-2767, 2134-2873, 2134-2874, 2134-2877, 2134-2879, 2134-2880, 2163-2878, 2168-2879, 2196-2880, 2201-2879, 2202-2785, 2219-2878, 2340-2879, 2345-2879, 2418-2879, 2441-2879, 2642-2879, 2680-2879, 2700-3328, 2891-3463, 2891-3556, 3064-3440, 3064- 3720, 3532-3760, 3537-3948, 3566-4725, 3566-8957, 3969-4236, 4559-5074, 4654-5242, 4727-4971, 5000-5313, 5000-5408, 5085-5205, 5293-5756, 5417-5678, 5510-5940, 5626-5932, 5764-5901, 5809-5901, 6572-6821, 6572-6834, 6866-7496, 6940- 7356, 6943-7371, 6951-7392, 6957-7680, 6964-7426, 6987-7332, 6997-7544, 7010-7767, 7026-7767, 7044-7674, 7049-7544, 7063-7727, 7073-7767, 7083-7696, 7089-7642, 7145-7741, 7165-7767, 7166-7767, 7171-7246, 7187-7685, 7195-7432, 7196-7449, 7196-7496, 7214- 7767, 7257-7767, 7317-7541, 7383-7767, 7402-8151, 7415-7767, 7433-7765, 7592-8031, 7687-7922, 8064-8777, 8224-8890, 8287-8632, 8415-8670 129/2579533CB1/1-413, 1-1537, 185-436, 185-575, 185-603, 185-604, 185-614, 185-639, 185-652, 185-666, 185-669, 185-671, 185-675, 185-684, 185-687, 2755 185-714, 185-729, 185-740, 185-777, 185-796, 185-807, 185-824, 185-833, 185-848, 185-854, 185-859, 185-862, 185-891, 232-693, 338- 413, 353-758, 369-413, 414-801, 512-601, 640-1241, 970-1832, 978-1066, 1550-1759, 1550-1801, 1759-2746, 1799-1982, 1802-2446, 1827-2109, 1870-2466, 1915-2193, 1915-2267, 1915-2331, 1915-2364, 1915-2382, 1915-2388, 1919-2366, 1919-2667, 1944-2608, 1944- 2720, 1972-2679, 2002-2172, 2007-2228, 2007-2446, 2027-2228, 2047-2202, 2050-2754, 2051-2504, 2063-2275, 2063-2280, 2084-2752, 2090-2751, 2091-2710, 2120-2708, 2133-2755, 2136-2755, 2139-2754, 2139-2755, 2165-2697, 2167-2693, 2170-2755, 2171-2707, 2171- 2709, 2171-2710, 2173-2585, 2179-2755, 2184-2705, 2184-2709, 2185-2312, 2188-2755, 2208-2668, 2217-2628, 2229-2457, 2243-2755, 2251-2439, 2253-2705, 2259-2693, 2260-2446, 2264-2666, 2267-2666, 2270-2693, 2272-2746, 2282-2718, 2302-2683, 2302-2700, 2305- 2751, 2323-2753, 2327-2752 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 130/7511097CB 1/1-257, 1-315, 1-327, 1-575, 1-617, 1-648, 1-657, 2-503, 2-603, 2-670, 55-705, 152-855, 186-907, 199-904, 221-779, 250-523, 261-825, 262- 1641 841, 269-863, 286-766, 294-802, 308-966, 389-935, 389-997, 408-1120, 411-995, 434-1039, 446-546, 470-1155, 485-1092, 491-921, 505- 743, 512-1044, 547-1067, 556-1188, 566-1288, 588-1092, 588-1202, 602-1144, 620-1321, 626-1136, 628-1312, 645-1182, 662-1312, 708- 1199, 718-1283, 753-1447, 761-1279, 765-1350, 767-1321, 774-1387, 779-1171, 838-1312, 842-1550, 848-1443, 855-1585, 865-984, 907- 1447, 910-1641, 1200-1551 131/7510842CB1/1-624, 2-1672, 9-61, 9-179, 9-241, 13-221, 13-233, 13-249, 15-249, 15-271, 15-570, 16-223, 16-233, 16-266, 16-334, 16-413, 17-223, 17- 1686 226, 17-288, 17-302, 17-314, 17-535, 18-238, 18-258, 18-272, 18-276, 18-278, 18-282, 18-285, 18-296, 18-297, 18-301, 18-303, 18-313, 18- 321, 18-349, 18-436, 18-451, 18-457, 18-471, 18-536, 18-570, 18-584, 18-609, 18-624, 18-642, 19-323, 19-343, 20-266, 23-242, 24-303, 28- 284, 30-288, 30-299, 30-487, 30-617, 31-293, 31-325, 31-621, 32-296, 32-312, 32-580, 33-226, 33-259, 33-385, 33-414, 33-421, 33-564, 33- 643, 34-164, 34-204, 34-292, 34-348, 35-289, 35-606, 37-286, 37-297, 37-342, 37-482, 39-300, 40-238, 40-594, 42-617, 44-266, 44-298, 44- 299, 44-336, 44-338, 44-547, 44-582, 44-600, 44-629, 46-592, 50-553, 50-582, 51-559, 55-321, 56-292, 56-348, 56-508, 56-562, 59-538, 80- 490, 84-288, 88-377, 105-247, 105-253, 105-276, 105-282, 105-287, 105-309, 105-325, 105-375, 105-538, 105-636, 106-399, 107-330, 108- 362, 110-361, 110-364, 110-407, 111-186, 112-601, 116-385, 120-437, 136-639, 137-281, 144-287, 144-453, 147-323, 147-406, 164-444, 197-437, 206-476, 221-497, 221-556, 223-640, 228-474, 263-512, 263-519, 294-609, 301- 627, 306-494, 342-563, 363-644, 364-620, 364-644, 379-620, 386-520, 405-593, 406-603, 420-630, 420-643, 425-644, 430-629, 459-670, 461-644, 645-819, 645-842, 645-847, 645-873, 645-874, 645-883, 645-884, 645-896, 645-907, 645-919, 645-923, 645-925, 645-926, 645- 929, 645-1019, 645-1059, 645-1105, 645-1106, 645-1136, 645-1224, 645-1228, 645-1244, 645-1337, 648-920, 650-732, 651-894, 652-717, 654-948, 654-1029, 657-1246, 658-891, 658-916, 669-899, 671-910, 674-953, 676-974, 681-904, 681-1184, 682-1078, 685-808, 687-940, 689-915, 692-949, 693-926, 693-972, 698-1000, 699-927, 699-1312, 700-1275, 701-845, 704-912, 706-1110, 706-1182, 706-1235, 708- 912, 709-888, 709-1214, 712-1000, 713-1004, 714-912, 714-1213, 715-1124, 718-1300, 719-934, 719-989, 722-945, 724-1190, 725-992, 727-973, 730-924, 731-1247, 733-1316, 736-954, 740-850, 740-1293, 741-1022, 743-1057, 743-1285, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 743-1350, 744-1023, 746-1003, 746-1022, 747-972, 752-1005, 754-1032, 756-1058, 759-1028, 759-1086, 763-1054, 763-1068, 763-1221, 765-1033, 766-991, 766-1008, 766-1010, 774-1132, 774-1134, 775-1290, 776-1107, 779-1044, 782-1071, 782-1081, 785-1495, 787-1156, 789-1308, 795-1043, 795-1047, 799-1036, 799-1048, 799-1060, 799-1087, 799-1194, 799-1387, 800-992, 800-1068, 800-1597, 804-1311, 804-1312, 805-998, 808-1303, 813-1075, 825-1319, 826-999, 828-999, 830-1063, 831-1049, 834-1298, 845-1439, 847-1085, 847-1098, 847- 1102, 847-1119, 847-1145, 849-1080, 853-1185, 853-1604, 862-1086, 862-1142, 866-1138, 866-1585, 867-1651, 868-1244, 871-1096, 876- 1226, 876-1320, 883-1147, 883-1388, 891-1164, 893-1172, 896-1220, 905-1343, 905-1424, 906-1479, 910-1139, 912-1552, 914-1674, 915- 1195, 915-1517, 915-1631, 916-1191, 918-1156, 922-1139, 922-1178, 923-1567, 924-1609, 929-1637, 935-1180, 936-1570, 940-1527, 941- 1164, 945-1588, 950-1228, 950-1231, 952-1171, 953-1231, 956-1154, 956-1201, 956-1217, 956-1325, 956-1430, 957-1161, 959-1376, 961-1162, 961-1425, 962-1155, 962-1181, 963-1655, 965-1260, 968-1090, 970-1339, 970-1396, 972-1244, 973-1247, 973-1249, 975-1536, 977-1639, 978-1233, 978-1386, 979-1216, 979-1224, 979-1236, 979-1237, 980-1685, 983-1232, 983-1435, 988-1268, 988-1285, 988-1573, 989-1188, 989-1193, 990-1612, 991-1576, 994-1280, 994-1281, 997-1253, 997-1263, 997-1561, 998-1461, 998-1610, 999-1130, 1000-1608, 1003-1276, 1004-1259, 1007-1192, 1007-1612, 1007-1677, 1010-1170, 1010-1608, 1010-1686, 1016-1233, 1019-1253, 1021-1257, 1023-1283, 1025-1254, 1027-1647, 1027-1659, 1029-1282, 1030-1413, 1030-1466, 1030-1486, 1030- 1506, 1030-1588, 1031-1257, 1034-1635, 1036-1153, 1036-1248, 1036-1252, 1036-1334, 1036-1337, 1037-1276, 1037-1284, 1037-1285, 1037-1317, 1037-1402, 1037-1649, 1037-1682, 1039-1349, 1040-1677, 1041-1110, 1041-1294, 1044-1637, 1046-1280, 1049-1309, 1051- 1295, 1051-1487, 1053-1632, 1053-1686, 1054-1519, 1054-1568, 1054-1686, 1055-1279, 1055-1344, 1055-1353, 1056-1539, 1058-1630, 1060-1648, 1061-1336, 1061-1630, 1061-1676, 1062-1293, 1062-1311, 1062-1330, 1062- 1351, 1062-1604, 1062-1683, 1064-1294, 1065-1189, 1065-1346, 1068-1329, 1068-1341, 1069-1685, 1070-1349, 1073-1333, 1073-1686, 1075-1316, 1075-1570, 1075-1686, 1078-1204, 1078-1406, 1078-1486, 1084-1319, 1084-1598, 1084-1680, 1085-1309, 1085-1501, 1086- 1213, 1087-1192, 1088-1686, 1091-1372, 1092-1531, 1093-1359, 1094-1356, 1094-1513, 1095-1584, 1096-1212, 1096-1345, 1096-1374, 1099-1328, 1100-1397, 1101-1337, 1101-1357, 1101-1599, 1102-1487, 1102-1627, 1109-1296, 1110-1333, 1113-1589, 1116-1369, 1116- 1370, 1117-1246, 1117-1379, 1117-1395, 1117-1400, 1117-1686, 1120-1307, 1124-1338, 1125-1528, 1125-1625, 1127-1373, 1128-1347, 1128-1371, 1128-1379, 1128-1385, 1133-1287, 1133-1322, 1133-1686, 1135-1336, 1135-1412, 1136-1399, 1136-1686, 1137-1686, 1141- 1686, 1147-1458, 1152-1539, 1159-1359, 1159-1360, 1163-1296, 1167-1434, 1167-1623, 1170-1677, 1171-1454, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 1171-1478, 1172-1686, 1173-1686, 1174-1401, 1182-1425, 1184-1686, 1185-1683, 1185-1686, 1186-1686, 1190-1686, 1191-1443, 1191- 1686, 1193-1437, 1193-1623, 1193-1677, 1195-1416, 1196-1623, 1199-1638, 1203-1686, 1204-1677, 1205-1677, 1206-1686, 1209-1638, 1210-1498, 1215-1385, 1219-1686, 1220-1508, 1220-1678, 1221-1505, 1222-1676, 1222-1686, 1224-1686, 1225-1414, 1225-1505, 1225- 1678, 1226-1636, 1226-1677, 1227-1451, 1227-1452, 1227-1461, 1227-1676, 1228-1488, 1228-1497, 1228-1531, 1228-1679, 1228-1686, 1229-1678, 1230-1516, 1230-1677, 1231-1686, 1233-1394, 1233-1677, 1234-1686, 1235-1672, 1240-1363, 1240-1686, 1242-1486, 1242- 1683, 1242-1685, 1243-1677, 1243-1686, 1244-1677, 1244-1678, 1244-1682, 1245-1677, 1247-1605, 1248-1686, 1249-1677, 1250-1685, 1255-1677, 1256-1504, 1256-1560, 1256-1686, 1257-1662, 1258-1517, 1259-1675, 1259-1682, 1259-1686, 1260-1683, 1263-1677, 1263- 1686, 1266-1679, 1266-1686, 1267-1489, 1267-1677, 1267-1683, 1268-1677, 1268-1686, 1270-1677, 1271-1433, 1271-1676, 1271-1677, 1272-1636, 1272-1677, 1272-1684, 1273-1504, 1273-1506, 1273-1554, 1273-1678, 1273-1686, 1275-1662, 1275-1686, 1276-1571, 1276- 1684, 1277-1677, 1277-1678, 1278-1677, 1280-1533, 1280-1683, 1281-1677, 1281-1686, 1282-1618, 1282-1685, 1282-1686, 1283-1561, 1283-1565, 1284-1603, 1284-1677, 1289-1524, 1289-1686, 1292-1329, 1292-1553, 1292-1572, 1292-1686, 1296-1557, 1296-1677, 1296- 1681, 1297-1499, 1297-1535, 1297-1559, 1297-1684, 1298-1638, 1299-1677, 1301-1685, 1301-1686, 1304-1680, 1304-1686, 1307-1543, 1308-1553, 1309-1676, 1310-1674, 1310-1677, 1312-1678, 1314-1585, 1314-1677, 1315-1677, 1317-1577, 1318-1679, 1321-1678, 1321- 1684, 1322-1605, 1325-1677, 1325-1681, 1326-1557, 1329-1672, 1333-1686, 1334-1608, 1334-1624, 1337-1678, 1343-1677, 1344-1622, 1344-1677, 1346-1677, 1346-1680, 1347-1677, 1348-1588, 1350-1686, 1352-1631, 1353-1672, 1355-1676, 1358-1682, 1360-1630, 1365- 1619, 1367-1627, 1367-1683, 1367-1686, 1370-1677, 1371-1672, 1371-1677, 1373-1608, 1373-1681, 1374-1681, 1375-1645, 1375-1672, 1377-1672, 1377-1684, 1378-1594, 1379-1683, 1380-1672, 1381-1677, 1382-1685, 1384-1677, 1385-1676, 1385- 1677, 1386-1672, 1386-1677, 1386-1686, 1388-1677, 1389-1677, 1390-1677, 1391-1647, 1392-1677, 1393-1677, 1393-1680, 1394-1679, 1395-1686, 1397-1680, 1399-1672, 1399-1680, 1400-1677, 1400-1678, 1401-1521, 1402-1677, 1404-1672, 1404-1686, 1405-1677, 1408- 1686, 1409-1642, 1409-1672, 1411-1686, 1413-1677, 1415-1672, 1416-1677, 1416-1686, 1417-1672, 1423-1648, 1423-1672, 1424-1682, 1425-1677, 1429-1680, 1429-1683, 1436-1686, 1437-1583, 1438-1672, 1438-1685, 1441-1652, 1446-1686, 1448-1662, 1456-1680, 1457- 1672, 1462-1686, 1464-1677, 1477-1677, 1478-1677, 1478-1680, 1481-1686, 1482-1677, 1484-1677, 1510-1686, 1516-1686, 1526-1679, 1529-1677, 1529-1686, 1531-1672, 1537-1677, 1545-1677, 1554-1686, 1556-1680, 1557-1672, 1560-1667, 1568-1678, 1568-1686, 1569- 1686, 1585-1686, 1589-1686, 1604-1686, 1619-1686 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 132/7511249CB 1/1-548, 2-276, 2-293, 2-2368, 5-553, 10-269, 12-278, 17-453, 20-266, 20-267, 20-436, 21-253, 21-307, 21-517, 22-349, 23-270, 25-526, 31- 2534 244, 32-349, 34-307, 36-326, 41-524, 41-553, 43-262, 43-315, 48-279, 53-306, 95-239, 103-673, 149-382, 164-388, 203-465, 255-518, 283- 553, 293-492, 492-798, 551-752, 552-734, 552-952, 552-1163, 554-783, 569-872, 574-840, 595-1282, 631-1275, 636-1137, 641-939, 667- 929, 668-942, 682-925, 682-1237, 688-1209, 781-1055, 812-1060, 814-1228, 823-1241, 823-1268, 830-1083, 830-1191, 830-1413, 891- 1469, 895-1170, 910-1489, 913-1136, 917-1072, 917-1172, 917-1182, 919-1073, 920-1186, 922-1181, 922-1187, 932-1390, 968-1529, 999- 1120, 999-1266, 1002-1247, 1015-1315, 1024-1288, 1069-1680, 1071-1332, 1071-1342, 1072-1547, 1120-1740, 1153-1441, 1167-1603, 1191-1354, 1191-1532, 1194-1490, 1196-1422, 1200-1803, 1206-1830, 1218-1415, 1220-1441, 1220-1444, 1220-1603, 1256-1487, 1260- 1502, 1263-1522, 1270-1507, 1278-1791, 1290-1831, 1294-1873, 1319-1905, 1333-1822, 1333-1835, 1335-1579, 1335-1910, 1361-1462, 1361-1822, 1361-1845, 1365-1595, 1365-1620, 1365-1636, 1365-1795, 1367-1612, 1380-2308, 1385- 1861, 1389-1820, 1392-2000, 1394-2041, 1397-1668, 1397-1848, 1397-1861, 1398-1583, 1398-1603, 1404-1589, 1408-1664, 1408-1677, 1408-1995, 1414-1753, 1417-1994, 1428-1652, 1428-1656, 1428-1679, 1428-1684, 1438-1933, 1442-1674, 1444-2302, 1447-1943, 1451- 1703, 1466-1707, 1466-1993, 1473-2139, 1478-1623, 1488-1733, 1488-1935, 1501-1837, 1504-2079, 1522-1819, 1529-1800, 1532-1799, 1532-2044, 1545-1818, 1547-1800, 1548-2076, 1552-1784, 1569-1823, 1578-2248, 1585-1841, 1585-1844, 1586-1826, 1609-1906, 1613- 2286, 1620-2314, 1622-1863, 1632-1918, 1648-2244, 1686-1923, 1692-1835, 1701-2310, 1706-1952, 1726-1949, 1726-2013, 1734-1986, 1770-2016, 1774-2370, 1785-2047, 1793-2375, 1800-2056, 1801-2318, 1807-2318, 1822-2278, 1822-2375, 1830-2057, 1838-2105, 1839- 2127, 1846-2104, 1851-2313, 1854-2337, 1855-2375, 1864-2351, 1871-2375, 1873-2405, 1878-2360, 1880-2377, 1882-2360, 1884-2352, 1885-2357, 1887-2352, 1888-2356, 1891-2359, 1894-2352, 1894-2357, 1896-2377, 1898-2377, 1900-2352, 1901- 2156, 1903-2352, 1905-2357, 1906-2360, 1910-2358, 1912-2359, 1915-2352, 1915-2377, 1916-2364, 1924-2357, 1924-2366, 1927-2351, 1934-2363, 1936-2357, 1937-2358, 1938-2351, 1940-2353, 1941-2357, 1943-2360, 1943-2361, 1944-2351, 1944-2354, 1944-2357, 1944- 2358, 1945-2375, 1946-2357, 1947-2357, 1948-2358, 1949-2296, 1957-2387, 1967-2351, 1967-2377, 1970-2357, 1977-2233, 1977-2237, 1986-2360, 1986-2364, 1989-2351, 1991-2362, 1994-2358, 1997-2357, 2000-2357, 2001-2357, 2011-2357, 2011-2360, 2024-2357, 2028- 2357, 2032-2357, 2042-2371, 2043-2362, 2044-2355, 2048-2351, 2049-2333, 2056-2351, 2058-2357, 2059-2357, 2067-2195, 2079-2357, 2080-2351, 2081-2363, 2083-2357, 2100-2357, 2104-2357, 2119-2353, 2123-2356, 2127-2372, 2137-2388, 2152-2351, 2160-2351, 2167- 2357, 2184-2351, 2213-2357, 2218-2351, 2220-2351, 2220-2355, 2241-2319, 2241-2345, 2241-2361, 2269-2366, 2291-2534 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 133/7511254CB1/1-250, 1-257, 1-310, 1-324, 1-358, 1-502, 1-572, 1-589, 1-605, 1-633, 1-648, 1-658, 1-672, 1-682, 1-711, 1-717, 1-720, 1-754, 1-2143, 2- 2143 537, 2-617, 2-633, 2-674, 2-753, 4-672, 8-284, 8-427, 8-489, 8-522, 8-530, 14-624, 14-672, 14-676, 16-623, 19-533, 19-709, 20-654, 21- 438, 31-683, 54-288, 54-466, 54-471, 54-586, 54-657, 54-677, 54-713, 54-716, 55-410, 58-753, 63-711, 67-733, 77-339, 77-391, 77-442, 77- 546, 77-641, 77-661, 77-680, 77-694, 77-696, 77-730, 77-736, 78-713, 104-700, 194-744, 200-369, 200-753, 228-581, 268-922, 336-633, 346-700, 368-633, 368-652, 410-707, 423-751, 753-1292, 753-1393, 753-1507, 760-1156, 760-1462, 772-1386, 779-1486, 785-1447, 789- 1494, 810-1334, 810-1438, 815-1518, 822-1434, 822-1598, 830-1464, 839-1547, 844-1389, 870-1126, 870-1361, 870-1411, 876-1421, 876- 1502, 891-1537, 901-1707, 902-1514, 908-1518, 913-1741, 917-1491, 921-1504, 926-1618, 932-1476, 949-1579, 958-1664, 987-1685, 1000-1664, 1030-1743, 1049-1708, 1055-1634, 1062-1743, 1063-1486, 1075-1667, 1075-1835, 1100-1743, 1110-1743, 1115-1615, 1122-1297, 1122-1688, 1134-1743, 1135-1715, 1140-1702, 1152-1704, 1156-1693, 1157-1415, 1157-1652, 1157-1739, 1173- 1850, 1205-1983, 1209-1494, 1211-1563, 1220-1845, 1222-1827, 1232-1743, 1302-1952, 1302-1957, 1322-1777, 1335-1927, 1338-1555, 1357-1476, 1387-1743, 1388-2143, 1405-1662, 1419-1548, 1433-1578, 1443-1579, 1552-1886, 1586-1866, 1624-1953, 1685-1938, 1761- 1927 134/7511274CB1/1-688, 3-569, 13-150, 13-275, 13-279, 13-281, 13-758, 13-3526, 15-661, 16-236, 18-266, 19-247, 19-578, 22-312, 32-661, 33-143, 33-300, 3526 33-482, 33-532, 33-587, 34-288, 34-602, 39-275, 39-520, 42-683, 48-435, 53-647, 53-661, 55-296, 55-330, 77-320, 77-370, 103-746, 112- 591, 112-597, 112-675, 112-694, 112-704, 112-706, 112-719, 112-723, 112-727, 112-728, 112-741, 112-788, 112-810, 112-812, 112-813, 112-875, 112-916, 113-757, 168-363, 201-685, 304-848, 310-520, 332-488, 364-571, 370-654, 404-1236, 416-533, 471-1154, 473-1153, 536-1076, 543-1245, 556-748, 637-934, 637-1165, 691-1276, 696-967, 723-1486, 731-1298, 769-1266, 772-1460, 856-1475, 869-1125, 877- 1412, 881-1122, 885-1085, 900-1121, 900-1128, 917-1538, 938-1218, 953-1213, 958-1473, 971-1598, 1044-1319, 1089-1839, 1105-1840, 1109-1270, 1137-1550, 1148-1771, 1159-2116, 1175-1721, 1206-1331, 1231-1440, 1288-1384, 1364-1560, 1385-1630, 1399-1517, 1414- 1934, 1434-1718, 1434-1859, 1436-1676, 1436-2093, 1442-1996, 1450-1708, 1463-1940, 1504-1880, 1518-1718, 1521-1838, 1528-2137, 1539-1820, 1551-2214, 1578-2143, 1580-2124, 1585-2401, 1602-2203, 1610-1764, 1620-2067, 1648- 2146, 1672-1933, 1673-2006, 1679-1942, 1682-1940, 1695-1972, 1699-1980, 1703-1960, 1705-2028, 1705-2038, 1706-2281, 1711-2006, 1718-1993, 1735-1976, 1742-2202, 1745-2117, 1745-2293, 1749-2012, 1773-2347, 1773-2386, 1784-2053, 1788-2065, 1798-2078, 1804- 2208, 1806-2096, 1815-2124, 1816-2094, 1827-2085, 1841-2175, 1849-2097, 1884-2176, 1884-2191, 1904-2454, 1922-2365, 1924-2087, 1924-2419, 1929-2345, 1943-2221, 1968-2285, 1968-2299, 1974-2678, 1987-2186, 2018-2290, 2033-2239, 2033-2260, 2057-2345, 2061- 2310, 2061-2324, 2061-2381, 2061-2495, 2061-2537, 2063-2249, 2065-2198, 2065-2309, 2065-2347, 2069-2269, 2092-2396, 2122-2426, 2125-2378, 2139-2411, 2139-2417, 2139-2641, 2140-2345, 2141-2397, 2141-2411, 2142-2708, 2143-2351, 2143-2501, 2164-2648, 2178- 2793, 2192-2785, 2193-2429, 2212-2441, 2221-2500, 2230-2592, 2236-2492, 2236-2500, 2248-2686, 2251-2472, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 2252-2483, 2252-2492, 2263-2499, 2270-2704, 2271-2563, 2278-2489, 2278-2496, 2278-2570, 2280-2562, 2285-2539, 2298-2542, 2298- 2560, 2300-3174, 2301-2919, 2304-2488, 2313-2579, 2326-2618, 2330-2516, 2348-2610, 2352-2576, 2358-2620, 2359-2612, 2360-2646, 2369-2608, 2369-2644, 2369-2681, 2371-2638, 2374-2606, 2375-2637, 2386-2707, 2391-2606, 2396-2652, 2397-2694, 2405-2628, 2405- 2658, 2405-2680, 2426-2690, 2427-2641, 2427-2704, 2428-2656, 2428-2875, 2449-2717, 2449-2988, 2451-3037, 2472-2759, 2484-2705, 2486-2738, 2488-2930, 2490-2746, 2493-2940, 2493-2942, 2500-3057, 2502-2729, 2515-3221, 2517-2802, 2520-2796, 2523-2803, 2529- 2761, 2534-3185, 2546-2944, 2548-2791, 2548-2861, 2553-2927, 2554-3040, 2564-2806, 2564-2832, 2565-2795, 2582-2805, 2582-2810, 2584-2794, 2585-3000, 2595-2804, 2604-3208, 2605-2903, 2612-2809, 2622-2874, 2637-2844, 2640-2862, 2640-2866, 2640-3205, 2643- 2880, 2648-2850, 2648-2852, 2654-3197, 2670-2955, 2690-3285, 2698-2983, 2701-2929, 2708-2964, 2708-3001, 2708-3300, 2709-2940, 2713-2955, 2713-2973, 2717-3181, 2719-2965, 2725-3109, 2737-2942, 2743-3206, 2747-3038, 2761-2986, 2766- 2971, 2767-3008, 2773-3038, 2773-3053, 2773-3262, 2786-3062, 2791-3058, 2795-3245, 2797-3037, 2801-3045, 2811-3062, 2811-3071, 2815-3144, 2816-3146, 2824-3078, 2831-3008, 2849-3145, 2852-3114, 2861-3127, 2868-3106, 2868-3118, 2871-3125, 2873-3070, 2877- 2986, 2877-3296, 2878-3165, 2880-3169, 2884-3171, 2890-3156, 2893-3252, 2896-3156, 2898-3139, 2901-3173, 2918-3153, 2918-3173, 2925-3204, 2926-3142, 2926-3169, 2926-3200, 2965-3135, 2982-3255, 2986-3216, 2992-3250, 2993-3240, 2998-3244, 2998-3250, 3147- 3418, 3147-3477, 3147-3522, 3305-3504, 3311-3522, 3405-3511, 3437-3522, 3457-3526 135/7511303CB 1/1-275, 13-887, 65-263, 196-425, 272-530, 274-534, 276-522, 276-585, 276-812, 276-822, 279-830, 280-870, 284-887, 288-865, 302-679, 887 303-874, 305-871, 307-835, 308-471, 308-590, 309-789, 309-874, 312-862, 313-521, 313-719, 322-836, 325-523, 325-558, 325-741, 325- 767, 325-817, 326-592, 327-395, 333-506, 333-790, 338-599, 342-643, 351-835, 369-676, 370-625, 370-631, 377-636, 390-835, 400-846, 400-874, 403-647, 403-887, 409-600, 409-787, 409-813, 412-692, 412-831, 413-670, 413-813, 419-700, 423-836, 430-835, 435-830, 438- 791, 442-833, 445-714, 449-789, 452-870, 465-632, 465-828, 467-837, 468-745, 469-789, 471-887, 479-791, 486-585, 486-755, 488-835, 494-887, 495-791, 496-789, 509-887, 512-791, 512-838, 513-705, 524-789, 526-789, 527-789, 539-789, 547-791, 557-789, 562-789, 571- 789, 579-789, 586-789, 594-789, 599-789, 615-789, 675-789, 684-791 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Lez tu 136/7511309CB1/, 1-620, 1-624, 1-695, 1-1767, 2-254, 2-297, 2-470, 2-514, 2-519, 2-521, 2-529, 2- 1767 595, 2-607, 2-771, 2-773, 2-779, 3-235, 4-228, 4-374, 4-444, 4-504, 4-513, 4-640, 7-569, 11-380, 14-814, 16-251, 17-247, 23-750, 25-302, 25-306, 25-588, 25-707, 27-620, 28-275, 28-310, 29-334, 30-627, 31-546, 35-619, 36-391, 40-559, 41-312, 42-319, 43-540, 43-713, 52-835, 73-496, 82-301, 82-735, 82-890, 82-909, 82-918, 82-921, 82-948, 82-981, 82-983, 82-1004, 82-1037, 85-1010, 107-662, 114-899, 135-377, 135-527, 161-943, 168-746, 229-952, 235-481, 244-832, 257-457, 274-786, 313-539, 317-968, 326-596, 327-949, 329-581, 332-875, 332- 1163, 334-871, 334-934, 347-940, 352-987, 363-893, 372-976, 377-1167, 380-974, 380-1167, 381-1167, 382-892, 393-940, 410-1167, 427- 1120, 431-1016, 433-968, 434-983, 445-1106, 447-1078, 454-1078, 461-902, 461-1014, 466-1078, 467-1022, 474-1167, 494-1074, 494- 1090, 500-774, 528-1153, 541-1078, 541-1154, 544-1167, 546-1147, 551-1030, 559-1035, 584-1155, 586-1004, 587-870, 613-997, 619-852, 621-1163, 625-870, 642-1163, 650-884, 659-854, 675-925, 677-1162, 683-1220, 687-893, 690- 1174, 692-1009, 692-1021, 692-1037, 692-1086, 692-1087, 692-1099, 692-1100, 692-1106, 692-1117, 692-1121, 692-1135, 692-1146, 692- 1160, 692-1166, 692-1168, 692-1170, 692-1173, 692-1174, 695-983, 703-876, 721-1170, 726-1220, 740-993, 768-1033, 768-1109, 774- 1023, 802-1018, 811-1167, 830-991, 830-994, 927-1174, 945-1174, 1038-1167, 1082-1167, 1179-1430, 1252-1706, 1284-1577, 1312-1663, 1321-1575, 1321-1665, 1376-1762, 1472-1694, 1621-1712, 1622-1767, 1636-1694, 1636-1706, 1696-1762, 1697-1760, 1697-1761, 1697- 1762, 1713-1762 137/7511314CB1/1-290, 1-2392, 56-856, 58-368, 58-500, 81-476, 86-423, 87-420, 97-226, 97-244, 97-258, 97-349, 97-360, 97-442, 97-502, 97-574, 97-589, 2425 97-593, 97-611, 97-692, 97-720, 100-535, 112-770, 130-256, 133-379, 134-427, 137-698, 167-427, 175-458, 264-485, 297-781, 297-897, 438-1000, 455-1003, 618-1246, 640-1212, 753-1545, 758-1126, 758-1171, 783-1276, 783-1371, 795-1545, 855-1548, 880-1433, 902-1434, 917-1181, 931-1548, 988-1206, 990-1717, 1008-1289, 1008-1366, 1029-1297, 1035-1484, 1041-1286, 1170-1404, 1177-1376, 1187-1805, 1191-1443, 1193-1805, 1259-1562, 1266-1595, 1297-1549, 1306-1762, 1306-1771, 1309-1562, 1309-1600, 1333-1624, 1401-1701, 1419- 1629, 1557-1805, 1568-1801, 1590-1805, 1622-2086, 1635-1805, 1803-2003, 1807-2077, 1807-2210, 1814-2254, 1816-2060, 1833-2383, 1839-2112, 1873-2126, 1887-2343, 1891-2238, 1891-2337, 1895-2333, 1903-2148, 1903-2194, 1903-2207, 1903-2211, 1908-2151, 1909- 2258, 1913-2377, 1916-2374, 1917-2164, 1917-2377, 1922-2112, 1926-2144, 1926-2188, 1927-2216, 1929-2380, 1939-2379, 1940-2373, 1940-2383, 1949-2377, 1955-2314, 1966-2263, 1966-2377, 1971-2283, 1973-2377, 1976-2381, 1982- 2375, 1983-2410, 1986-2140, 1987-2384, 1988-2150, 1990-2379, 2003-2377, 2007-2375, 2008-2142, 2014-2252, 2014-2377, 2049-2383, 2063-2373, 2074-2283, 2094-2362, 2100-2384, 2110-2380, 2143-2358, 2166-2343, 2178-2425, 2179-2378, 2180-2376, 2185-2373, 2185- 2403, 2187-2335, 2194-2403, 2195-2326, 2218-2334, 2218-2362, 2218-2373, 2231-2403, 2242-2375, 2262-2333 Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 138/7511316CB1/1-259, 1-495, 1-1229, 7-296, 7-408, 7-413, 7-427, 7-428, 7-1240, 8-276, 44-297, 46-255, 105-549, 111-565, 118-618, 146-300, 182-605, 1240 225-572, 225-575, 269-431, 284-567, 318-617, 331-612, 353-613, 366-539, 366-562, 374-612, 407-617, 472-714, 618-917, 637-880, 642- 790, 650-765, 667-901, 675-1222, 677-857, 853-1228, 859-1003 139/7511391CB1/1-1854, 23-506, 23-539, 23-905, 230-325, 238-329, 239-498, 401-1221, 419-1225, 430-1225, 431-1225, 448-1225, 497-759, 497-1096, 497- 1855 1225, 505-792, 505-1034, 519-987, 534-1068, 537-1118, 546-925, 569-1185, 574-1058, 575-884, 579-844, 595-985, 611-1257, 622-1063, 646-1225, 659-1176, 663-945, 665-943, 668-1259, 669-1317, 672-1261, 703-1240, 711-898, 717-1247, 741-1436, 750-1410, 752-948, 769- 1338, 775-1334, 795-1429, 799-1351, 800-1339, 800-1551, 821-1377, 845-1074, 885-1334, 895-1456, 904-1511, 933-1127, 933-1128, 938- 1208, 945-1510, 951-1430, 976-1503, 981-1366, 984-1343, 984-1523, 1054-1680, 1064-1650, 1069-1694, 1084-1323, 1084-1341, 1084- 1365, 1087-1355, 1091-1572, 1093-1533, 1141-1343, 1146-1454, 1187-1507, 1190-1321, 1199-1814, 1204-1469, 1221-1771, 1228-1586, 1228-1587, 1249-1337, 1290-1855, 1301-1415, 1324-1803, 1345-1845, 1364-1855, 1365-1496, 1371-1853, 1427-1843, 1437-1843, 1454- 1776, 1461-1843, 1509-1752, 1529-1622, 1587-1845, 1589-1782, 1608-1703, 1621-1845, 1622-1843, 1627-1845, 1684-1765, 1756-1855 140/7510144CB1/1-79, 2-624, 2-628, 2-636, 2-655, 2-658, 2-4562, 240-1108, 620-1339, 1465-1969, 2011-2511, 2022-2553, 2388-2819, 2397-2979, 2778- 4562 3251, 3187-4141, 3221-3901, 3239-3772, 3245-3761, 3268-3897, 3272-3875, 3284-3906, 3291-3948, 3301-3581, 3303-3982, 3307-3568, 3337-3935, 3361-3864, 3378-3965, 3383-4013, 3421-4022, 3449-3715, 3449-4010, 3454-3937, 3482-3812, 3491-4340, 3495-3874, 3512- 4103, 3518-3927, 3528-3729, 3528-3747, 3529-3942, 3554-3847, 3559-3817, 3561-4349, 3600-4142, 3618-4218, 3627-3902, 3642-3872, 3643-4198, 3679-3918, 3679-4349, 3687-4006, 3690-4300, 3702-3940, 3704-3911, 3704-4006, 3737-4001, 3750-4029, 3757-4011, 3758- 4006, 3809-4006, 3820-4006, 3820-4072, 3821-4366, 3860-4155, 3863-4006, 3863-4086, 3863-4089, 3864-4091, 3868-4374, 3870-4111, 3873-4087, 3884-4183, 3884-4562, 3900-4371, 3928-4193, 3930-4364, 3939-4212, 4019-4070, 4038-4367, 4039-4070, 4046-4366, 4151- 4344. 4151-4348, 4152-4360, 4152-4374, 4159-4374, 4163-4372, 4164-4372, 4270-4343, 4281-4352, 4281-4355 141/7510810CB1/1-493, 1-593, 7-651, 20-365, 23-306, 24-256, 24-311, 25-179, 25-307, 25-575, 26-256, 26-277, 26-542, 26-559, 26-573, 26-667, 26-2256, 2267 32-264, 32-270, 32-417, 32-471, 32-473, 32-483, 32-500, 32-515, 32-534, 32-543, 32-592, 32-613, 32-615, 32-643, 35-259, 35-607, 40-703, 43-613, 46-531, 46-542, 49-487, 54-704, 56-599, 105-671, 142-377, 143-377, 209-760, 232-760, 249-817, 277-866, 314-517, 314-552, 314- 700, 314-801, 396-932, 411-700, 466-701, 466-827, 467-718, 484-915, 525-1104, 543-1174, 588-1175, 617-1169, 624-1175, 720-911, 743- 1143, 787-1043, 787-1134, 867-1121, 868-1175, 903-1148, 903-1304, 914-1157, 1168-1825, 1174-1663, 1174-1670, 1174-1861, 1175- 1718, 1175-1739, 1176-1587, 1178-1471, 1180-1453, 1189-1710, 1193-1708, 1202-1689, 1202-1854, 1203-1568, 1203-1718, 1207-1556, 1209-1681, 1217-1798, 1218-1733, 1222-1462, 1228-1724, 1232-1525, 1233-1827, 1239-1918, 1243-1831, 1252-1892, 1256-1520, 1262- 1362, 1290-1806, 1296-1848, 1313-1887, 1315-1792, 1315-1802, 1317-1846, 1324-1569, 1335-1776, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 1343-1909, 1354-1839, 1357-1905, 1361-1819, 1376-1784, 1377-1923, 1382-1859, 1382-1946, 1384-1933, 1385-1817, 1388-1905, 1402- 1721, 1403-1721, 1408-1948, 1410-1931, 1412-2092, 1412-2113, 1414-1785, 1420-2127, 1427-2012, 1427-2037, 1428-1867, 1436-1699, 1436-1995, 1439-1665, 1472-2058, 1475-1980, 1481-1711, 1481-1946, 1483-1827, 1484-1784, 1484-2064, 1499-1982, 1503-2032, 1508- 2165, 1511-2077, 1517-2265, 1521-2239, 1534-2033, 1535-2165, 1540-2021, 1541-1946, 1549-1970, 1550-1791, 1553-2064, 1557-1970, 1565-2112, 1568-1845, 1583-2146, 1588-1840, 1589-1894, 1593-2033, 1597-2103, 1604-1846, 1605-2147, 1626-2171, 1629-2154, 1631- 2202, 1636-1874, 1636-2018, 1659-2265, 1672-2249, 1677-2207, 1683-2243, 1694-2265, 1697-2136, 1697-2265, 1700-2205, 1701-1963, 1703-2265, 1710-2249, 1710-2252, 1712-2258, 1724-1992, 1727-1913, 1743-2252, 1749-2244, 1754-2255, 1757-2008, 1762-2230, 1766- 2235, 1767-2201, 1768-2253, 1769-2262, 1776-2033, 1781-2244, 1785-2246, 1786-2237, 1788-2265, 1791-2226, 1794-2201, 1799-2249, 1800-2244, 1802-2242, 1804-2265, 1828-2246, 1828-2265, 1833-2265, 1838-2241, 1841-2088, 1841-2235, 1855- 2241, 1856-2261, 1864-2128, 1869-2105, 1869-2257, 1882-2201, 1888-2242, 1913-2241, 1926-2241, 1971-2264, 1977-2265, 1986-2242, 1994-2256, 2009-2236, 2030-2241, 2071-2241, 2113-2243, 2125-2230, 2125-2267 142/7511241CB1/1-276, 1-702, 9-503, 12-252, 12-272, 12-331, 12-577, 12-3077, 14-375, 14-600, 14-761, 18-338, 18-499, 22-157, 31-512, 66-192, 69-364, 3077 74-338, 85-486, 86-368, 94-550, 114-593, 116-369, 122-682, 122-743, 122-772, 140-718, 146-380, 201-872, 336-450, 336-704, 352-772, 373-653, 378-461, 464-720, 467-771, 548-771, 569-765, 770-1319, 770-1442, 771-984, 777-1316, 788-1044, 797-1332, 798-1102, 813- 1311, 813-1453, 842-1605, 844-1439, 848-1420, 850-1337, 856-1379, 858-1098, 875-1078, 875-1151, 897-1414, 906-1196, 911-1379, 919- 1223, 919-1324, 928-1508, 931-1493, 955-1213, 956-1417, 965-1367, 966-1508, 978-1295, 984-1267, 992-1467, 1025-1551, 1025-1605, 1055-1334, 1068-1641, 1070-1278, 1078-1718, 1102-1558, 1104-1426, 1109-1554, 1114-1333, 1155-1726, 1163-1463, 1163-1907, 1170- 1809, 1174-1476, 1178-1441, 1181-1681, 1195-1706, 1200-1761, 1216-1845, 1222-1541, 1226-1838, 1230-1837, 1253-1799, 1263-1750, 1263-1864, 1263-1898, 1266-1528, 1266-1538, 1277-1501, 1279-1608, 1286-1563, 1289-1437, 1332-1679, 1423-1988, 1439-1724, 1470-1736, 1485-1693, 1496-1960, 1500-1893, 1501-1677, 1507-1580, 1515-1677, 1558-1802, 1563-2050, 1572- 2155, 1581-1697, 1602-2153, 1628-2124, 1633-1870, 1656-1758, 1662-1881, 1681-2283, 1684-1956, 1684-2263, 1684-2291, 1684-2321, 1690-2270, 1691-2254, 1709-1983, 1716-2369, 1731-2014, 1734-1924, 1744-1903, 1752-2370, 1756-2385, 1762-2023, 1776-2387, 1788- 2549, 1795-2387, 1801-2060, 1833-2117, 1844-2341, 1844-2347, 1844-2449, 1856-2297, 1860-2123, 1861-2170, 1890-2137, 1895-2655, 1903-2489, 1907-2167, 1907-2407, 1907-2645, 1907-2691, 1928-2552, 1928-2646, 1928-2647, 1932-2208, 1932-2218, 1932-2567, 1934- 2220, 1938-2076, 1938-2144, 1938-2149, 1946-2188, 1946-2578, 1951-2607, 1962-2243, 1963-2235, 1963-2250, 1963-2579, 1963-2630, 1966-2507, 1967-2553, 1977-2212, 1980-2551, 1984-2280, 1993-2607, 2001-2287, 2005-2147, 2005-2247, 2005-2265, 2005-2282, 2005- 2544, 2010-2267, 2017-2274, 2021-2551, 2025-2607, 2027-2408, 2031-2585, 2048-2210, 2061-2653, 2070-2630, Table 4 Polynucleotide Sequence Fragments SEQ ID NO :/ Incyte ID/Sequence Length 2079-2628, 2080-2596, 2095-2607, 2107-2354, 2107-2598, 2113-2357, 2116-2236, 2118-2369, 2124-2609, 2136-2683, 2139-2549, 2145- 2388, 2153-2404, 2153-2416, 2153-2620, 2157-2567, 2171-2451, 2172-2421, 2203-2461, 2206-2520, 2206-2688, 2208-2688, 2217-2690, 2217-2707, 2217-2715, 2233-2510, 2251-2379, 2258-2530, 2266-2533, 2267-2489, 2277-2689, 2295-2512, 2313-2681, 2314-2545, 2330- 2614, 2345-2630, 2351-2589, 2351-2680, 2352-2612, 2354-2607, 2354-2619, 2354-2717, 2359-2608, 2362-2611, 2362-2628, 2384-2716, 2404-2619, 2408-2661, 2424-2672, 2457-2718, 2459-2613, 2469-2716, 2473-2701, 2493-2514, 2493-2516, 2515-2668, 2574-2745 Table 5 Polynucleotide SEQ Incyte Project ID : Representative Library ID NO : 72 2828629CB 1 PANCTUT02 73 7509905CB 1 BEPINOTO1 74 7502048CB 1 LNODNOT03 75 7510031CB1 PITUNOTO1 76 7510116CBl LIVRTUTl3 77 7500548CB 1 SINTNOR01 78 7504807CB1 PANCNOT04 79 7504988CB 1 PANCNOT04 80 7505051CB1 THYMFET03 81 7505079CB 1 BRSTNOT04 83 7510086CB 1 BRSTNOT07 84 7510131CB l FIBPFEN06 85 7510137CBl BRAYDIN03 86 7510690CB 1 TLYMNOT08 87 7510695CBl BRAIFEC01 88 7504781CB1 ADRETUT05 89 7504798CB 1 EOSITXT01 90 7504800CB 1 EOSITXT01 91 7504902CB 1 PONSAZT01 92 _ 7510792CB 1 COLNNOT09 93 7510557CB 1 NGANNOTO1 _ __ 94 7510649CB 1 EOSIHET02 95 ___ _10264CB 1 COLRTUE01 __ 96 7506464CB 1 DENDNOT01 97 7510101CB1 THPLAZTOI 98 7510845CB l CONUTUT01 99 7510846CB 1 FIBAUNT02 1007510921CB1 PANCNOT17 101 7505097CB 1 ENDANOTO1 102 7506527CB 1 BRACDIK08 103 7504894CB 1 LIVRNON08 104 7510529CB l 293TFlT01 105 7510581CB 1 GBLATUTO1 105 7510581CB 1 GBLATUT01 106 7510582CB 1 GBLATUTO1 107 7510583CB 1 GBLATUT01 108 7510596CB 1 BRAIFET02 109 7510643CB l BRATDIC01 110 7506671CB1 BRAITUT02 111 7510518CB 1 TMLR2DT01 112 7510585CB l SYNORAT05 113 7510590CB1 BRAINOT14 114 7510617CB 1 LUNGNON03 115 7510618CB 1 DENDNOTO1 116 7510620CB 1 PANCNOT04 117 7510628CB l SINTNOR01 118 7510650CB I BMARNOT03 119.-7506644CB I BRABNOE02 120 7506692CB l PROSTUS23 121 7504938CB 1 NEUTLPTO1 Table 5 Polynucleotide SEQ Incyte Project ID : Representative Library ID NO : 122 7505625CB 1 ADRETUE02 123 7506468CB l LIVRNOT01 124 7510682CB 1 CORPNOT02 125 7505420CB 1 BRAFNON02 126 7505604CB 1 BMARNOT03 127 7505606CB I ESOGTME01 128 7511044CB 1 TLYJNOT01 129 2579533CB1 PGANNOT01 130 7511097CB 1 OVARNOT02 131 7510842CB1 HUVELPBO1 132 7511249CB 1 THYRNOT03 133 7511254CB1 HELATXT01 134 7511274CB 1 SCORNOTO1 135 7511303CB1 PROSNOT19 136 7511309CB1 PANCNOT08 137 7511314CB 1 PROSTUS23 138 7511316CB 1 LUNGAST01 139 7511391CB1 SCORNON02 140 7510144CB 1 PROSTUS23 141 7510810CB 1 THP 1NOT03 142 7511241CB 1 PITUDIR01 Table 6 Library Vector Library Description 293TF1T01 pINCY Library was constructed using RNA isolated from a transformed embryonal cell line (293-EBNA) derived from kidney epithelial tissue. The cells were transformed with adenovirus 5 DNA. ADRETUE02 PCDNA2.1 This 5' biased random primed library was constructed using RNA isolated from right adrenal tumor tissue removed from a 49- year-old Caucasian maleduring unilateral adrenalectomy. pathology indicated adrenal cortical carcinoma comprising nearly the entire specimen. The tumor was attached to the adrenal gland which showed mild cortical atrophy. The tumor was encapsulated, being surrounded by a thin (1-3 mm) rim of connective tissue. The patient presented with adrenal cancer, abdominal pain, pyrexia of unknown origin, and deficiency anemia. patient history included benign hypertension. previous surgeries included adenotonsillectomy. Patient medications included aspirin, calcium, and iron. Family history included atherosclerotic coronary artery disease in the mother; cerebrovascular accident and atherosclerotic coronary artery disease in the father; and benign hypertension in the grandparent(s). ADRETUT05 pINCY Library was constructed using RNA isolated from adrenal tumor tissue removed from a 52-year-old Caucasian female during a unilateral adrenalectomy. pathology indicated a pheochromocytoma. EPINOT01 PSPORT1 Library was constructed using RNA isolated from a bronchial epithelium primary cell line derived from a 54-year-old Caucasian male. BMARNOT03 pINCY Libary was constructed using RNA isolated from the left tibial bone marrow tissue of a 16-year-old Caucasian male during a partial left tibial ostectomy with free skin graft. patient history included an abnormality of the red blood cells. previous surgeries included bone and bone marrow biopsy, and soft tissue excision. Family history included osteoarthritis. BRABNOE02 PBK-CMV This 5' biased random primed library was constructed using RNA isolated from vermis tissue removed from a 35-year-old Caucasian male who died from cardiac failure. Pathology indicated moderate leptomeningeal fibrosis and multiple microinfarctions of the cerebral neocortex. Patient history included dilated cardiomyopathy, congestive heart failure, cardiomegaly, and an enlarged spleen and liver. patient medicatuions included simethicone, Lasix, Digoxin, Colace, Zantac, captopril, and Vasotec. BRACDIK08 PSPORT1 This amplified and normalized library was constructed using RNA isolated from diseased corpus callosum tissue removed from the brain of a 57-year-old Caucasian male who died from a cerebrovascular accident. Serologies were negative. patient history included Huntington's disease, emphysema, and tobacco abuse (3-4 packs per day for 40 years).

Table 6 Library Vector Library Description BRAFNON02 pINCY This normalized frontal cortex tissue library was constructed from 10.6 million independent clones from a frontal cortex tissue library. Starting RNA was made from superior frontal cortex tissue removed from a 35-year-old Caucasian male who died from cardiac failure. Pathology indicated moderate leptomeningeal fibrosis and multiple microinfarctions of the cerebral neocortex. Grossly, the brain regions examined and cranial nerves were unremarkable. No atherosclerosis of the major vessels was noted. Microscopically, the cerebral hemisphere revealed moderate fibrosis of the leptomeninges with focal calcifications. There was evidence of shrunken and slightly eosinophilic pyramidal neurons throughout the cerebral hemispheres. There were also multiple small microscopic areas of cavitation with surrounding gliosis scattered throughout the cerebral cortex. Patient history included dilated cardiomyopathy, congestive heart failure, cardiomegaly, and an enlarged spleen and liver. patient medicatuions included simethicone, Lasix, Digoxin, Colace, Zantac, captopril, and Vasotec. The library was normalized in two rounds using conditions adapted from Soares et al., PNAS (1994) 91:9228 and Bonaldo et al., Genome Research (1996) 6:791, except that a significantly longer (48 hours/round) reannealing hybridization was used. BRAIFEC01 pINCY This large size-fractionated library was constructed using RNA isolated from brain tissue removed from a Caucasian male fetus who was stillborn with a hypoplastic left heart at 23 weeks' gestation. BRAIFET02 pINCY Library was constructed using RNA isolated from brain tissue removed from a Caucasian male fetus, who was stillborn with a hypoplastic left heart at 23 weeks' gestation. BRAINOT14 pINCY Library was constructed using RNA isolated from brain tissue removed from the left frontal lobe of a 40-year-old Caucasian female during excision of a cerebral meningeal lesion. pathology for the associated tumor tissue indicated grade 4 gemistocytic astrocytoma. BRAITUT02 PSPORT1 Library was constructed using RNA isolated from brain tumor tissue removed from the frontal lobe of a 58-year-old Caucasian male during excision of a cerebral meningeal lesion. Pathology indicated a grade 2 metastatic hypernephroma. Patient history included a grade 2 renal cell carcinoma, insomnia, and chronic airway obstructiuon. Family history included a malignant neoplasm of the kidney.

Table 6 Library Vector Library Description BRATDIC01 pINCY This large size-fractionated library was constructed using RNA isolated from diseased brain tissue removed from the left temporal lobe of a 27-year-old Caucasian male during a brain lobectomy. pathology for the left temporal lobe, including the mestial temporal structures, indicated focal, marked pyramidal cell loss and gliosis in hippocampal sector CA1, consistent with mestial temporal sclerosis. The left frontal lobe showed a focal deep white matter lesion, characterized by marked gliosis, calcifications, and hemosiderin-laden macrophages, consistent with a remote perinatal injury. The frontal lobe tissue also showed mild to moderate generalized gliosis, predominantly subpial and subcortical, consistent with chronic seizure disorder. GFAP was positive for astrocytes. The patient presented with ntractable epilepsy, focal epilepsy, hemiplegia, and an unspecified brain injury. Patient history included cerebral palsy, abnormality of gait, depressive disorder, and tobacco abuse in remission. Previous surgeries included tendon transfer. Patient medications included minocycline hydrochloride, Tegretol, phenobarbital, vitamin C, Pepcid, and Pevaryl. Family history included brain cancer in the father. BRAYDIN03 pINCY This normalized library was constructed from 6.7 millionindependent clones from a brain tissue library. Starting RNA was made from RNA isolated from diseased hypothalamus tissue removed from a 57-year-old Caucasian male who died from a cerebrovascular accident. Patient history included Huntington's disease and emphysema. The library was normalized in 2 rounds using conditions adapted from Soares et al., PNAS (1994) 91:9228 and Bonaldo et al., Genome Research (1996) 6:791, except that a significantly longer (48-hours/round) reannealing hybridization was used. The library was linearized and recircularized to select for insert containing clones. BRSTNOT04 PSPORT1 Library was constructed using RNA isolated from breast tissue removed from a 62-year-old East Indian female during a unilateral extended simple mastectomy. Pathology for the associated tumor tissue indicated an invasive grade 3 ductal carcinoma. Patient history included benign hypertension, hyperlipidemia, and hematuria. Family history included cerebrovascular and cardiovascular disease, hyperlipidemia, and liver cancer. BRSTNOT07 pINCY Library was constructed using RNA isolated from diseased breast tissue removed from a 43-year-old Caucasian female during a unilateral extended simple mastectomy. Pathology indicated mildly proliferative fibrocystic changes with epithelial hyperplasia, papillomatosis, and duct ectasia. Pathology for the associated tumor tissue indicated invasive grade 4, nuclear grade 3 mammary adenocarcinoma with extensive comedo necrosis. Family history included epilepsy, cardiovascular disease, and type II diabetes. COLNNOT09 PSPORT1 Library was constructed using RNA isolated from colon tissue removed from a 60-year-old Caucasian male during a left hemicolectomy.

Table 6 Library Vector Library Description COLRTUE01 PSPORT1 This 5' biased random primed library was constructed using RNA isolatedfrom rectum tumor tissue removed from a 50-year- old Caucasian male duringclosed biopsy of rectum and resection of rectum. Pathology indicated grade 3 colonic adenocarcinoma which invades through the muscularis propria to involve pericolonic fat. Tubular adenoma with low grade dysplasia was also identified. The patient presented with malignant rectal neoplasm, blood in stool, and constipation. Patient history included benign neoplasm of the large bowel, hyperlipidemia, benign hypertension, alcohol abuse, and tobacco abuse. Previous surgeries included above knee amputation and vasectomy. Patient medications included allopurinol, Zantac, Darvocet, Centrum vitamins, and an unspecified stool softener. Family history included congestive heart filure in the mother; and benign neoplasm of the large bowel and polypectomy in the sibling(s). CONUTUT01 pINCY Library was constructed using RNA isolated from signmoid mesentery tumor tissue obtained from a 61-year-old female during a total abdominalhysterectomy and bilateral salpingo-oophorectomy with regional lymph node excision. Pathology incidated a metastatic grade 4 malignant mixed mullerian tumor present in the sigmoid mesentery at two sites. CORPNOT02 pINCY Library was constructed using RNA isolated from diseased corpus callosum tissue removed from the brain of a 74-year-old Caucasian male who died from Alzheimer's disease. DENDNOT01 pINCY Library was constructed using RNA isolated from untreated dendritic cells from peripheral blood. ENDANOT01 PBLUESCRIPT Library was constructed using RNA isolated from aortic endothelial cell tissue from an explanted heart removed from a male during a heart rransplant. EOSIHET02 PBLUESCRIPT Library was constructed using RNA isolated fromperipheral blood cells apheresed from a 48-year-old Caucasian male. Patient history included hypereosinophilia. The cell population was determined to be greater than 77% eosinophils by Wright's staining. EOSITXT01 pINCY Library was constructed using RNA isolated from eosinophils stimulated with IL-5.

Table 6 Library Vector Library Description ESOGTME01 PSPORT This 5' biased random primed library was constructed using RNA isolated from esophageal tissue removed from a 53-year-old Caucasian male during a partial esophagectomy, proximal gastrectomy, and regional lymph node biopsy. pathology indicated no significant abnormality in the non-neoplastic esophagus. Pathology for the matched tumor tissue indicated invasive grade 4 (of 4) adenocarcinoma, forming a sessile mas situalte din the lower esophagus, 2 cm from the gastroesophageal junction and 7 cm from the proximal margin. The tumor ivnaded through the muscularis propria into the adventitial soft tissue. Metastic carcinoma was identified in 2 of 5 paragastric lymph nodes with perinodal extension. The patient presented with dysphagia. Patient history included membranous nephritis, hyperlipidemia, benign hypertension, and anxiety state. previoussurgeries included an adenotonsillectomy, appendectomy, and inguinal hernia repair. The patient was not taking any medications. Family history included atherosclerotic coronary artery disease, alcoholic cirrhosis, alcohol abuse, and an abdominal aortic aneurysm rupture int he father; breast cancer in the mother; a myocardial infarction and atherosclerotic coronary artery disease in the sibling(s); and mycoardial infarction and atherosclerotic coronary artery diesease in the grandparent(s). FIBAUNT02 pINCY Library was constructed using RNA isolated from untreated aortic adventitial fibroblasts obtained from a 65-year-old Caucasian female. FIBPFEN06 pINCY The normalized prostate stromal fibroblast tissue libraries were constructed from 1.56 million independent clones from a prostate fibroblast library. Starting RNA was made from fibroblasts of prostate strom aremoved from a male fetus, who died after 26 weeks' gestation. The libraries were normalized in two round using condition adapted from Soares et al., PNAS (1994) 91:9228 and Bonaldo et al., Genome Research (196) 6:791, except hat a significantly longer (48- hours/round)reannealing hybridization was used. the library was then linearized and recircularized to select for isnert containing clones as follos: plasmid DNA was prepped from approximately l1 million clones from the nromalized prostate stromal fibroblast tissue libraries following soft agar transformation. GBLATUT01 pINCY Library was constructed using RNA isolated from gallbladder tumor tissue removed from a 78-year-old Caucasian female during a cholecystectomy. Pathology indicated invasive grade 2 squamous cell carcinoma, forming a mass in the gallbladder. patient history included diverticulitis of the colon, palpitations, benign hyopertension, and hyperlipidemia. Family history included a cholecystectomy, atherosclerotic coronary artery disease, atherosclerotic coronary artery disease, hyperlipidemia, and benign hypertension. HELATXT01 pINCY Library was constructed using RNA isolated from HeLa cells treated with TNF-a and IL-1b, 10ng/nl each for 20 hours. The HeLa cell line is derived from cervical adenocarcinoma removed from a 31-year-old Black female.

Table 6 Library Vector Library Description HUVELPB01 PBLUESCRIPT Library was constructed using RNA isolated from HUV-EC-C (ATCC CRL 1730) cells that were stimulated with cytokine/LPS. RNA was isolated from two pools of HUV-EC-C cells that had been treated with either gamma IFN and TNF- alpha or IL-1 beta and LPS. In the first instance, HUV-EC-C cells weretreated with 4 units/ml TNF and 2 units/ml IFNg for 96 hours. In the second instance, cells were treated with 1 units/ml IL-1 and 100 ng/ml LPS for 5 hours. LIVRNON08 pINCY This normalized library was constructed from 5.7 million idnependent clones from a pooled liver tissue library. Starting RNA was made from pooled liver tissue removed from a 4-year-old Hispanic male who died from anoxia and a 16 week female fetus who died after 16-weeks gestation from anencephaly. Serologies ere positive for cytolomegalovirus in the 4-year-old. history included taking daily prenatal vitamins and mitral valve prolapse in the mother of the fetus. The library was normalized in 2 rounds using conditions adapted from Soares et al., PNAS (1994) 91:9228 and Bonaldo et al., Genome Research 6 (1996):791, except that significantly longer (48 hours/round) reannealing hybridization was used. LIVRNOT01 PBLUESCRIPT Library was constructed at Stratagene, using RNA isolated from the liver tissue of a 49-year-old male. LIVRTUT13 pINCY Library was constructed using RNA siolated from lvier tumor tissue removed from a 62-year-old Caucasian female during partial hepatectomy and exploratory laparotomy. Pathology indicated metastatic intermediate grade neuroendocrine carcinoma, consistent with islet cell tumor, forming nodules ranging in size, in the lateral and medial left liver lobe. The pancreas showed fibrosis, chronic inflammation and fat necrosis consitent with pseudocyst. The gall bladder showed mild chronic cholecystitis. patient history included malignant neoplasm of the pancreas tail, pulmonary embolism, hyperlipidemia, thrombophlebitis, joint pain in multiple joint,s type II diabetes, benign hypertension, and cerebrovascular disease. Family history included pancreas cancer, secondary liver cancer, benign hypertension, and hyperlipidemia. LNODNOT03 pINCY Library was constructed using RNA isolated from lymph node tissue obtained from a 67-year-old Caucasian male during a segmental lung resection and bronchoscopy. On microscopic exam, this tissue was found to be extensively necrotic with 10% viable tumor. Pathology for the associated tumor tissue indicated invasive grade 3-4 squamous cell carcinoma. patient history included hemangioma. Family history included atherosclerotic coronary artery disease, benign hypertension, congestive heart failure, atherosclerotic coronary artery disease. LUNGAST01 PSPORT1 Library was constructed using RNA isolated from the lung tissue of a 17-year-old Caucasian male, who died from head trauma. Patient history included asthma.

Table 6 Library Vectory Library description LUNGNON03 PSPORT1 This normalized library was constructed from 2.56 million independent clones from a lung tissue library. RNA was made from lung tissue removed from the left lobe of a 58-year-old Caucasian male during a segmental lung resection. Pathology for the associated tumor tissue indicated a metastatic grade 3 (of 4) osteosarcoma. Patient history included soft tissue cancer, secondary cancer of the lung, prostate cancer, and an acute duodenal ulcer with hemorrhage. Patient also received radiation therapy to the retroperitoneum. family history included prostate cancer, breast cancer, and acute leukemia. The normalization and hybridization conditions were adapted from soares et al., PNAS (19940 91:9228; Swaroop et al., NAR (1991) 19:1954; and Bonaldo et al., Genome Research (1996) 6:791. NEUTLPT01 PBLUESCRIPT Library was constructed using RNA isolated from peripheral bloodgranulocytes collected by density gradient centrifugation through Ficoll-Hypaque. The cells were isolated from buffy coat uits obtained from unrelated male and female donors. Cells were cultured in 100 ng/ml E. coli LPS for 30 minutes, lysed in GuSCN, and spun through CsCl to obtain RNA for library construction. NGANNOT01 PSPORT1 Library was constructed using RNA isolated from tumorous neuroganglion tissue removed from a 9-year-old Caucasian male during a soft tissue excision of the chest wall. Pathology indicated a ganglioneuroma. Family history included asthma. OVARNOT02 PSPORT1 Library was constructed using RNA isolated from ovarian tissue removed from a 59-year-old Caucasian female who died of a myocarial infarction. Patient history included cardiomyopathy, coronary artery disease, previous myocardial infarctions, hypercholesterolemia, hypotension, and arthritis. PANCNOT04 PSPORT1 Library was constructed using RNA isolted from the pancreatic tissue of a 5-year-old Caucasian male who died in a motor vehicle accident. PANCNOT08 pINCY Library was constructed using RNA isolated frompancreatic tissue removed from a 65-year-old Caucasian female during radical subtotal pancreatectomy. Pathology for the associated tumor tissue idnicate an invasive grade 2 adenocarcinoma. Patient history included type II diabetes, osteoarthritis, cardiovascular disease, benign neoplasm in the large bowel, and a cataract. Previous surgeries included a total splenectomy, cholecystectomy, and abodminal hysterectomy. Family history included cardiovascular disease, type II diabetes, and stomach cancer. PANCNOT17 pINCY Library was constructed using RNA isolated from pancreatic tissue removed from a 65-year-old female. Pathology for the associated tumor tissue indicated well-differentiated, metastiatic, neuroendocrine carcinoma (nuclear grade 1).

Table 6 Library Vector Library Description PANCTUT02 pINCY Library was constructed using RNA isolated from pancreatic tumor tissue removed from a 45-year-old Caucasian female during radical pancreaticoduodenectomy. Pathology indicated a grade 4 anaplastic carcinoma. Family history included benign hypertension, hyperlipidemia and atherosclerotic coronary artery disease. PGANNOT01 PSPORT1 Library was constructed using RNA isolated from paraganglionic tumor tissue removed from the intra-abdominal region of a 46-year-old Caucasian male during exploratory laparotomy. Pathology indicated a benign paragnglioma and was associated with a grade 2 renal cell carcinoma, clear cell type, which did not penetrate the capsule. Surgical margins were negative for tumor. PITUDIR01 PCDNA2.1 This random primed library was constructed using RNA isolated from pituitary gland tissue removed from a 70-year-old female who died from metastatic adenocarcinoma. PITUNOT01 PBLUESCRIPT Library was constructed using RNA obtained from Clontech (CLON 6584-2, lot 35278). The RNA was isolated from the pituitary glands removed from a pool of 18 male and female Caucasian donors, 16 to 70 years old, who died from trauma. PONSAZT01 pINCY Library was constructed using RNA isolated from diseased pons tissue removed from the brain of a 74-year-old Caucasian male who died from Alzheimer's disease. PROSNOT19 pINCY Library was constrcted using RNA isolated from diseased prostate tissue removed from a 59-year-old Caucasian male during a radical prostatectomy with regional lymph node excision. Patholgy indicated adenofibromatous hyperplasia. Pathology for the associated tumor tissue indicated an adenocarcinoma (Gleason grade 3+3). The patient presented with elevated prostate- specific antigen (PSA). Patient history included colon diverticuli, asbestosis, and thrombophlebitis. Previous surgeries included a partial colectomy. Family history included benign hypertension, multiple myeloma, hyperlipidemia and rheumatoid arthritis. PROSTUS23 pINCY This subtracted prostate tumor library was constructed using 10 million clones from a pooled prostate tumor library that was subjected to 2 rounds of subtractive hybridization with 10 million clones from a pooled prostate tissue library. The starting library for subtraction was constructed by pooling equal numbers of clones from 4 prostate tumor libraries using mRNA isolated from prostate tumor removed from Caucasian males at ages 58 (A), 61 (B), 66 (C), and 68 (D) during prostatectomy with lymph node excision. Pathology indicated adenocarcinoma in all donors. History included elevated PSA, induration and tabacco abuse in donor A; elevated PSA, induration, prostate hyperplasia, renal failure, osteoarthritis, renal artery stenosis, benign HTN, thrombocytopenia, hyperlipidemia, tobacco/alcohol abuse and hepatitis C (carrier) in donor B; elevated PSA, induration, and tobacco abuse in donor C; and elevated PSA, induration, hypercholesterolemia, and kidney calculus in donor D.

Table 6 Library Vector Library Description The hybridization probe for subtraction was constructed by pooling equal numbers of cDNA clones from 3 prostate tissue libraries derived from prostate tissue, prostate epithelial cells, and fibroblasts from prostate stroma from 3 different donors. Subtractive hybridization conditions were based on the methodologies of Swaroop et al., NAR 19 (1991):1954 and Bonaldo, et al. Genome Research 6 (1996):791. SCORNON02 PSPORT1 This normalized spinal cord library was constructed from 3.24M independent clones from the a spinal cord tissue library. RNA was isolated from the spinal cord tissue removed from a 71-year-old Caucasian male who died from respiratory arrest. Patient history included myocardial infarction, gangrene, and end stage renal disease. the normalization and hybridization conditions were adapted from soares et al.(PNAS (1994) 91:9228). SCORNOT01 PSPORT1 Library was constructed using RNA isolated from spinal cord tissue removed from a 71-year-old Caucasian male who died from respiratory arrest. Patient history included myocardial infarction, gangrene, and end stage renal disease. SINTNOR01 PCDNA2.1 This random primed library was constructed using RNA isolated from small intestine tissue removed from a 31-year-old Caucasian female during Roux-en-Y gastric bypass. Patient history included clinical obesity. SYNORAT05 PSPORT1 Library was constructed using RNA isolated from the knee synovial tissue of a 62-year-old female with rheumatoid arthritis. THP1AZT01 pINCY Library was constructed using RNA isolated from THP-1 promonocyte cells treated for three days with 0.8 micromolar 5-aza- 2'-deoxycytidine. THP-1 (ATCC TIB 202) is a human promonocyte line derived from peripheral blood of a 1-year-old Caucasian male with acute monocytic leukemia (Int. J. Cancer (1980) 26:171). THP1NOT03 pINCY Library was constructed using RNA isolated from untreated TP-1 cells. THP-1 is a human promonocyte line derived from the peripheral blood of a 1-year-old Caucasian male with acute monocytic leukemia (ref; Int. J. Cancer (1980) 26:171). THYMFET03 pINCY Library was constructed using RNA isolated from thymus tissue removed from a Caucasian male fetus. THYRNOT03 pINCY Library was constructed using RNA isolated from thyroid tissue removed from the left thyroid of a 28-year-old Caucasian female during a complete thyroidectomy. Pathology indicated a small nodule of adenomatous hyperplasia present in the left thyroid Pathlogy for the associated tumor tissue indicated dominant follicular adenoma, forming a well-encapsulated mass in the left thyroid. TLYJNOT01 pINCY Library was constructed using RNA isolated from an untreated Jurkat cell line derived from the T cells of a male. Patient history included acute T-cell leukemia.

Table 6 Library Vector Library Description TLYMNOT08 pINCY The library was constructed using RNA isolated from anergicallogenic T-lymphocyte tissue removed from an adult (40-50-year old) Caucasian male. the cells were incubated for 3 days in the presence of 1 microgram/ml OKT3 mAb and 5% human serum. TMLR2DT01 PBLUESCRIPT Library was constructed using RNA isolated from non-adherent peripheral blood mononuclear cells. The blood was obtained from unrelated male and female donors. Cells from each donor were purified on Ficoll Hypaque, then co-cultured for 24 hours in medium containing normal human serum at a cell density of 2 million cells/ml.

Table 7 Pro ram Descri tion Reference Parameter Threshold g P ABI FACTURA A program that removes vector sequences and masks Applied Biosystems, Foster City, CA. ambiguous bases in nucleic acid sequences. ABI/PARACEL FDF A Fast Data Finder useful in comparing and Applied Biosystems, Foster City, CA ; Mismatch <50% annotating amino acid or nucleic acid sequences. Paracel Inc., Pasadena, CA. ABI AutoAssembler A program that assembles nucleic acid sequences. Applied Biosystems, Foster City, CA. BLAST A Basic Local Alignment Search Tool useful in Altschul, S. F. et al. (1990) J. Mol. Biol. ESTs : Probability value = 1. OE- sequence similarity search for amino acid and nucleic 215 : 403-410 ; Altschul, S. F. et al. (1997) 8 or less ; Full Length sequences : acid sequences. BLAST includes five functions : Nucleic Acids Res. 25 : 3389-3402. Probability value = 1. OE-10 or blastp, blastn, blastx, tblastn, and tblastx. less FASTA A Pearson and Lipman algorithm that searches for Pearson, W. R. and D. J. Lipman (1988) Proc. ESTs : fasta E value = 1. 06E-6 ; similarity between a query sequence and a group of Natl. Acad Sci. USA 85 : 2444-2448 ; Pearson, Assembled ESTs : fasta Identity sequences of the same type. FASTA comprises as W. R. (1990) Methods Enzymol. 183 : 63-98 ; = 95% or greater and Match least five functions : fasta, tfasta, fastx, tfastx, and and Smith, T. F. and M. S. Waterman (1981) length = 200 bases or greater ; ssearch. Adv. Appl. Math. 2 : 482-489. fastx E value = 1. OE-8 or less ; Full Length sequences : fastx score = 100 or greater BLIMPS A BLocks IMProved Searcher that matches a Henikoff, S. and J. G. Henikoff (1991) Probability value = 1. OE-3 or sequence against those in BLOCKS, PRINTS, Nucleic Acids Res. 19 : 6565-6572 ; Henikoff, less DOMO, PRODOM, and PFAM databases to search J. G. and S. Henikoff (1996) Methods for gene families, sequence homology, and structural Enzymol. 266 : 88-105 ; and Attwood, T. K. et fingerprint regions. al. (1997) J. Chem. Inf. Comput. Sci. 37 : 417- 424.

Table 7 Parameter Threshold HMMER An algorithm for searching a query sequence against Krogh, A. et al. (1994) J. Mol. Biol. PFAM, INCY, SMART or hidden Markov model (HMM)-based databases of 235 : 1501-1531 ; Sonnhammer, E. L. L. et al. TIGRFAM hits : Probability protein family consensus sequences, such as PFAM, (1988) Nucleic Acids Res. 26 : 320-322 ; value = 1. OE-3 or less ; Signal INCY, SMART and TIGRFAM. Durbin, R. et al. (1998) Our World View, in peptide hits : Score = 0 or greater a Nutshell, Cambridge Univ. Press, pp. 1- 350. ProfileScan An algorithm that searches for structural and Gribskov, M. et al. (1988) CABIOS 4 : 61-66 ; Normalized quality score > GC sequence motifs in protein sequences that match Gribskov, M. et al. (1989) Methods specified"HIGH"value for that sequence patterns defined in Prosite. Enzymol. 183 : 146-159 ; Bairoch, A. et al. particular Prosite motif. (1997) Nucleic Acids Res. 25 : 217-221. Generally, score = 1. 4-2. 1. I Phred A base-calling algorithm that examines automated Ewing, B. et al. (1998) Genome Res. 8 : 175- sequencer traces with high sensitivity and probability. 185 ; Ewing, B. and P. Green (1998) Genome Res. 8 : 186-194. Phrap A Phils Revised Assembly Program including Smith, T. F. and M. S. Waterman (1981) Adv. Score = 120 or greater ; Match SWAT and CrossMatch, programs based on efficient Appl. Math. 2 : 482-489 ; Smith, T. F. and length = 56 or greater implementation of the Smith-Waterman algorithm, M. S. Waterman (1981) J. Mol. Biol. 147 : 195- useful in searching sequence homology and 197 ; and Green, P., University of assembling DNA sequences. Washington, Seattle, WA. Consed A graphical tool for viewing and editing Phrap Gordon, D. et al. (1998) Genome Res. 8 : 195- assemblies. 202. SPScan A weight matrix analysis program that scans protein Nielson, H. et al. (1997) Protein Engineering Score = 3. 5 or greater sequences for the presence of secretory signal 10 : 1-6 ; Claverie, J. M. and S. Audic (1997) peptides. CABIOS 12 : 431-439. TMAP A program that uses weight matrices to delineate Persson, B. and P. Argos (1994) J. Mol. Biol. transmembrane segments on protein sequences and 237 : 182-192 ; Persson, B. and P. Argos determine orientation. (1996) Protein Sci. 5 : 363-371.

Table 7 Program Description Reference Parameter Threshold TMHMMER A program that uses a hidden Markov model (HMM) Sonnhammer, E. L. et al. (1998) Proc. Sixth to delineate transmembrane segments on protein Intl. Conf. On Intelligent Systems for Mol. sequences and determine orientation. Biol., Glasgow et al., eds., The Am. Assoc. for Artificial Intelligence (AAAI) Press, Menlo Park, CA, and MIT Press, Cambridge, MA, pp. 175-182. Motifs A program that searches amino acid sequences for Bairoch, A. et al. (1997) Nucleic Acids Res. patterns that matched those defined in Prosite. 25 : 217-221 ; Wisconsin Package Program Manual, version 9, page M51-59, Genetics Computer Group, Madison, WI.

Table 8 SEQ PID EST ID SNP ID EST CB 1 T EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP Allele 1 2 Allele 1 Allele l Allele l Allele 1 NO : frequency frequency frequency frequency I i 72 2828629 1270817H 1 SNP00007805 12 2575 l A A G noncoding n/a n/a n/a n/a 72 2828629 1270817H1 SNP00007806 156 2718 l T T C noncoding 0. 62 n/a n/a n/a 72 2828629 1270817H1 SNP00107784 72 2635 G G A noncoding n/d n/a n/a n/a 72 2828629 1345356H1 SNP00033582 87 235 G A G noncoding n/a n/a n/a n/a I I 72 2828629 1562910H1 SNP00062531 69 2542 C C T noncoding n/a n/a n/a n/a 72 2828629 1675153H1 SNP00004174 132 2249 T T C noncoding n/d n/d 0. 21 0. 43 72 2828629 1693582H1 SNP00007806 109 2719 T T C noncoding 0. 62 n/a n/a n/a i l l I 72 2828629 1731831H1 SNP00108561 131 993 G A G T230 0. 16 0. 44 0. 12 0. 34 72 2828629 1867507H1 SNP00007805 75 2571 A A G noncoding n/a n/a n/a n/a 72 2828629 1867507H1 SNP00062531 108 2538 C C T noncoding n/a n/a n/a n/a l l l l l l l l l l l I 72 2828629 1867507H1 SNP00107784 15 2631 G G A noncoding n/d n/a n/a n/a 72 2828629 2099327H1 SNP00057034 120 2123 C C T noncoding n/a n/a n/a n/a 72 2828629 2099327H1 SNP00108563 197 2200 A A G noncoding n/a n/a n/a n/a I I I I I I I I I I,, 72 2828629 2262828H1 SNP00004174 85 2248 T T C noncoding n/d n/d 0. 21 0. 43 72 2828629 2276094H1 SNP00007805 67 2574 GAG noncoding n/a n/a n/a n/a I I l I I I___I, I I I i 72 2828629 2276094H1 SNP00062531 100 2541 C C T noncoding n/a n/a n/a n/a 72 2828629 2276094H1 SNP00107784 7 2634 G G A noncoding n/d n/a n/a n/a 72 2828629 2448954H1 SNP00033582 83 236 A A G noncoding n/a n/a n/a n/a I I l l I I I I I I. 72 2828629 2654420H1 SNP00057034 146 2112 C C T noncoding n/a n/a n/a n/a 72 2828629 2654420H1 SNP00108563 223 2189 A A G noncoding n/a n/a n/a n/a 72 2828629 3088462H1 SNP00007805 150 2530 A A G noncoding n/a n/a n/a n/a 72 2828629 3088462H1 SNP00062531 183 2496 C C T noncoding n/a n/a n/a n/a l l l l l l I I,,, 72 2828629 3088462H1 SNP00107784 90 2591 G G A noncoding n/d n/a n/a n/a 72 2828629 3168491H1 SNP00004174 148 2247 C T C noncoding n/d n/d 0. 21 0. 43 , I,, I, l l l l l l l 72 2828629 3207088H1 SNP00007806 56 2681 T T C noncoding 0. 62 n/a n/a n/a 72 2828629 3207088H1 SNP00107784 140 2597 G G A noncoding n/d n/a n/a n/a l l l l I, l l l l l l l 72 2828629 3513937H1 SNP00007805 70 2555 A A G noncoding n/a n/a n/a n/a l l l l I I, l l I,,, 72 2828629 3513937H1 SNP00062531 103 2522 C C T noncoding n/a n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST CB 1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency 72 2828629 3527543H 1 SNP00062530 174 2879. A A G noncoding n/a n/a n/a n/a 72 2828629 3674609H1 SNP00057033 235 1977 T T G noncoding 0. 90 n/a n/a n/a 72 2828629 3961677H1 SNP00007805 96 2508 A A G noncoding n/a n/a n/a n/a 72 2828629 3961677H 1 SNP00062531 129 2475 C C T noncoding n/a n/a n/a n/a 72 2828629 4114958H1 SNP00007805 159 2519 G A G noncoding n/a n/a n/a n/a 72 2828629 4114958H1 SNP00062531 192 2486 T | C T noncoding n/a n/a n/a n/a 72 2828629 4440675H1 SNP00062531 122 2540 C C T noncoding n/a n/a n/a n/a i I I I I, l l 72 2828629 4500882H1 SNP00033582 91 227 A A G noncoding n/a n/a n/a n/a 72 2828629 4600141H1 SNP00007805 13 2570 A A G noncoding n/a n/a n/a n/a 72 2828629 4600141H1 SNP00007806 157 2714 T T C noncoding 0. 62 n/a n/a n/a 72 2828629 4600141H1 SNP00107784 73 2630 G G A noncoding n/d n/a n/a n/a 72 2828629 4797817H1 SNP00007805 100 2573 A A G noncoding n/a n/a n/a n/a 72 2828629 4797817H1 SNP00007806 244 2717 ! T | T T C noncoding 0. 62 n/a n/a n/a 72 2828629 4797817H1 SNP00107784 160 2633 G G A noncoding n/d n/a n/a n/a 72 2828629 4851201H1 SNP00007805 202 2576 A A G noncoding n/a n/a n/a n/a 72 2828629 4851201H1 SNP00007806 58'2720 T T C noncoding 0. 62 n/a n/a n/a 72 2828629 4851201H1 SNP00107784 142 2636 G G A noncoding n/d n/a n/a n/a 72 2828629 5100026H1 SNP00007805 138 2568 A A G noncoding n/a n/a n/a n/a l l l l I, l l l l l 72 2828629 5100026H1 SNP00062531 171 2535 C C T noncoding n/a n/a n/a n/a 72 2828629 5100026H1 SNP00107784 78 2628 G G A noncoding n/d n/a n/a n/a 72 2828629 5662941H1 SNP00057034 43 2122 C C T noncoding n/a n/a n/a n/a 72 2828629 5662941H1 SNP00108563 120 2199 A A G noncoding n/a n/a n/a n/a 72 2828629 5677175H1 SNP00033582 62 208 A A G'noncoding n/a n/a n/a n/a 72 2828629 5810145H1 SNP00007806 78 2716 T T C noncoding 0. 62 n/a n/a n/a 72 2828629 6422535H1 SNP00033582 71 217 A A G noncoding n/a n/a n/a n/a 72 2828629 6784416H1 SNP00076056 291 1065 C C T R254 n/a n/a n/a n/a 72 2828629 6814531H1 SNP00057033 356 1982 T T G noncoding 0. 90 n/a n/a n/a 72 2828629 6938337H1 SNP00007805 171 2562 A A G noncoding n/a n/an/a n/a Table 8 SEQ PID EST ID SNP ID EST CB1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele l NO : frequency frequency frequency frequency 72 2828629 6938337H1 SNP00007806 315 2706 T T C noncoding 0. 62 n/a n/a n/a 72 2828629 6938337H1 SNP00062531 138 2529 C C T noncoding n/a n/a n/a n/a l 72 2828629 6938337H1 SNP00107784 231 2622 G G A noncoding n/d n/a n/a n/a 72 2828629 6949559H1 SNP00108562 381 j 1068 C T C 1255 n/a n/a n/a n/a 72 2828629 7033983H1 SNP00108562 152 1067 T T C 1255 n/a n/a n/a n/a l I 73 7509905 1348630H1 SNP00132574 21 471 T T C H117 n/a n/a n/a n/a 73 7509905 1473085H1 SNP00073583 127 1669 C C T noncoding n/d n/a n/a n/a I l, l I l 73 7509905 1845334H1 SNP00115181 199 2408 G G A noncoding n/a n/a n/a n/a 73 7509905 1879703H 1 SNP00115181 245 2410 G G A noncoding n/a n/a n/a n/a I, I I I s 73 7509905 1979634H1 SNP00028947 57 2117 A A G noncoding n/a n/a n/a n/a 73 7509905 2675044H1 SNP00070789 140 372 c c A T84 0. 59 n/a n/a n/a 73 7509905 2895120H1 SNP00028945 207 974 G G A S285 n/a n/a n/a n/a l I I I I I. I, 73 7509905 2957969H1 SNP00028945 141 981 G G A P287 n/a n/a n/a n/a 73 7509905 3012110H1 SNP00115181 216 2409 G G A noncoding n/a n/a n/a n/a 73 7509905 3533809H1 SNP00070789 245 371 C C A T84 0. 59 n/a n/a n/a 73 7509905 3588879H1 SNP00070789 91 369 C C A A83 0. 59 n/a n/a n/a 73 7509905 3588879H1 SNP00132574 191 469 T T C Y117 n/a n/a n/a n/a 73 7509905 3815151H1 SNP00028945 190 980 G G A R287 n/a n/a n/a n/a l l l l l l l l l l l 73 7509905 3964722H1 SNP00073583 99 1666 C C T noncoding n/d n/a n/a n/a 73 7509905 4631942H1 SNP00005932 5 2054 G G C noncoding 0. 58 n/a n/a n/a 73 7509905 4744556H1 SNP00028945 212 979 G G A A287 n/a n/a n/a n/a I I I I I I, 73 7509905 4823852H1 SNP00028945 136 978 G G A M286 n/a n/a n/a n/a 73 7509905 5018292H1 SNP00028946 66 1689 T C T noncoding 0. 79 n/a n/a n/a 73 7509905 6781329H1 SNP00005932 528 2057 G G C noncoding 0. 58 n/a n/a n/a 73 7509905 7037030H1 SNP00073583 180 1668 T C T noncoding n/d n/a n/a n/a 73 7509905 7354101H1 SNP00028946 9 1690 C C T noncoding 0. 79 n/a n/a n/a 73 7509905 8504647H1 SNP00028946 197 1320 C C T P400 0. 79 n/a n/a n/a 75 7510031 1210324H1 SNP00149379 127 2908 G G A noncoding n/a n/a I n/a n/a Table 8 SEQ PID EST ID SNP ID EST CB 1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele l Allele l Allele l NO : frequency frequency frequency frequency I 75 7510031 1366605H 1 SNP00120139 121 2539 A A G H831 n/d n/d n/d n/d 75 7510031 2269735H1 SNP00120139 36 2547 A A G I834 n/d n/d n/d n/d 75 7510031 2305731H1 SNP00149379 65 2909 G G A noncoding n/a n/a n/a n/a 75 7510031 3117735H1 SNP00149379 277 2903 G G A noncoding n/a n/a n/a n/a 75 7510031 5272434H1 SNP00120139 114 2541 A A G I832 n/d n/d n/d n/d 76 7510116 138343H1 SNP00047285 160 2243 C C A noncoding n/a n/a n/a n/a l l, l 76 7510116 2512866H1 SNP00047285 49 2258 ! C C A noncoding n/a n/a n/an/a 76 7510116 2683926H1 SNP00010494 94 94 C C T T25 n/a n/a n/a n/a 76 7510116 3434203H1 SNP00040707 231 1774 A i C A V585 n/d n/a n/a n/a 76 7510116 4285145H1 SNP00010494 92 92 C C TP25 n/a n/a n/a n/a 76 7510116 4419328H1 SNP00119698 131 2391 T T C noncoding n/d 0. 91 n/d n/d | l 76 7510116 5035711H1 SNP00040707 113 1772 C C A L585 n/d n/a n/a n/a 76 7510116 5035866H1 SNP00010494 82 88 T C T H23 n/a n/a n/a n/a 76 7510116 5037336H1 SNP00122818 49 408 G G A G130 0. 75 0. 73 0. 69 0. 54 76 7510116 5518909H1 SNP00122818 90 409 A G A V130 0. 75 0. 73 0. 69 0. 54 76 7510116 7245129H1 SNP00119698 88 2392 C T C noncoding n/d 0. 91 n/d n/d 76 7510116 7245129H1 SNP00119699 234 2538 C T C noncoding n/d 0. 63 n/d n/d 77 7500548 1496262H1 SNP00059853 74 1847 C C T H553 n/d n/d n/d n/d 77 7500548 1496739H1 SNP00032140 82 2082 C C T L632 n/a n/a n/a n/a 77 7500548 1545114H1 SNP00059851 184 1201 T T C F338 n/a n/a n/a n/a ., I l l l I. 77 7500548 1547334H1 SNP00132306 135 1415 G G A G409 n/a n/a n/a n/a 77 7500548 1913208H1 SNP00059853 163 1845 C C T H553 n/d n/d n/d n/d 77 7500548 2408102H1 SNP00007079 79 2354 C C T noncoding n/a n/a n/a n/a 77 7500548 2876567H1 SNP00032140 107 2080 C C T S631 n/a n/a n/a n/a 77 7500548 3970675H1 SNP00059853 41 1844 C C T Y552 n/d n/d n/d n/d 77 7500548 4595862H1 SNP00059851 243 1196 T T C N336 n/a n/a n/a n/a 77 7500548 4641095H1 SNP00059853 163 1846 C C T P553 n/d n/d n/d n/d 77 7500548 4645354H1 SNP00032140 261 2078 C C T D630 n/a n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST CB 1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency 77 7500548 6727421H1 SNP00059851 96 1202 C T C S338 n/a n/a n/a n/a 77 7500548 6727421H1 SNP00059852 141 1247 G A G T353 n/a n/a n/a n/a 77 7500548 7067784H1 SNP00007079 33 2356 C C T noncoding n/a n/a n/a n/a 77 7500548 8134237H1 SNP00032141 263 2293 A A C Y702 0. 65 0. 61 0. 61 0. 61 77 7500548 826655H1 SNP00032139 186 920 C C T D244 n/a n/a n/a n/a 78 7504807 1328542H1 SNP00069238 157 233 C C G T59 n/a n/a n/a n/a 78 7504807 1329587H1 SNP00008179 167 689 T C T D211 n/a n/a n/a n/a 78 7504807 1329587H1 SNP00034054 48 570 A A G 1172 n/a n/a n/a n/a 78 7504807 1464665H1 SNP00008179 167 688 T C T V211 n/a n/a n/a n/a 78 7504807 1464665H1 SNP00034054 48 569 A A G A171 n/a n/a n/a n/a 78 7504807 1465174H1 SNP00069238 135 234 C C G P60 n/a n/a n/a n/a 78 7504807 1529652H1 SNP00069238 180 230 C C G P58 n/a n/a n/a n/a 78 7504807 2071910H1 SNP00008179 167 687 C C T H211 n/a n/a n/a n/a l l l l l l l l 78 7504807 2085912H1 SNP00008179 133 690 T C T S212 n/a n/a n/a n/a l l I l I I I l I 78 7504807 2089982H1 SNP00034054 109 571 A A G N172 n/a n/a n/a n/a 78 7504807 222437H1 SNP00008179 62 685 C C T P210 n/a n/a n/a n/a 78 7504807 223227H1 SNP00034054 32 564 A A G T170 n/a n/a n/a n/a , I l l l l I l, I 78 7504807 225610H1 SNP00069238 166 232 C C G T59 n/a n/a n/a n/a 78 7504807 2773610H1 SNP00034054 163 553 A A G E166 n/a n/a n/a n/a 78 7504807 3454956H1 SNP00034054 17 568 A A G D171 n/a n/a n/a n/a 78 7504807 3663204H1 SNP00034054 228 566 A A G P170 n/a n/a n/a n/a 78 7504807 3664204H1 SNP00069238 177 231 C C G P59 n/a n/a n/a n/a l l l l l l l l, I 78 7504807 3666110H1 SNP00069238 215 227 C C G S57 n/a n/a n/a n/a 78 7504807 3831244H1 SNP00069238 184 205 C C G P50 n/a n/a n/a n/a 78 7504807 3833145H1 SNP00008179 251 686 T C T L210 n/a n/a n/a n/a i l l l l l l l l 78 7504807 3833145H1 SNP00034054 132 567 A A G T171 n/a n/a n/a n/a 78 7504807 4166132H1 SNP00069238 97 229 C C G P58 n/a n/a n/a n/a 78 7504807 4170775H1 SNP00069238 185 208 C C G P51 n/a n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST Cob 1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency 78 7504807 5019439H1 SNP00034054 164 552 ! A"*'A G R166 n/a l nia | nia n/a 78 7504807 5067373H1 SNP00069238 181 218 C C G F54 n/a n/a n/a n/a 78 7504807 5067435H1 SNP00069238 24 228 C C G P58 n/a n/a n/a n/a 78 7504807 5068303H1 SNP00069238 146 224 C C G N56 n/a n/a n/a n/a 78 7504807 5071648H1 SNP00069238 101 225 C C G P57 n/a n/a n/a n/a 78 7504807 740744H1 SNP00008179 23 693 T C T L213 n/a n/a n/a n/a H 78 7504807 885417H1 SNP00008179 13 671 T C T S205 n/a n/a n/a n/a l I l l 80 7505051 3525952H1 SNP00031768 281 927 A A G Q309 0. 92 0. 99 0. 94 n/d I I I l l 80 7505051 4741811H1 SNP00031768 184 925 G A G E308 0. 92 0. 99 0. 94 n/d 80 7505051 7384390H1 SNP00031768 251 928 A A G L309 0. 92 0. 99 0. 94 n/d 83 7510086 056724H1 SNP00075048 5 1120 C C T H364 n/a n/a n/a n/a 83 7510086 056724H1 SNP00149705 114 1229 G G A A401 n/a n/a n/a n/a 83 7510086 113352H1 SNP00075047 159 1017 A A G K330 n/a n/a n/a n/a 83 7510086 1484637H1 SNP00075047 92 1041 A A G N338 n/a n/a n/a n/a l l l l l l l l l l I 83 7510086 2622574H1 SNP00040882 64 1627 C C T noncoding n/a n/a n/a n/a 83 7510086 3002056H1 SNP00075047 173 1038 A A G K337 n/a n/a n/a n/a 83 7510086 3118848H1 SNP00075047 217 1039 A A G K337 n/a n/a n/a n/a l I I I I I I I I I l 83 7510086 3535542H1 SNP00149705 10 1226 G G A E400 n/a n/a n/a n/a 83 7510086 3750957H1 SNP00040882 98 1628 C C T noncoding n/a n/a n/a n/a l l l l l I I.,. 83 7510086 4604205H1 SNP00116760 33 1985 A A C noncoding n/a n/a n/a n/a 83 7510086 4605156H1 SNP00116760 28 1980 A A C noncoding n/a n/a n/a n/a 83 7510086 4763462H1 SNP00075047 128 1040 A A G N338 n/a n/a n/a n/a 83 7510086 5667208H1 SNP00075047 168 1042 A A G K338 n/a n/a n/a n/a 83 7510086 6096113H1 SNP00040882 77 1625 C C T noncoding n/a n/a n/a n/a 83 7510086 8610155H1 SNP00149707 43 1754 T T C noncoding n/a n/a n/a n/a l l l l l l l l l l I 84 7510131 1270817H1 SNP00007805 12 2622 A A G noncoding n/a n/a n/a n/a 84 7510131 1270817H1 SNP00007806 156 2765 T T C noncoding 0. 62 n/a n/a n/a 84 7510131 1270817H1 SNP00107784 72 2682 G G A noncoding n/d n/a n/a n/a Table 8 U ct (D C, 3 ct S-'3'5g-B'B'B-Sg'B-B-5'B'B'Bg'B'5'B'B s < e nt'- <j SM cQT3M5caca'aea'a ; aT3n<Mc9can ! caT3'o''UfaSM '3 MMOOM MMMMMMMMM MMMaOMMMMMMM M) ct eecc cccccceec : ecccccceccc c cr C) C) '-. G' z _ 6 oooo ooooooooo oooooooooooo Q a O O O O M G ^ U <UH<< : UOU< : E-<< : UOU<U<<UOO<UH< : oo C'UHHO< : UOU<HOUOU<U< : <UOUHO< : UH< M - cu.-o\oOrootDooO [-. T) ooo\. <7\orroot-oo't'cocN') fQ ooo\o'n'-'oor--t--'t-o\ () oooocNS') f [-j-f) 0rt-oo-') c i-c c ö c N c} c c c ö c c c c c c c c c c _ tc c c c} c _ ! _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ d d w gaz : 3 a : N cG c'b N _ cct'c'O c cG''O cC cd'b c c5 ctt cO c eC'O'b N'l7 ctS tC cO to C) h... CD OC) Q viz . °- on bn an on on an on on on on on dn an c4 on on co on on op op on U G G G G G C G G C G G G G G G G G C G C G C C G _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ O O O O O M O O O O O O O O O N O O O O O O O O O O O O . r., U U U U N U U U U U U U U U U U U U U U U U U U U U GGCGEw"GGGGGGGGC'GCCGCCGGGGGaG O O O O O O O O O O O O O O O O O O O O O O O O O d G G G G C G C C C G C G G G G G G G C G G C C G C N _°= N C7 E- U U C7 C7 E- d E- C7 U C7 E- d F- C7 E C7 C7 E- d U U d C7 E- C7 C7 d O ~ ¢ U Ev H ¢ ¢ U V U ¢ H ¢ U V U ¢ C) ¢ ¢ U O H Ev CD ¢ U H ¢ 0 = C7 U E- E-i C7 d U C7 U d E- C7 U C7 U d U d d U C7 U E C7 d U F- d d .-, OW O D oo n oo O h n 00, Ov OW O t M oo 00 N Ov N v1 p 00 OWO ^ 00 h I_ Ov N 00 00 N V1 M h d'M Ov N i'O \O v1 ,-, n N t y0 n O N N O n O"_,- N n v1 N tw0 v0 n OW > U V N N N N N N N N N N N N N N N N N N N N N N- N W r > crz n o _ X tn O ao m mxo e t N o so o t Xo o o o m xo Cn M O M h O"y N O O h \O pp wt N V'7 00 h O M N ^'- d'D d' M d'n W D N V M V V d'O V1 M v 00 M h O O O M 00 M O h O M OO V'1 00 M \O O M 00 h O OO O M M O MMMMOOMMGOMMMMMMMMMOOOOMMOQOOOQMMMM M N t 00 h N h h o0 h N h D M h o0 h N h 't t h N h h M O O O O O O O Vl O O O O h M V O O O O O O O O v O R 8 8 8 8 õ 818 õ 8 õ 8 818 õ 8 8 8 õ 8 8 õ 8 8 õ 8 8 g 8 O O O O O O O O O O O O O O O O O O O O O O O O O O O O U7 .-r .. r.-r. . .--i.-u. ,--n.--n.--n.-r .-n .--n .-n .-- , r xxxxxxxxxxxxxxxxxxxxxxxxxxxx ""O O_ M N-i h t t h h o0 M O O N N N ^ O 00 h t U h --------- C, 4 C, 4 N N N N N cli cq m m m c m m m m cn m r. l t \0 b o \ D o o a ç > I > b t m I m r » O0 rvo 90 O O _ _ > s rn m ç xD > rx) l rx) rm O O t1 t1 1 N O1 t t \ 0 O O O _ t1 CS m m xD _ _ _ _ _-I-_ c9 cs N n I N N c9 N N I cs m n rn n n en m n n _ _ _ _ _ I _ _ _ _ I _ _ _ t _ _ _ _ _ _ _ _ _ N N N N N N N N N N M M M M M M M M M M _ _ _ _ _ _I_ _ _ _ _ _I_ _ _ _ _I_ _ _ _ _ _ _ _ _ _ _ MM_MMMMMMMMMM_MMMMMMMM_M_MMM_MMMM O O O O O O O O O O O O O O O O O O O O O O O O O O O O kn kn Ln W) tn tn tn tn tn kn Ln kn W) tn W) fT] }-\or--o\f\o\ooo\orr-r-r' ; t-tooooooooo-<-'ro t h h h h h h h h t h h t h h h h h h t h h h t h h h h --<<--rrc (< () r) <) r<'s) crff*ir) <) fr) rff<) 0'IT"t'IT'Tr It, d."t, t't"I. 7t, It It IT r"I."t't, t't t S S3S3S5oS53S33SS3S3S55S353335 o0 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 v _* z rDo oo oo rx) rvo rt I rx) oo rvo oo rvo so I oo oo oo oo r » I oo oo oo rt oo rvo oo oo rvo I rx) oo Table 8 SEQ PID EST ID SNP ID EST CB 1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP | Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency 84 7510131 3961677H1 SNP00062531 129 2522 C C T noncoding n/a n/a n/a n/a 84 7510131 4114958H1 SNP00007805 159 2566 G A G noncoding n/a n/a n/a n/a 84 7510131 4114958H1 SNP00062531 192 2533 T C T noncoding n/a n/a n/a n/a 84 7510131 4440675H1 SNP00062531 122 2587 C C T noncoding n/a n/a n/a n/a 84 7510131 4500882H1 SNP00033582 91 101 A A G noncoding n/a n/a n/a n/a 84 7510131 4600141H1 SNP00007805 13 2617 A A G noncoding n/a n/a n/a n/a l l l l l 84 7510131 4600141H1 SNP00007806 157 2761 T T C noncoding 0. 62 n/a n/a n/a 84 7510131 4600141H1 SNP00107784 73 2677 G G A noncoding n/d n/a n/a n/a 84 7510131 4797817H1 SNP00007805 100 2620 A A G noncoding n/a n/a n/a n/a 84 7510131 4797817H1 SNP00007806 244 2764 T T C noncoding 0. 62 n/a n/a n/a 84 7510131 4797817H1 SNP00107784 160 2680 G G A noncoding n/d n/a n/a n/a I l I I I,., 84 7510131 4851201H1 SNP00007805 202 2623 A A G noncoding n/a n/a n/a n/a 84 7510131 4851201H1 SNP00007806 58 2767 T T C noncoding 0. 62 n/a n/a n/a 84 7510131 4851201H1 SNP00107784 142 2683 G G A noncoding n/d n/a n/a n/a I l i I l I I I I I 84 7510131 5100026H1 SNP00007805 138 2615 A A G noncoding n/a n/a n/a n/a 84 7510131 5100026H1 SNP00062531 171 2582 C C T noncoding n/a n/a n/a n/a 84 7510131 5100026H1 SNP00107784 78 2675 G G A noncoding n/d n/a n/a n/a 84 7510131 5662941H1 SNP00057034 43 2169 C C T noncoding n/a n/a n/a n/a 84 7510131 5662941H1 SNP00108563 120 2246 A A G noncoding n/a n/a n/a n/a 84 7510131 5677175H1 SNP00033582 62 82 A A G noncoding n/a n/a n/a n/a 84 7510131 5810145H1 SNP00007806 78 2763 T T C noncoding 0. 62 n/a n/a n/a 84 7510131 6422535H1 SNP00033582 71 91 A A G noncoding n/a n/a n/a n/a 84 7510131 6610009H1 SNP00108562 115 1030 C T C R285 n/a n/a n/a n/a 84 7510131 6938337H1 SNP00007805 171 2609 A A G noncoding n/a n/a n/a n/a 84 7510131 6938337H1 SNP00007806 315 2753 T T C noncoding 0. 62 n/a n/a n/a I I l l I, I I I I I l 84 7510131 6938337H1 SNP00062531 138 2576 C C T noncoding n/a n/a n/a n/a 84 7510131 6938337H1 SNP00107784 231 2669 G G A noncoding n/d n/a n/a n/a 84 7510131 6949559H1 SNP00108562 381 1032 C T C S285 n/an/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST CB 1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele At Allele l Allele 1 Allele l NO : frequency frequency frequency frequency 84 7510131 7595362H 1 SNP00057033 356 1947 T T G L590 0. 90 n/a n/a n/a 85 7510137 103484H1 SNP00011209 247 592 C C T A180 n/d 0. 73 0. 76 0. 96 85 7510137 4008189H1 SNP00011209 38 576 C C T P175 n/d 0. 73 0. 76 0. 96 85 7510137 5900651H1 SNP00011209 7 589 C C T D179 n/d 0. 73 0. 76 0. 96 85 7510137 5941419H1 SNP00011209 83 590 C C T P180 n/d 0. 73 0. 76 0. 96 85 7510137 6871445H1 SNP00138926 358 911 A G A R287 n/a n/a n/a n/a 85 7510137 6908245J1 SNP00011209 541 586 C C T R178 n/d 0. 73 0. 76 0. 96 I l I I I I l 85 7510137 7134630H1 SNP00138924 56 233 G A G V61 n/a n/a n/a n/a l I l l I I I I 85 7510137 7134630H1 SNP00138925 170 342 A A G D97 n/a n/a n/a n/a 85 7510137 7963077H1 SNP00138926 64 912 G G A R287 n/a n/a n/a n/a 86 7510690 2325715H1 SNP00037182 16 747 C C G noncoding n/d n/a n/a n/a 86 7510690 3881478H1 SNP00037182 217 746 C C G noncoding n/d n/a n/a n/a 86 7510690 4346359H1 SNP00037182 226 745 C C G noncoding n/d n/a n/a n/a 86 7510690 4346760H1 SNP00037182 225 744 C C G noncoding n/d n/a n/a n/a l I I I I I I,.. 86 7510690 4905030H1 SNP00075581 18 681 A A G L85 0. 70 0. 86 0. 84 0. 85 86 7510690 4907258H2 SNP00037182 79 698 C C G noncoding n/d n/a n/a n/a l l l l l l l l l l l I 86 7510690 4907646H1 SNP00037182 252 737 C C G noncoding n/d n/a n/a n/a I l I I I. I l I I l l 86 7510690 5203909H1 SNP00069844 126 588 G G A M54 n/a n/a n/a n/a 86 7510690 5567236H1 SNP00069844 161 590 A G A Q55 n/a n/a n/a n/a I l I I l,. 86 7510690 5568175H1 SNP00075581 213 685 A A G T87 0. 70 0. 86 0. 84 0. 85 87 7510695 1858113H1 SNP00019645 127 1707 T T C noncoding n/a n/a n/a n/a 87 7510695 2594169H1 SNP00019645 8 1706 T T C noncoding n/a n/a n/a n/a l l l l l l l l l l 87 7510695 3617928H1 SNP00002032 7 1958 G G A noncoding n/a n/a n/a n/a 87 7510695 4289648H1 SNP00074255 229 765 A A G P200 n/a n/a n/a n/a l I I, I 87 7510695 4367125H1 SNP00002033 141 2111 G G A noncoding n/d n/a n/a n/a 87 7510695 4950546H1 SNP00069648 14 1822 A A G noncoding n/a n/a n/a n/a 87 l 7510695 5389255H1 SNP00057523 19 1576 A C A T471 n/a n/a n/a n/a I, I,, I I I., I 87 7510695 6119621H1 SNP00069648 303 1826 A A G noncodin n/a n/a nla n/a Table 8 SEQ PID EST ID SNP ID EST CB 1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency 87 7510695 6206776H1 SNP00002033 240 2113 G G A noncoding n/d n/a n/a n/a 87 7510695 6209724H1 SNP00057523 54 381 G G T E72 n/a n/a n/a n/a 88 7504781 003870H1 SNP00062789 131 1245 T C T noncoding n/a n/a n/a n/a 88 7504781 028746H1 SNP00062789 19 1263 C C T noncoding n/a n/a n/a n/a 88 7504781 065076H1 SNP00137315 12 1220 A A G noncoding n/a n/a n/a n/a 88 7504781 1267545H1 SNP00003278 127 1624 G G T noncoding n/a n/a n/a n/a 88 7504781 1326326H1 SNP00124936 202 672 A A G noncoding n/a n/a n/a n/a l l 88 7504781 1347290H1 SNP00124936 214 674 G A G noncoding n/a n/a n/a n/a l l l l 88 7504781 1352513H1 SNP00003279 64 1868 C T C noncoding 0. 94 n/a n/a n/a 88 7504781 1387266H1 SNP00003279 238 1867 T T C noncoding 0. 94 n/a n/a n/a l I I I I 88 7504781 1478579H1 SNP00003278 6 1621, G G T noncoding n/a n/a n/a n/a 88 7504781 1492340H1 SNP00116972 13 769 T T G noncoding n/d n/a n/a n/a l l l l l l 88 7504781 1494716H1 SNP00003279 41 1857 C T C noncoding 0. 94 n/a n/a n/a c 88 7504781 1543639H1 SNP00062789 146 1261 C j C T noncoding n/a n/a n/a n/a 88 7504781 1555589H1 SNP00034674 172 1246 G G T noncoding n/a n/a n/a n/a l l l I, l I. + I 88 7504781 1682540HI SNP00066786 165 841 T T G noncoding n/a n/a n/a n/a l 88 7504781 1731867H1 SNP00003276 69 650 G G A noncoding 0. 97 n/a n/a n/a 88 7504781 195486H1 SNP00124936 35 641 A A G noncoding n/a n/a n/a n/a l l l l l l l l l l l 88 7504781 2045731H1 SNP00116972 32 768 T T G noncoding n/d n/a n/a n/a l l l l l l l l l l l 88 7504781 2045731H1 SNP00124936 127 673 A A G noncoding n/a n/a n/a n/a 88 7504781 2372538H1 SNP00066786 142 836 T T G noncoding n/a n/a n/a n/a 88 7504781 2372538H1 SNP00116972 70 764 T T G noncoding n/d n/a n/a n/a l l l l l l l I, l l l 88 7504781 2451646H1 SNP00003277 66 1291 T C T noncoding n/a n/a n/a n/a 88 7504781 2451646H1 SNP00034674 20 1245 GOT noncoding n/a n/a n/a n/a I l, I 88 7504781 2451646H1 SNP00075753 213 1438 C C T noncoding n/a n/a n/a n/a 88 7504781 265090H1 SNP00066786 133 840 T T G noncoding n/a n/a n/a n/a 88 7504781 2707992H1 SNP00116972 246 765 T T G noncoding n/d n/a n/a n/a 88 7504781 2707992H1 SNP00124936 151 670 A A G noncoding n/a n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST COB 1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allege 1 2 Allele 1 Allele 1 Allele 1 Allele i NO : frequency frequency frequency frequency 88 7504781 2818159H1 SNP00066786 258 842 T T G noncoding n/a n/a nua n/a 88 7504781 2818159H1 SNP00116972 186 766 T T G noncoding n/d n/a n/a n/a 88 7504781 2818159H1 SNP00124936 92 671 A A G noncoding n/a n/a n/a n/a 88 7504781 2820979H1 SNP00075753 161 1586 G G A noncoding n/a n/a n/a n/a 88 7504781 2894406H1 SNP00003279 161 1865 T T C noncoding 0. 94 n/a n/a n/a 88 7504781 2932385H1 SNP00003275 78 218 T C T noncoding n/a n/a n/a n/a 88 7504781 2932385H1 SNP00021680 12 152 T T C noncoding n/a n/a n/a n/a 88 7504781 2957213H1 SNP00062789 104 1262 C C T noncoding n/a n/a n/a n/a 88 7504781 3001765H1 SNP00003275 151 213 C C T noncoding nua n/a n/a n/a 88 7504781 3072833H1 SNP00003278 250 1625 G G T noncoding n/a n/a n/a n/a 88 7504781 3170509H1 SNP00003277 121 1290 T C T noncoding n/a n/a n/a n/a 88 7504781 3177166H1 SNP00003278 96 1623 GOT noncoding nua n/a n/a n/a 88 7504781 3234514H1 SNP00003275 81 216 C C T noncoding n/a n/a n/a n/a 88 7504781 3234514H1 SNP00021680 15 150 T T C encoding n/a n/a n/a n/a 88 7504781 3267993H1 SNP00003275 112 215 T C T noncoding n/a n/a n/a nua 88 7504781 3267993H1 SNP00021680 46 149 T T C noncoding n/a n/a n/a n/a 88 7504781 3271976H1 SNP00003279 172 1863 C T C noncoding 0. 94 n/a n/a n/a 88 7504781 3297177H1 SNP00003279 173 1866 T T C noncoding 0. 94 n/a n/a n/a 88 7504781 3387615H1 SNP00146723 17 1235 T T C encoding n/a n/a n/a n/a 88 7504781 3389271H1 SNP00003278 71 1622 GOT noncoding n/a n/a n/a n/a 88 7504781 3425930H1 SNP00062789 131 1260 C C T noncoding n/a n/a n/a n/a 88 ! 7504781 3459650H1 SNP00003275 78 200 T C T noncoding n/a n/a n/a n/a 88 7504781 3459650H1 SNP00021680 12 134 T T C noncoding n/a n/a n/a n/a 88 7504781 3532187H1 SNP00062789 120 1255 C C T noncoding n/a n/a n/a n/a 88 7504781 3579830H1 SNP00003275 78 217 T C T noncoding n/a n/a nua n/a 88 7504781 3579830H1 SNP00021680, 12 151 T T C noncoding n/a n/a n/a n/a 88 7504781 3717630H1 SNP00003279 195 1864 T T C noncoding 0. 94 n/a n/a n/a 88 7504781 3748182H1 SNP00062789 224 1256 C C T noncoding n/a n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST CB 1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 l 2 | Allele l Allele l Allele l Allele l NO : frequency frequency frequency frequency 88 7504781 4021133H1 SNP00034674 222 1255 G G T noncoding n/a n/a n/a n/a 88 7504781 4175105H1 SNP00066786 281 838 T T G noncoding n/a n/a n/a n/a 88 7504781 4358013H1 SNP00146723 5 1236 T T C noncoding n/a n/a n/a n/a 88 7504781 4612294H1 SNP00034674 146 1244 T G T noncoding n/a n/a n/a n/a 88 7504781 4624350H1 SNP00066786 23 839 T T G noncoding n/a n/a n/a n/a 88 7504781 4932529H1 SNP00003278 170 1615 G G T noncoding n/a n/a n/a n/a 88 7504781 5221462H1 l SNP00075753 l 99 1439 C C T l noncoding n/a n/a n/a n/a I I l I 88 7504781 5261757H1 SNP00034674 195 1267 G G T noncoding n/a n/a n/a n/a 88 7504781 577002H1 SNP00066786 99 774 T T G noncoding n/a n/a n/a n/a 88 7504781 5855522H1 SNP00075753 103 1621 G G A noncoding n/a n/a n/a n/a 88 7504781 5877558H1 SNP00003276 215 628 A G A noncoding 0. 97 n/a n/a n/a l l l l l l l 88 7504781 6021943H1 SNP00124936 229 666 A A G noncoding n/a n/a n/a n/a 88 7504781 6027623H1 SNP00124936 232 669 A A G noncoding n/a n/a n/a n/a 88 7504781 632010H1 SNP00034674 109 1247 G G T noncoding n/a n/a n/a n/a l l l l l l l l 88 7504781 6447166H1 SNP00003276 502 623 A G A noncoding 0. 97 n/a n/a n/a 88 7504781 6526273H1 SNP00137315 50 1221 A A G noncoding n/a n/a n/a n/a | l l l 88 7504781 6526273H1 SNP00146723 66 1237 T T C noncoding n/a n/a n/a n/a 88 7504781 6716612H1 SNP00003278 191 1618 G G T noncoding n/a n/a n/a n/a 88 7504781 6809231J1 SNP00003278 554 1616 G G T noncoding n/a n/a n/a n/a ., I, l l l l l l I 88 7504781 6809231J1 SNP00137315 151 1213 A A G noncoding n/a n/a n/a n/a 88 7504781 6809231J1 SNP00146723 167 1229 T T C noncoding n/a n/a n/a n/a , l l l l l l l l l l 88 7504781 6906879H1 SNP00003279 135 1856 T T C noncoding 0. 94 n/a n/a n/a l l l l l l l l l l I 88 7504781 6935838H1 SNP00003276 385 649 G G A noncoding 0. 97 n/a n/a n/a 88 7504781 7621676J1 SNP00062789 350 1253 C C T noncoding n/a n/a n/a n/a 88 7504781 7661858H1 SNP00062789 56 1251 C C T noncoding n/a n/a n/a n/a 88 7504781 7661858H1 SNP00066786 477 829 T T G noncoding n/a n/a n/a n/a 88 7504781 832499H1 SNP00003279 191 1862 T T C noncoding 0. 94 n/a n/a n/a 89 7504798 1923362H1 SNP00115459 168 2318 C C A noncodin n/d n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST CB l | EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP | Allele l 2 Allele l Allele l Allele l Allele l NO : frequency frequency frequency frequency 89 7504798 6780166J 1 SNP00095379 467 608 C T C T78 n/d n/d n/a n/a 89 7504798 7352479H1 SNP00149098 259 2075 C C A noncoding n/a n/a n/a n/a 90 7504800 1923362H1 SNP00115459 168 2312 C C A noncoding n/d n/a n/a n/a 90 7504800 6780166J1 SNP00095379 467 608 C T C T78 n/d n/d n/a n/a 90 7504800 7352479H1 SNP00149098 259 2069 C C A noncoding n/a n/a n/a n/a 91 7504902 1354965H1 SNP00029525 64 1645 C C T H527 n/d n/a n/a n/a 91 7504902 1390457H1 SNP00029523 43 920 C C T R286 n/a n/a n/a n/a I I I I 91 7504902 1390457H1 SNP00076266 180 1057 C C T F331 n/a n/a n/a n/a l I l I I l. 91 7504902 1733588H1 SNP00029525 13 1644 C C T P527 n/d n/a n/a n/a 91 7504902 1751291H1 SNP00029524 167 1577 C C T H505 n/a n/a n/a n/a 91 7504902 2482791H1 SNP00120136 208 1394 T T C Y444 n/d n/d n/d n/d l l l l l l 91 7504902 2504886H1 SNP00155194 143 1382 C C A R440 n/a n/a n/a n/a 91 7504902 2745375H1 SNP00029523 211 919 C C T D285 n/a n/a n/a n/a l l l l l l l l l 91 7504902 3049959H1 SNP00076266 134 1058 l C l C l T L332 n/a n/a n/a n/a 91 7504902 3212938H1 SNP00063512 72 113 T T C L17 n/a n/a n/a n/a 91 7504902 3216326H1 SNP00063512 174 114 C T C P17 n/a n/a n/a n/a l l l l l 91 7504902 3660340H1 SNP00029523 287 918 C C T A285 n/a n/a n/a n/a 91 7504902 3879585H1 SNP00029525 57 1643 C C T H527 n/d n/a n/a n/a 91 7504902 3891059H1 SNP00155194 134 1375 C C A Y437 n/a n/a n/a n/a I. I, I 91 7504902 4580092H1 SNP00155194 83 1378 C C A Y438 n/a n/a n/a n/a l l l l l l l 91 7504902 4628714H1 SNP00120136 247 1392 T T C V443 n/d n/d n/d n/d 91 7504902 5044243H1 SNP00029523 165 921 C C T P286 n/a n/a n/a n/a 91 7504902 5117042H1 SNP00155194 204 1379 C C A P439 n/a n/a n/a n/a l l l l l l 91 7504902 5674810H1 SNP00076266 216 1056 C C T S331 n/a n/a n/a n/a l l l l l l l 91 7504902 6178745H1 SNP00029524 157 1582 C C T L506 n/a n/a n/a n/a l l I, l l l l 91 7504902 6178745H1 SNP00029525 225 1650 C C T A529 n/d n/a n/a n/a 91 7504902 6912928H1 SNP00155194 330 1368 C C A A435 n/a n/a n/a n/a 93 7510557 100616H1 SNP00147967 8 1442 T T C F437 n/a n/a n/a n/a Table 8 SEQ PID EST ID | SNP ID | EST CB 1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele l Allele 1 NO : frequency frequency frequency frequency 93 7510557 1593903Hl SNP00140768 191 2799 G G A L889 n/a n/a n/a n/a l 93 7510557 1855626H1 SNP00012552 246 2763 C C T P877 n/a n/a n/a n/a 93 7510557 2328790H1 SNP00140767 8 2563 G G A A811 n/a n/a n/a n/a 93 7510557 3213039H1 SNP00055359 98 1347 A A C G405 n/a n/a n/a n/a l l 93 7510557 4996807T9 SNP00151073 99 3542 G G A Go137 n/a n/a n/a n/a 93 7510557 5558493H1 SNP00005123 129 2797 C T C L889 0. 82 n/a n/a n/a l l l 93 7510557 609683T6 SNP00151073 130 3556 G G A E1142 n/a n/a n/a n/a 93 7510557 7403616H1 SNP00100532 68 1002 C C T F290 n/a n/a n/a n/a 95 7510264 5863227H1 SNP00064031 243 2748 C C T A896 n/d n/a n/a n/a 95 7510264 6203567H1 SNP00110990 53 82 C T C Y7 n/d n/a n/a n/a 95 7510264 6486955H1 SNP00064031 280 2755 T C T H898 n/d n/a n/a n/a 96 7506464 010477H1 SNP00001335 44 85 C C T noncoding 0. 42 n/a n/a n/a 96 7506464 139325H1 SNP00001335 61 81 C C T noncoding 0. 42 n/a n/a n/a l I l l l l l l I 96 7506464 1880129H1 SNP00115478 97 1028 l A | A G noncoding n/a n/a n/a n/a 96 7506464 1973941H1 SNP00001336 204 449 C T C R113 0. 27 0. 18 0. 29 0. 28 96 7506464 2094831H1 SNP00064445 67 132 C C T A7 n/a n/a n/a n/a 96 7506464 2642576H1 SNP00064445, 176 135 T C T L8 n/a n/a n/a n/a 96 7506464 2749201H1 SNP00001335 28 84 C C T noncoding 0. 42 n/a n/a n/a 96 7506464 3225435H1 SNP00001335 33 82 C C T noncoding 0. 42 n/a n/a n/a 96 7506464 3233976H1 SNP00001335 75 83 T C T noncoding 0. 42 n/a n/a n/a 96 7506464 3493854H1 SNP00115478 59 1027 A A G noncoding n/a n/a n/a n/a l I. I 96 7506464 3567630H1 SNP00001336 222 446 C T C H112 0. 27 0. 18 0. 29 0. 28 l l 96 7506464 366064H1 SNP00115478 154 1019 A A G noncoding n/a n/a n/a n/a 96 7506464 3796845H1 SNP00115478 87 1026 A A G noncoding n/a n/a n/a n/a 96 7506464 4055446H1 SNP00001335 54 79 T C T noncoding 0. 42 n/a n/a n/a 96 7506464 4242214H1 SNP00111981 260 331 T C T Y73 n/d n/a n/a n/a l l 96 7506464 430318H1 SNP00001335 50 60 C C T noncoding 0. 42 n/a n/a n/a 96 7506464 4436906H1 SNP00064445 117 130 C C T C6"n/a ! n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST CB 1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency 96 7506464 4583791H1 SNP00001335 24 72 C C T noncoding 0. 42 n/a n/a n/a 96 7506464 4729185H1 SNP00001335 18 75 C C T noncoding 0. 42 n/a n/a n/a 96 7506464 4853208H1 SNP00001336 107 444 T T C L111 0. 27 0. 18 0. 29 0. 28 96 7506464 570059H1 SNP00115478 167 1025 A A G noncoding n/a n/a n/a n/a 96 7506464 655344H1 SNP00001335 48 76 C C T noncoding 0. 42 n/a n/a n/a I I I 96 7506464 6967873H1 SNP00111981 223 334 T C T D74 n/d n/a n/a n/a l l I I I 96 7506464 6967873H1 SNP00111982 356 467 G A G V119 n/a n/a n/a n/a 96 7506464 796522H1 SNP00001335 52 80 C C T noncoding 0. 42 n/a n/a n/a 97 7510101 1666585H1 SNP00030118 84 133 C C T P43 n/d n/a n/a n/a 97 7510101 1831161H1 SNP00154958 169 887 T T C noncoding n/a n/a n/a n/a 97 7510101 1831161H1 SNP00154959 173 891 A A G noncoding n/a n/a n/a n/a 97 7510101 2394957H1 SNP00030118 83 132 C C T S42 n/d n/a n/a n/a 97 7510101 2446403H1 SNP00030118 66 124 C C T Q40 n/d n/a n/a n/a 97 7510101 2619334H1 SNP00154958 8 886 T T C noncoding n/a n/a n/a n/a l l l l I I I,, l l I 97 7510101 2619334H1 SNP00154959 4 890 A A G noncoding n/a n/a n/a n/a 97 7510101 3109891H1 SNP00154958 269 880 T T C noncoding n/a n/a n/a n/a 98 7510845 003028H1 SNP00009708 12 735 C C T H209 n/a n/a n/a n/a 98 7510845 1272841H1 SNP00009707 15 36 T T C noncoding n/a n/a n/a n/a 98 7510845 1308107H1 SNP00037981 23 996 C C T noncoding n/a n/a n/a n/a 98 7510845 1308107H 1 SNP00037982 45 1018 C C T noncoding n/a n/a n/a n/a l l l l l l l l l l l l l 98 7510845 1398314H1 SNP00112087 57 202 G G A E32 n/a n/a n/a n/a 98 7510845 1398452H1 SNP00125910 48 193 T T C F29 n/a n/a n/a n/a 98 7510845 1647586H1 SNP00009707 7 35 T T C noncoding n/a n/a n/a n/a 98 7510845 2690828H1 SNP00009708 128 733 C C T H209 n/a n/a n/a n/a 98 7510845 2824958H1 SNP00009707 29 33 T T C noncoding n/a n/a n/a n/a 98 7510845 2896143H1 SNP00112087 26 200 G G A C31 n/a n/a n/a n/a 98 7510845 2896143H1 SNP00125910 17 191 T T C V28 n/a n/a n/a n/a 98 7510845 3001567H1 SNP00009707 36 34 T T C noncoding n/a n/a n/an/a Table 8 SEQ PID EST ID SNP II7 EST CB 1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele | l 2 Allele l Allele l Allele 1 Allele l NO : frequency frequency frequency frequency 98 7510845 3081959H1 SNP00009707 34 31 T T C noncoding n/a n/a n/a n/a 98 7510845 3134784H1 SNP00112087 7 201 G G A S31 n/a n/a n/a n/a 98 7510845 3140509H1 SNP00009708 79 732 C C T N208 n/a n/a n/a n/a 98 7510845 3247750H1 SNP00037981 117 997 C C T noncoding n/a n/a n/a n/a 98 7510845 3247750H1 SNP00037982 139 1019 C C | C | T noncoding n/a n/a n/a n/a 98 7510845 3344415H1 SNP00125910 36 192 T T C V28 n/a n/a n/a n/a 98 7510845 3355802H1 SNP00009707 35 32, C T C noncoding n/a n/a n/a n/a 98 7510845 3491345H1 SNP00009708 115 734 C C T P209 n/a n/a n/a n/a 98 7510845 3572258H1 SNP00112087 1 190 G G A V28 n/a n/a n/a n/a 98 7510845 4057167H1 SNP00009707 20 30 C T C noncoding n/a n/a n/a n/a l l l l l l l l l I 98 7510845 4187882H1 SNP00009708 199 736 C C T Q210 n/a n/a n/a n/a 98 7510845 4400538H1 SNP00009708 173 729 C C T N207 n/a n/a n/a n/a 98 7510845 4763495H1 SNP00009707 20 29 C T C noncoding n/a n/a n/a n/a _, l l l l l l l l 98 7510845 4795438H1 SNP00037981 162 995 C C T noncoding n/a n/a n/a n/a 98 7510845 4795438H1 SNP00037982 184 1017 T C T noncoding n/a n/a n/a n/a 98 7510845 5295396H1 SNP00009707 7 15 T T C noncoding n/a n/a n/a n/a 98 7510845 6134341H1 SNP00009707 29 43 T T C noncoding n/a n/a n/a n/a I I I l I I I i, ; ; 98 7510845 6824368J1 SNP00009708 107 724 T C T F206 n/a n/a n/a n/a 99 7510846 066035H1 SNP00065053 29 607 T C T Sll n/a n/a n/a n/a 99 7510846 1225479H1 SNP00065053 62 605 C C T A10 n/a n/a n/a n/a 99 7510846 1321639H1 SNP00065053 29 557 C C T noncoding n/a n/a n/a n/a 99 7510846 149550H1 SNP00065053 31 587 C C T S4 n/a nla nla n/a , I I I I, I. I I I I 99 7510846 1544487H1 SNP00065053 56 597 C C T I7 n/a n/a n/a n/a 99 7510846 1625738H1 SNP00065053 44 606 C C T A10 n/a n/a n/a n/a 99 7510846 1896213HI SNP00065053 79 604 c c T Plo n/a n/a n/a n/a 99 7510846 2450347H1 SNP00065053 55 609 C C T Pll n/a n/a n/a n/a 99 7510846 2526109H1 SNP00065053 33 592 C C T P6 n/a n/a n/a n/a 99 7510846 2799069H1 SNP00065053 78 610'C C T R12 n/a n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST Cob 1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency 99 7510846 3029054H1 SNP00003214 36 603 | G G C S9 n/a n/a n/a n/a 99 7510846 3029054H1 SNP00146129 104 671 C C T P32 n/a n/a n/a n/a 99 7510846 3168031H1 SNP00065053 44 603 C C T S9 n/a n/a n/a n/a 99 7510846 3237714H1 SNP00065053 66 598 C C T H8 n/a n/a n/a n/a 99 7510846 3295982H1 SNP00065053 33 593 C C T A6 n/a n/a n/a n/a I I I l l I 99 7510846 3328661H1 SNP00065053 32 589 C C T P5 n/a n/a n/a n/a I l I l I I I 99 7510846 3465172H1 SNP00003214 18 607 G G C All n/a n/a n/a n/a 99 7510846 3465172H1 SNP00146129 86 675 C C T Y33 n/a n/a n/a n/a I I I I, l I I l 99 7510846 3637473H1 SNP00065053 35 599 C C T S8 n/a n/a n/a n/a 99 7510846 3783766H1 SNP00146129 54 673 C C T H33 n/a n/a n/a n/a I I I I l I,, i 99 7510846 3791924H1 SNP00065053 37 602 C C T S9 n/a n/a n/a n/a 99 7510846 3892462H1 SNP00065053 75 596 C C T T7 n/a n/a n/a n/a 99 7510846 4084828H1 SNP00146129 64 672 C C T P32 n/a n/a n/a n/a I. l l 99 7510846 4416378H1 SNP00065053 34 594 C C T A6 n/a n/a n/a n/a 99 7510846 4417557HI SNP00065053 35 595 C C T L7 n/a n/a n/a n/a l l l l l l 99 7510846 4543669H1 SNP00146129 62 674 C C T S33 n/a n/a n/a n/a 99 7510846 4791821H1 SNP00065053 78 608 C C T Pll n/a n/a n/a n/a l l l l l l l l l l l l 99 7510846 4803311H1 SNP00065053 50 600 C C T Y8 n/a n/a n/a n/a 99 7510846 6010234H1 SNP00065053 37 601 C C T P9 n/a n/a n/a n/a 99 7510846 6098355H1 SNP00065053 77 615 C C T S13 n/a n/a n/a n/a 99 7510846 6515382H1 SNP00135923 308 858 G G A K94 n/a n/a n/a n/a 99 7510846 7718126H1 SNP00021628 74 111 G G A noncoding 0. 41 0. 20 0. 15 0. 47 100 | 7510921 | 1309710H1 | SNP00038194 | 69 | 94 | C | C | T | V21 | n/a | n/a | rista I ni/a 100 7510921 1309710H1 SNP00038194 69 94 C C T V21 n/a n/a n/a n/a I I I I I I, 100 7510921 1309710H1 SNP00060750 204 229 C C A S66 n/d n/d n/d n/d 100 | 7510921 | 1328762H1 | SNP00146722 | 22 | 54 | C | C | T | S8 | n/a | n/a | n/a | n a 100 | 7510921 1 1329558H1 I SNP00021643 1 153 | 461 | G | G | C | A144 | n/d | n/a | n/a I n/a I I I I I l l I i, i i i 100 7510921 1329558H1 SNP00021643 153 461 G G C A144 n/d n/a n/a n/a 100 7510921 1330246H1 SNP00038196 155 478 C C T P149 n/d n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST CB 1 I EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency 1001 7510921 1331558HI SNPOOT27944 129 196 T T C T55 n/a n/a n/a n/a 100 7510921 1456971H1 SNP00021643 151 462 G G C G144 n/d n/a n/a n/a 100 7510921 1461406H1 SNP00038196 241 470 C c T H147 n/d n/a n/a n/a 100 7510921 1462902H1 SNP00003242 224 646 A A G noncoding n/a n/a n/a n/a 100 7510921 1465137H1 SNP00038194 126 95 c c T P22 n/a n/a n/a n/a 100 7510921 1465307H1 SNP00038196 45 475 C C T F148 n/d n/a n/a n/a 100 7510921 1465307H1 SNP00141541 95 525 C C G T165 n/a n/a n/a n/a 100 7510921 1529369H1 SNP00021643 80 458 G G C G143 n/d n/a n/a n/a 100 7510921 1529611H1 SNP00038194 15 92 C C T L21 n/a n/a n/a n/a 100 7510921 1529611H1 SNP00050871 138 215 C C T R62 n/d n/a n/a n/a 100 7510921 1529611H1 SNP00060750 150 227 C C A R66 n/d n/d n/d n/d I I I l l I I l 100 7510921 1529778H1 SNP00038194 14 91 C C T G20 n/a n/a n/a n/a 100 7510921 1529778H1 SNP00050871 137 213 C C T A61 n/d n/a n/a n/a 100 7510921 1529890H1 SNP00038196 149 474 C C T S148 n/d n/a n/a n/a 100 7510921 2074702H1 SNP00003242 176 644 A A G noncoding n/a n/a n/a n/a 100 7510921 2077654H1 SNP00146722 22 51 T C T L7 n/a n/a n/a n/a 100 7510921 2078881H1 SNP00060750 242 231 C C A A67 n/d n/d n/d n/d 100 7510921 2085547H1 SNP00038196 162 486 C C T T152 n/d n/a n/a n/a 100 7510921 2085764H1 SNP00093109 42 299 G G A D90 n/d n/d n/d n/d 100 7510921 2087860H1 SNP00038196 251 479 C C T P150 n/d n/a n/a n/a 100 7510921 2088843H1 SNP00003242 233 645 A A G noncoding n/a n/a n/a n/a 100 7510921 2090260H1 SNP00003242 186 642 A A G noncoding n/a n/a n/a n/a 100 7510921 2091459H1 SNP00146722 15 53 C C T P8 n/a n/a n/a n/a 100 7510921 222785H1 SNP00027944 85 197 T T C C56 n/a n/a n/a n/a 100 7510921 223662H1 SNP00021643 73 453 G G C R141 n/d n/a n/a n/a 100 7510921 223859H1 SNP00141541 95 527 C C G R166 n/a n/a n/a n/a 100 7510921 225363H1 SNP00038196 107 460 C C T S143 n/d n/a n/a n/a i | 4 100 7510921 225940H1 SNP00038196 104 477 C C T P149 n/d n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST CB1 l EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency 100 7510921 226539H1 SNP00027944 146 186 T T C L52 n/a n/a n/a | n/a 100 7510921 227357H1 SNP00027944 176 202 T T C F57 n/a n/a n/a n/a 100 7510921 229071H1 SNP00101233 81 427 C C T F132 n/a n/a n/a n/a 100 7510921 251916H1 SNP00050871 187 214 C C T G61 n/d n/a n/a n/a 100 7510921 252397H1 SNP00038196 158 472 C C T D147 n/d n/a n/a n/a 100 7510921 252534H1 SNP00038194 64 93 C C T A21 n/a n/a n/a n/a 100 7510921 252534H1 SNP00050871 187 216 T C T V62 n/d n/a n/a n/a 100 7510921 252534H1 SNP00060750 199 228 C C A T66 n/d n/d n/d n/d 100 7510921 255445H1 SNP00021643 111 439 G G C V136 n/d n/a n/a n/a I I I 100 7510921 255614H1 SNP00038196 52 465 T C T V145 n/d n/a n/a n/a 100 7510921 2775144H1 SNP00038194 67 89 C C T R20 n/a n/a n/a n/a l l l l l l 100 7510921 2775144H1 SNP00050871 190 212 C C T R61 n/d n/a n/a n/a 100 7510921 2775144H1 SNP00060750 202 224 C C A L65 n/d n/d n/d n/d 100 7510921 3832360H1 SNP00060750 197 226 C C A I65 n/d n/d n/d n/d 100 7510921 3832481H1 SNP00027944 169 191 C T C Q54 n/a n/a n/a n/a 100 7510921 3834414H1 SNP00146722 23 52 C C T L7 n/a n/a n/a n/a 100 | 7510921 | 3834414Hl | SNP00146722 | 23 | 52 l C | C | T | L7 | n/a | n/a | n/a | n/a 100 7510921 3868811H1 SNP00038194 62 84 C C T A18 n/a n/a n/a n/a 100 7510921 3868875H1 SNP00050871 189 210 C C T S60 n/d n/a n/a n/a 100 7510921 3868875H1 SNP00060750 201 222 C C A P64 n/d n/d n/d n/d 100 7510921 4075117H1 SNP00003242 110 641 G A G noncoding n/a n/a n/a n/a I I I I I | I 100 7510921 4167112H1 SNP00038196 238 476 C C T P149 n/d n/a n/a n/a 100 7510921 4168155H1 SNP00141541 232 526 i C C G N165 n/a n/a n/a n/a 100 7510921 4168575H1 SNP00060750 168 225 C C A T65 n/d n/d n/d n/d 100 7510921 4170784H1 SNP00021643 106 459 G G C S143 n/d n/a n/a n/a 100 7510921 4171048H1 SNP00021643 88 460 G G C R143 n/d n/a n/a n/a 100 7510921 4220303H1 SNP00093109 263 298 G G A L89 n/d n/d n/d n/d l l l l l, l l I l I I k 100 7510921 4221016H1 SNP00027944 205 193 T T C N54 n/a n/a n/a n/a 100 7510921 4222662H1 SNP00027944 190 192 T T C 154 n/a n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST CB1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency 100 7510921 4225165H1 SNP00021643 172 464 G G C D 145 n/d n/a n/a n/a 100 7510921 5018332H1 SNP00101233 86 422 C C T R131 n/a n/a n/a n/a 100 7510921 5018412H1 SNP00146722 28 55 C C T S8 n/a n/a n/a n/a 100 7510921 5068816H1 SNP00038196 231 467 C C T H146 n/d n/a n/a n/a 100 7510921 949535H1 SNP00003242 183 643 G A G noncoding n/a n/a n/a n/a l l 100 7510921 949676H1 SNP00141541 182 528 G C G G166 n/a n/a n/a n/a l l l 100 7510921 949988H1 SNP00038194 54 90 C C T A20 n/a n/a n/a n/a 101 7505097 040713H1 SNP00006712 91 1281 G G T noncoding n/a n/a n/a n/a l l l l l l l 101 7505097 040713H1 SNP00019827 57 1247 T T C noncoding n/a n/a n/a n/a l l l l l 101 7505097 045822H1 SNP00142582 76 1287 G G A noncoding n/a n/a n/a n/a 101 7505097 1314571H1 SNP00021297 236 557 A A G D165 n/a n/a n/a n/a 101 7505097 1415484H1 SNP00136197 86 558 T T G D165 n/a n/a n/a n/a | 101 7505097 1545644H1 SNP00006712 116 1278 G G T noncoding n/a n/a n/a n/a 101 7505097 1545644H1 SNP00019827 82 1244 T T C noncoding n/a n/a n/a n/a l l l l 101 7505097 1650125H1 SNP00142582 131 1286 G G A noncoding n/a n/a n/a n/a 101 7505097 1756155H1 SNP00006712 131 1282 G G T noncoding n/a n/a n/a n/a 101 7505097 1756155H1 SNP00019827 97 1248 T T C noncoding n/a n/a n/a n/a 101 7505097 2276529H1 SNP00136197 34 582 T T G T173 n/a n/a n/a n/a 101 7505097 2382357H1 SNP00019827 118 1169 T T C V369 n/a n/a n/a n/a l I S I I. l l l l I 101 7505097 2682270H1 SNP00006712 166 1279 G G T noncoding n/a n/a n/a n/a l l l l l l l l l l I 101 7505097 2682270H1 SNP00019827 132 1245 T T C noncoding n/a n/a n/a n/a 101 7505097 2695535H1 SNP00006712 119 1280 T G T noncoding n/a n/a n/a n/a 101 7505097 2695535H1 SNP00019827 85 1246 T T C noncoding n/a n/a n/a n/a 101 7505097 2818056H1 SNP00006712 147 1277 G G T noncoding n/a n/a n/a n/a 101 7505097 2818056HI SNP00019827 113 1243 T T C noncoding n/a n/a n/a n/a I. I 101 7505097 3100039H1 SNP00136197 56 556 T T G Y165 n/a n/a n/a n/a 101 7505097 3123433H1 SNP00006712 172 1301 T G T noncoding n/a n/a n/a n/a 101 7505097 3123433H1 SNP00019827 138 1267 T T C noncoding n/a n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST CB1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency 101 7505097 3205553H1 SNP00019827 85 1242 T T C noncoding n/a n/a n/a n/a 101 7505097 3416663H1 SNP00021297 145 554 A A G K164 n/a n/a n/a n/a 101 7505097 3480294H1 SNP00142582 39 1285 G G A noncoding n/a n/a n/a n/a 101 7505097 3661375H2 SNP00006712 154 1272 T G T noncoding n/a n/a n/a n/a 101 7505097 3661375H2 SNP00019827 120 1238 T T C noncoding n/a n/a n/a n/a 101 7505097 3788419H1 SNP00058706 159 308 C C T A82 n/d n/a n/a n/a I I I 101 7505097 3790902H1 SNP00021297 100 555 A A G K164 n/a n/a n/a n/a 101 7505097 3792691H1 SNP00021297 177 550 A A G S163 n/a n/a n/a n/a 101 7505097 4295906H1 SNP00006712 132 1274 G G T noncoding n/a n/a n/a n/a 101 7505097 4295906H1 SNP00019827 98 1240 T T C noncoding n/a n/a n/a n/a 101 7505097 4577730H1 SNP00136197 41 557 T T G V165 n/a n/a n/a n/a 101 7505097 4586083H1 SNP00021297 29 556 A A G N165 n/a n/a n/a n/a 101 7505097 4746366H1 SNP00058706 153 309 C C T D82 n/d n/a n/a n/a 101 7505097 4836681H1 SNP00136197 191 523 T T G Y154 n/a n/a n/a n/a __ l l l l I I. l l 101 7505097 4839793H2 SNP00006712 58 1275 T G T noncoding n/a n/a n/a n/a 101 7505097 4909788H1 SNP00058706 129 311 C C T P83 n/d n/a n/a n/a 101 7505097 5762479H1 SNP00144635 384 1163 C C T A367 n/a n/a n/a n/a l l l l l l l l l l 101 7505097 5762479H1 SNP00144636 386 1165 T T C stop368 n/a n/a n/a nla 101 7505097 5945214H1 SNP00019827 68 1241 T T C noncoding n/a n/a n/a n/a 101 7505097 6152926H1 SNP00058706 158 305 C C T S81 n/d n/a n/a n/a 101 7505097 6398725H1 SNP00006712 166 1287 G G T noncoding n/a n/a n/a n/a 101 7505097 6398725H1 SNP00019827 132 1253 T T C noncoding n/a n/a n/a n/a 101 7505097 6921045H1 SNP00136055 116 936 C T C H291 n/a n/a n/a n/a 101 7505097 6923842H1 SNP00136197 23 553 T T G stopl64 n/a n/a n/a n/a 101 7505097 8609126J1 SNP00021297 557 559 A A G N166 n/a n/a n/a n/a 102 7506527 1354965H1 SNP00029525 64 1611 C C T noncoding n/d n/a n/a n/a 102 7506527 1390457H1 SNP00029523 43 886 C C _ T noncoding n/a n/a n/a n/a 102 7506527 1390457H1 SNP00076266 180 1023 C C T noncoding n/a n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST CB 1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele l Allele 1 NO : frequency frequency frequency frequency 102 7506527 1733588H l SNP00029525 13 1610 C | C T noncoding n/d n/a n/a n/a 102 7506527 1751291H1 SNP00029524 167 1543 C C T noncoding n/a n/a n/a n/a 102 7506527 2482791H1 SNP00120136 208 1360 T T C noncoding n/d n/d n/d n/d 102 7506527 2504886H1 SNP00155194 143 1 1348 C C A noncoding n/a n/a n/a n/a 102 7506527 2745375H1 SNP00029523 211 885 C C T noncoding n/a n/a n/a n/a l I l I I 102 7506527 3049959H1 SNP00076266 134 1024 C C T noncoding n/a n/a n/a n/a I I _ I I I I, 102 7506527 3212938H1 SNP00063512 72 113 T T C L17 n/a n/a n/a n/a I I I I,. I 102 7506527 3216326H1 SNP00063512 174 114 C T C P17 n/a n/a n/a n/a 102 7506527 3660340H1 SNP00029523 287 884 C C T noncoding n/a n/a n/a n/a I I I l I I I I I 102 7506527 3879585H1 SNP00029525 57 1609 C C T noncoding n/d n/a n/a n/a 102 7506527 3891059H1 SNP00155194 134 1341 C C A noncoding n/a n/a n/a n/a 102 7506527 4580092H1 SNP00155194 83 1344 C C A noncoding n/a n/a n/a n/a 102 7506527 4596105H1 SNP00029526 181 1882 T T G noncoding n/d n/a n/a n/a 102 7506527 4598228Hl SNP00029526 178 1880 T T G noncoding n/d n/a n/a n/a 102 7506527 4628714H1 SNP00120136 247 1358 T T C noncoding n/d n/d n/d n/d 102 7506527 5044243H1 SNP00029523 165 887 C C T noncoding n/a n/a n/a n/a 102 7506527 5117042H1 SNP00155194 204 1345 C C A noncoding n/a n/a n/a n/a 102 7506527 5674810H1 SNP00076266 216 1022 C C T noncoding n/a n/a n/a n/a l l l l l l l l I,.. 102 7506527 6178745H1 SNP00029524 157 1548 C C T noncoding n/a n/a n/a n/a 102 7506527 6178745H1 SNP00029525 225 1616 C C T noncoding n/d n/a n/a n/a 102 7506527 6912928H1 SNP00155194 330 1334 C C A noncoding n/a n/a n/a n/a l l l l l l l l l I I I. 102 7506527 8085148H1 SNP00029526 355 1881 G T G noncoding n/d n/a n/a n/a 103 7504894 3559382H1 SNP00135225 169 1424 A A G noncoding n/a n/a n/a n/a 103 7504894 5767906H1 SNP00034845 85 1666 C C T noncoding n/a n/a n/a n/a 104 7510529 1462469H1 SNP00016070 230 525 G G C E158 n/a n/a n/a n/a 104 7510529 1804179T6 SNP00016070 270 524 G G C G158 n/a n/a n/a n/a 104 7510529 2354065T6 SNP00016070 287 526 G G C A159 n/a n/a n/a n/a 105 7510581 1359502F6 SNP00136617 283 458 T T C S146 n/a n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST CB 1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency 105 7510581 1538120H1 SNP00024718 40 2094 C C T noncoding n/a n/a n/a n/a 105 7510581 1903432F6 SNP00074271 279 1984 A A G noncoding n/d n/d n/d n/d 105 7510581 2302790H1 SNP00149887 43 2037 C C T noncoding n/a n/a n/a n/a 105 7510581 2602020F6 SNP00122174 258 1052 G G C R344 n/a n/a n/a n/a 105 7510581 3593071T6 SNP00024718 345 2101 C C T noncoding n/a n/a n/a n/a 105 7510581 3777007H1 SNP00123535 160 184 A A G D55 0. 99 n/d n/d n/d 105 7510581 5021254T1 SNP00024718 352 2097 C C T noncoding n/a n/a n/a n/a I I I _ I I l 105 7510581 5021254T1 SNP00074271 462 1987 A A G noncoding n/d n/d n/d n/d I l I I l l I I I I 105 7510581 7750796J1 SNP00122174 442 1029 G G C D337 n/a n/a n/a n/a 105 7510581 7754296H1 SNP00123535 79 152 G A G Q44 0. 99 n/d n/d n/d l l l l I I I I I I 106 7510582 1359502F6 SNP00136617 283 458 T T C S146 n/a n/a n/a n/a I I I I I I I I I I I 106 7510582 1538120H1 SNP00024718 40 2264 C C T S748 n/a n/a n/a n/a 106 7510582 1903432F6 SNP00074271 279 2154 A A G R712 n/d n/d n/d n/d l l l l l l l l 106 7510582 2302790H1 SNP00149887 43 2207 C C T S729 n/a n/a n/a n/a I I I I, I I I I 106 7510582 2602020F6 SNP00122174 258 1451 G G C R477 n/a n/a n/a n/a 106 7510582 3593071T6 SNP00024718 345 2271 C C T H751 n/a n/a n/a n/a 106 7510582 3777007H 1 SNP00123535 160 184 A A G D55 0. 99 n/d n/d n/d 'I i. I I I I I I I 106 7510582 5021254T1 SNP00024718 352 2267 C C T N749 n/a n/a n/a n/a 106 7510582 5021254T1 SNP00074271 462 2157 A A G N713 n/d n/d n/d n/d I l I I l l I I I l I l 106 7510582 7750796J1 SNP00122174 442 1428 G G C D470 n/a n/a n/a n/a 106 7510582 7754296H1 SNP00123535 79 152 G A G Q44 0. 99 n/d n/d n/d l I l l I I I I I I I I 107 7510583 1359502F6 SNP00136617 283 458 T T C S146 n/a n/a n/a n/a I l I I I. I I I I I I 107 7510583 1538120H1 SNP00024718 40 2108 C C T S696 n/a n/a n/a n/a 107 7510583 1903432F6 SNP00074271 279 1998 A A G R660 n/d n/d n/d n/d I l l I I I I I I I 107 7510583 2302790H1 SNP00149887 43 2051 C C T S677 n/a n/a n/a n/a I I I I l I I I I I 107 7510583 2602020F6 SNP00122174 258 1067 G G C R349 n/a n/a n/a n/a I I I I I I I l I I. 107 7510583 3593071T6 SNP00024718 345 2115 C C T H699 n/a n/a n/a n/a 107 7510583 3777007H1 SNP00123535 160 184 A A G D55 0. 99 n/d n/d n/d Table 8 SEQ PID EST ID SNP ID EST CB 1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency 107 7510583 5021254T1 SNP00024718 352 2111 C C T N697 n/a n/a n/a n/a 107 7510583 5021254T1 SNP00074271 462 2001 A A G N661 n/d n/d n/d n/d 107 7510583 7750796J1 SNP00122174 442 1044 G G C D342 n/a n/a n/a n/a 107 7510583 7754296H1 SNP00123535 79 152 G A G Q44 0. 99 n/d n/d n/d 108 7510596 015833H1 SNP00105165 59 941 T T G noncoding n/a n/a n/a n/a 108 7510596 066275H1 SNP00006891 55 158 A A C Y18 n/a n/a n/a n/a 108 7510596 1286746F6 SNP00144475 16 90 C C T noncoding n/a n/a n/a n/a 108 7510596 1286746T6 SNP00105164 38 925 T T G noncoding n/d n/a n/a n/a I I I I 108 7510596 1290717H1 SNP00128820 145 435 T T C D110 n/a n/a n/a n/a 108 7510596 1599036T6 SNP00105164 7 940 T T G noncoding n/d n/a n/a n/a I I I I I I 108 7510596 1918157H1 SNP00127597 18 371 C C A S89 n/a n/a n/a n/a I I I I I l 108 7510596 1944842T6 SNP00105164 23 924 T T G noncoding n/d n/a n/a n/a 108 7510596 2343241H1 SNP00146640 60 995 T T C noncoding n/a n/a n/a n/a l l l l I. l l l 108 7510596 2506867T6 SNP00105164 15 930 T T G noncoding n/d n/a n/a n/a l I. I I. l l l 108 7510596 4625702H1 SNP00130705 193 267 A A C P54 n/a n/a n/a n/a l l I I, l l l l l 108 7510596 4625702H1 SNP00130706 226 300 A G A K65 n/a n/a n/a n/a 108 7510596 7409528H1 SNP00105165 5 997 G T G noncoding n/a n/a n/a n/a 108'7510596 7578643H1 SNP00006891 89 159 C A C S18 n/a n/a n/a n/a 108 7510596 7578643H1 SNP00127597 302 372 C C A S89 n/a n/a n/a n/a 109 7510643 1210324H1 SNP00149379 127 2510 G G A A821 n/a n/a n/a n/a l I I. l l I I. I 109 7510643 1366605H1 SNP00120139 121 2334 A A G 1763 n/d n/d n/d n/d 109 7510643 1997988H1 SNP00116990 42 2677 C C T noncoding n/d n/d n/d n/d 110 7506671 1344679H1 SNP00102385 116 445 T T G G105 0. 91 0. 88 0. 83 0. 93 110 7506671 3282384H1 SNP00067077 60 811 G G A Q227 0. 31 0. 42 0. 26 0. 33 110 7506671 7440574H1 SNP00098625 526 610 C C A Y160 n/a n/a n/a n/a Ill 7510518 011483H1 SNP00012600 94 195 G G A L29 n/d n/a n/a n/a 111 7510518 2108708H1 SNP00099902 34 383 G G C S92 n/a n/a n/a n/a III 7510518 3475068H1 SNP00106266 145 909 T T C noncoding n/d n/d n/d n/d Table 8 SEQ PID EST ID SNP ID EST CB 1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency I 112 7510585 1510424F6 SNP00054512 204 832 G G C E256 0. 93 n/a n/a n/a 112 7510585 1647871H1 SNP00041511 50 1756 C C T N564 n/a n/a n/a n/a 113 7510590 1273118T6 SNP00003123 372 861 T T C Y262 n/a n/a n/a n/a 113 7510590 1388104T6 SNP00003123 324 860 T T C L261 n/a n/a n/a n/a 113 7510590 1683819H1 SNP00003122 149 675 C C T L200 n/a n/a n/a n/a 113 7510590 2960501H1 SNP00154401 214 253 T T C L59 n/a n/a n/a n/a 113 7510590 6082626H1 SNP00092259 243 610 C C T T178 n/a n/a n/a n/a 114 7510617 001098H1 SNP00132468 48 1702 C C A noncoding n/a n/a n/a n/a I I 114 7510617 077015H1 SNP00097054 36 1074 C C A P298 n/d n/d n/d n/d 114 7510617 100877R6 SNP00132467 60 384 A A C E68 n/a n/a n/a n/a l l l l l l 114 7510617 100877T6 SNP00132468 136 1723 C C A noncoding n/a n/a n/a n/a 114 7510617 1262714H1 SNP00013100 167 233 G G A V18 n/a n/a n/a n/a 114 7510617 1262714R1 SNP00132467 242 377 A A C 166 n/a n/a n/a n/a I, l l l l 114 7510617 1528687H1 SNP00013101 95 1362 A A G H394 n/a n/a n/a n/a 114 ! 7510617 1746217T6 SNP00132468 156 1703 C C A noncoding n/a n/a n/a n/a 114 7510617 1985367T6 SNP00013101 483 1377 G G R399 n/a n/a n/a n/a I l I I l I I I I I I 114 7510617 1985367T6 SNP00132468 145 1715 C C A noncoding n/a n/a n/a n/a 114 7510617 2207356T6 SNP00132468 156 1706 C C A noncoding n/a n/a n/a n/a 114 7510617 2635921T6 SNP00132468 179 1704 C C A noncoding n/a n/a n/a n/a I. I I I I I I I I I I 114 7510617 3907620H1 SNP00132467 135 379 A A C I66 n/a n/a n/a n/a I I l I I I l I l I I 114 7510617 3907777H1 SNP00132467 134 378 A A C N66 n/a n/a n/a n/a 114 7510617 5651920H1 SNP00013101 31 1370 GAG A397 n/a n/a n/a n/a 114 7510617 5651920H1 SNP00132468 369 1707 C C A noncoding n/a n/a n/a n/a l l l l l l l l l l l 114 7510617 7415188T1 SNP00132468 118 1705 C C A noncoding n/a n/a n/a n/a I I I I I I I I 114 7510617 7712753J2 SNP00132467 60 355 A A C R58 n/a n/a n/a n/a . l l l l l l l l l 115 7510618 001098H1 SNP00132468 48 829 C C A noncoding n/a n/a n/a n/a 115 7510618 100877R6 SNP00132467 60 384 A A C E68 n/a n/a n/a n/a 115 ! 7510618 100877T6 SNP00132468 136 850 ! C C A noncoding n/a n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST 0 CB1 T EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency 115 7510618 1262714H1 SNP00013100 167 233 G G A V18 n/a n/a n/a n/a 115 7510618 1262714R 1 SNP00132467 242 377 A A C 166 n/a n/a n/a n/a 115 7510618 1447138H1 SNP00013101 59 491 G A G A104 n/a n/a n/a n/a 115 7510618 1746217T6 SNP00132468 156 830 C C A noncoding n/a n/a n/a n/a 115 7510618 1985367T6 SNP00013101 483 504 G A G R108 n/a n/a n/a n/a 115 7510618 1985367T6 SNP00132468 145 842 C C A noncoding n/a n/a n/a n/a 115 7510618 2207356T6 SNP00132468 156 833 C C A noncoding n/a n/a n/a n/a 115 7510618 2635921T6 SNP00132468 179 831 C C A noncoding n/a n/a n/a n/a I I I I I I 115 7510618 3907620H1 SNP00132467 135 379 A A C 166 n/a n/a n/a n/a I I I I I I 115 7510618 3907777H1 SNP00132467 134 378 A A C N66 n/a n/a n/a n/a 115 7510618 5651920H1 SNP00013101 31 496 G A G G105 n/a n/a n/a n/a l l l l l 115 | 7510618 1 5651920H1 I SNP00132468 369 834 i C C A noncoding n/a n/a n/a n/a l l l l 115 7510618 7415188T1 SNP00132468 118 832 C C A noncoding n/a n/a n/a n/a 115 7510618 7712753J2 SNP00132467 60 355 A A C R58 n/a n/a n/a n/a 116 7510620 1328542H1 SNP00069238 157 233 C C G T59 n/a n/a n/a n/a 116 7510620 1329587F6 SNP00008179 168 593 T C T D179 n/a n/a n/a n/a 116 7510620 1329587F6 SNP00034054 49 474 A A G I140 n/a n/a n/a n/a l l l l l l 116 7510620 7707707H1 SNP00069238 171 234 C C G P60 n/a n/a n/a n/a 116 7510620 7709463J1 SNP00008179 301 594 C C T P180 n/a n/a n/a n/a I l l l. I l 116 7510620 7709463J1 SNP00034054 420 475 G A G S140 n/a n/a n/a n/a 117 7510628 1453355H1 SNP00016648 5 531 A A G noncoding n/a n/a n/a n/a 117 7510628 2209582H1 SNP00103712 49 156 G G A noncoding n/a n/a n/a n/a 117 7510628 7747950H1 SNP00016648 520 532 A A G noncoding n/a n/a n/a n/a 119 7506644 654991H1 SNP00141070 78 1143 C C T noncoding n/a n/a n/a n/a 120 7506692 1298969H1 SNP00123974 56 332 G G A D49 n/d n/a n/a n/a 120 7506692 1299449T6 SNP00105710 260 2076 T T G noncoding n/a n/a n/a n/a 120 7506692 1306012H1 SNP00105710 202 1989 T T G noncoding n/a n/a n/a n/a 120 7506692 1319265T6 SNP00105710 317 2018 T T G noncoding n/a n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST CB 1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency 120 7506692 1433145R1 SNP00049053 372 2029 C T C noncoding n/a n/a n/a n/a 120 7506692 1494714H1 SNP00002390 93 1688 C C G noncoding n/a n/a n/a n/a 120 7506692 1543164H1 SNP00008989 61 1385 T T C noncoding n/a n/a n/a n/a 120 7506692 1543164H1 SNP00020398 112 1436 C C T noncoding n/a n/a n/a n/a 120 7506692 157168H1 SNP00123975 89 775 G G A T196 n/a n/a n/a n/a 120 7506692 1841631H1 SNP00020399 82 2207 A A G noncoding n/a n/a n/a n/a 120 7506692 1841631H1 SNP00020400 168 2293 A A G noncoding n/a n/a n/a n/a 120 7506692 1841631H1 SNP00049054 120 2245 C C T noncoding n/a n/a n/a n/a 120 7506692 2722572T6 SNP00105710 162 2159 T T G noncoding n/a n/a n/a n/a 120 7506692 2784420T6 SNP00105710 322 1998 T T G noncoding n/a n/a n/a n/a l I I I, I 120 7506692 3731749H1 SNP00049141 141 1268 T T C noncoding n/a n/a n/a n/a 120 7506692 7391146H2 SNP00101624 138 1268 T T C noncoding 0. 80 0. 52 0. 79 n/a l. l l l l l l l 120 7506692 7602173J1 SNP00008989 305 1384 T T C noncoding n/a n/a n/a n/a 120 7506692 7602173J1 SNP00020398 254 1435 C C T noncoding n/a n/a n/a n/a 120 7506692 7635431J1 SNP00123975 57 777 G G A G197 n/a n/a n/a n/a 122 7505625 1230537H1 SNP00076050 151 3234 C C T noncoding n/a n/a n/a n/a I I I. I I I l I 122 j 7505625 1270394H1 SNPOO 139636 36 2523 T T C noncoding n/a n/a n/a n/a 122 7505625 1413847H1 SNP00150112 53 688 T T C noncoding n/a n/a n/a n/a l I I I I I I l I 122 7505625 148652H1 SNP00150112 11 685 T T C noncoding n/a n/a n/a n/a 122 7505625 151255H1 SNP00140054 157 2871 T T G noncoding n/a n/a n/a n/a 122 7505625 1713820H1 SNP00076049 139 1987 G G T noncoding n/a n/a n/a n/a l 122 7505625 1754530H1 SNP00093322 92 2116 T C T noncoding n/a n/a n/a n/a 122 7505625 1810577H1 SNP00124931 61 2169 G G A noncoding n/a n/a n/a n/a 122 7505625 1968728H1 SNP00076050 9 3230 C C T noncoding n/a n/a n/a n/a l 122 7505625 2009215H1 SNP00076050 119 3233 C C T noncoding n/a n/a n/a n/a 122 7505625 2014165H1 SNP00140054 107 2872 T T G noncoding n/a n/a n/a n/a I I I I I I I I l l I 122 7505625 2093438H1 SNP00076050 60 3231 C C T noncoding n/a n/a n/a n/a 122 7505625 2160958H1 SNP00093322 149 2115 ! C C T noncoding n/a n/a) n/a n/a Table 8 SEQ PID EST ID SNP ID EST CB1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency 122 7505625 2625225H1 SNP00093322 35 2122 C C T noncoding n/a n/a n/a n/a 122 7505625 2657876H1 SNP00076050 97 3232 C C T noncoding n/a n/a n/a n/a 122 7505625 2742636H1 SNP00076048 209 1235 T T C noncoding n/a n/a n/a n/a 122 7505625 2988637H1 SNP00076048 14 1236 T T C noncoding n/a n/a n/a n/a 122 7505625 2992978H1 SNP00139636 167 2522 T T C noncoding n/a n/a n/a n/a 122 7505625 3096407H1 SNP00076050 11 3228 C C T noncoding n/a n/a n/a n/a 122 7505625 3404560H1 SNP00093322 239 2114 C C T noncoding n/a n/a n/a n/a 122 7505625 3584294H1 SNP00140054 127 2870 T T G noncoding n/a n/a n/a n/a l I 122 7505625 3961458H2 SNP00076049 206 1984 GOT noncoding n/a n/a n/a n/a 122 7505625 4028404H1 SNP00076049 170 1986 G G T noncoding n/a n/a n/a n/a l l l l., 122 7505625 4187606H1 SNP00076050 101 3229 C C T noncoding n/a n/a n/a n/a 122 7505625 4349651H1 SNP00140054 153 2867 T T G noncoding n/a n/a n/a n/a 122 7505625 4781883H1 SNP00140054 38 2869 T T G noncoding n/a n/a n/a n/a 122 7505625 4823176H1 SNP00076049 15 1985 G G T noncoding n/a n/a n/a n/a 122 7505625 4823176H1 SNP00124931 197 2167 G G A noncoding n/a n/a n/a n/a 122 7505625 5134491H1 SNP00076048 193 1237 T T C noncoding n/a n/a n/a n/a 122 7505625 5214217H1 SNP00124931 157 2168 G G A noncoding n/a n/a n/a n/a 122 7505625 5688072H1 SNP00124931 49 2166 G G A noncoding n/a n/a n/a n/a 122 7505625 5780554H1 SNP00093322 183 2112 C C T noncoding n/a n/a n/a n/a 122 7505625 5866201H1 SNP00150112 98 687 T T C noncoding n/a n/a n/a n/a 122 7505625 6103464H1 SNP00139636 181 2518 T T C noncoding n/a n/a n/a n/a l l l l I I I I, I 122 7505625 6334533H1 SNP00065445 493 2712 A C A noncoding n/a n/a n/a n/a . I. l l I. l l l l 122 7505625 6889802H1 SNP00094010 346 690 T C T noncoding 0. 01 n/a n/a n/a 122 7505625 7683293H1 SNP00112592 157 2236 GAG noncoding n/d n/a n/a n/a 123 7506468 085600H1 SNP00036984 65 158 T T C S5 n/a n/a n/a n/a 123 7506468 1604007H1 SNP00036986 99 429 G G A noncoding n/d n/d n/d n/d l l l l l l l l l l l I 123 7506468 4421022H1 SNP00036986 117 427 G G A noncoding n/d n/d n/d n/d 123 7506468 4795865H1 SNP00036984 53 162 C T C S6 n/a n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST CB 1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency 123 j 7506468 4989134H1 SNP00036984 83'165 T T C F7 n/a n/a n/a n/a 123 7506468 4992111H1 SNP00036986 54 424 G G A noncoding n/d n/d n/d n/d 124 7510682 029560H1 SNP00059815 170 757 A A G noncoding n/a n/a n/a n/a 124 7510682 5269338H1 SNP00059815 261 759 A A G noncoding n/a n/a n/a n/a 124 7510682 7047185H1 SNP00059815 329 756 A A G noncoding n/a n/a n/a n/a 125 7505420 2995019H1 SNP00105844 18 1226 A A G noncoding n/a n/a n/a n/a _ I I I l I I 125 7505420 3807920H1 SNP00105844 69 1223 A A G noncoding n/a n/a n/a n/a I l I I l I I. 125 7505420 5820296H1 SNP00105844 122 1222 A A G noncoding n/a n/a n/a n/a 125 7505420 7400455H1 SNP00105843 262 590 T T C V175 n/a n/a n/a n/a 127 7505606 3824919H1 SNP00142793 272 1908 T T C noncoding n/a n/a n/a n/a 127 7505606 459281H1 SNP00058776 98 2358 C T C noncoding 0. 78 0. 67 0. 50 0. 78 127 7505606 7324277H1 SNP00070313 79 1047 C C A V324 n/a n/a n/a n/a l l l l l l 128 7511044 2534361H2 SNP00098144 86 5852 T T C V1757 n/d n/a n/a n/a 129 2579533 1313447H1 SNP00109175 28 2719 A A C noncoding n/a n/a n/a n/a 129 2579533 2867832H1 SNP00038182 28 2062 T T C F629 n/a n/a n/a n/a 129 2579533 3347602H1 SNP00093935 178 1175 G A G A334 n/a n/a n/a n/a l l l l l I. l 129 2579533 4847254T9 SNP00056963 100 2542 T T C noncoding n/a n/a n/a n/a l I I I I I I I I I I l 129 2579533 5439187F8 SNP00056963 155 2532 T T C noncoding n/a n/a n/a n/a 129 2579533 619113R6 SNP00038182 135 2049 C T C S625 n/a n/a n/a n/a 130 7511097 1303602H1 SNP00136613 40 229 A A G noncoding n/a n/a n/a n/a l l l l l l l l 131 7510842 1211127H1 SNP00092513 154 263 C C G P73 n/a n/a n/a n/a 131 7510842 1341718F6 SNP00092513 133 237 C C G R65 n/a n/a n/a n/a 131 7510842 2454451H1 SNP00150964 50 154 C G C P37 n/a n/a n/a n/a l l l I,. l l l 131 7510842 5670020H1 SNP00144801 5 1448 C C T noncoding n/a n/a n/a n/a 131 7510842 5787120H1 SNP00144800 122 1406 C G C noncoding n/a n/a n/a n/a 131 7510842 7417267T1 SNP00144800 175 1401 G G C noncoding n/a n/a n/a n/a l l l l l l l l l 131 7510842 7417267T1 SNP00144801 132 1443 C C _T noncoding n/a n/a n/a n/a 131 7510842 7438208H1 SNP00092513 153 261 C C G P73 n/a n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST CB1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency 131 7510842 7438654H1 SNP00092513 170 262 C C G P73 n/a n/a n/a n/a 132 7511249 066633H1 SNP00025039 122 2235 C C A noncoding n/a n/a n/a n/a | n/a 132 7511249 066633H1 SNP00099404 112 2245 T T G noncoding n/a n/a n/a n/a 132 7511249 1431646H1 SNP00004348 101 2078 C C A noncoding n/a n/a n/a n/a 132 7511249 1443929R1 SNP00004349 95 2257 C C T noncoding n/a n/a n/a n/a 132 7511249 1444381F7 SNP00069861 290 1119 T T C noncoding n/a n/a n/a n/a 132 7511249 1444381T6 SNP00004349 51 2256 C C T noncoding n/a n/a n/a n/a _ i I I 132 7511249 1444381T6 SNP00025038 317 1990 G G A noncoding n/a n/a n/a n/a 132 7511249 1695462H1 SNP00140901 20 50 A G A noncoding n/a n/a n/a n/a 132 7511249 1824233T6 SNP00004349 4 2296 T C T noncoding n/a n/a n/a n/a I I I I. I l l 132 7511249 1824233T6 SNP00025038 271 2030 G G A noncoding n/a n/a n/a n/a 132 7511249 2077282H1 SNP00025038 146 1991 A G A noncoding n/a n/a n/a n/a l l l l l 132 7511249 2640375T6 SNP00004348 188 2129 C C A noncoding n/a n/a n/a n/a 132 7511249 2640375T6 SNP00025039 31 2286 C c A noncoding n/a n/a n/a n/a 132 7511249 2640375T6 SNP00099404 21 2296 T T G noncoding n/a n/a n/a n/a 132 7511249 4052673H1 SNP00075658 158 1158 G T G noncoding n/a n/a n/a n/a 132 7511249 6464616H1 SNP00136219 254 130 A A C I21 n/a n/a n/a n/a 132 7511249 6824052J1 SNP00137963 269 155 C C T S29 n/a n/a n/a n/a 133 7511254 2530851F6 SNP00030357 103 103 G G A noncoding n/d n/a n/a n/a 133 7511254 2614485F6 SNP00151123 347 404 G G A A90 n/a n/a n/a n/a 133 7511254 2995373F6 SNP00103824 222 588 A G A E151 n/a n/a n/a n/a 133 7511254 2995373H1 SNP00103824 221 589 A G A V151 n/a n/a n/a n/a 134 7511274 100616H1 SNP00147967 8 1238 T T C F369 n/a n/a n/a n/a 134 7511274 1593903H1 SNP00140768 191 2595 G G A L821 n/a n/a n/a n/a 134 7511274 1855626H1 SNP00012552 246 2559 C C T P809 n/a n/a n/a n/a 134 7511274 2328790H1 SNP00140767 8 2359 G G A A743 n/a n/a n/a n/a l l I I I.-..,, I I I 134 7511274 3213039H1 SNP00055359 98 1143 ! A"A C G337 n/a n/a n/a n/a 134 7511274 4996807T9 SNP00151073 99 3338 G G A G 1069 n/a n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST CB1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency 134 7511274 5558493H1 SNP00005123 129 2593 C T C L82 1 0. 82 n/a n/a n/a 134 7511274 609683T6 SNP00151073 130 3352 G G A E1074 n/a n/a n/a n/a 134 7511274 7403616H1 SNP00100532 68 798 C C T F222 n/a n/a n/a n/a 135 7511303 1685649T6 SNP00036302 148 673 A A G noncoding n/a n/a n/a n/a 135 7511303 1861472T6 SNP00036302 105 714 A A G noncoding n/a n/a n/a n/a 135 7511303 1862352F6 SNP00036302 331 664 A A G noncoding n/a n/a n/a n/a l l l 135 7511303 2614846F6 SNP00008761 203 172 G G C Kll 0. 94 n/a n/a n/a 135 7511303 2614846T6 SNP00036302 141 670 A A G noncoding n/a n/a n/a n/a l l l l l l 135 7511303 2668780T6 SNP00036302 155 680 A A G noncoding n/a n/a n/a n/a 135 7511303 3497873H1 SNP00036302 244 663 A A G noncoding n/a n/a n/a n/a 135 7511303 7679882HI SNP00036302 155 659 A A G noncoding n/a n/a n/a n/a l l l l l l I I I, I 135 7511303 7679882J1 SNP00036302 249 630 A A G noncoding n/a n/a n/a n/a 135 7511303 964204T6 SNP00036302 107 727 A A G noncoding n/a n/a n/a n/a 136 7511309 1362273H1 SNP00144781 15 1650 A A C noncoding n/a n/a n/a n/a 136 7511309 1362273H1 SNP00144782 60 1695 T C T noncoding n/a n/a n/a n/a 136 7511309 2170381F6 SNP00123174 272 406 G G A G109 n/a n/a n/a n/a 136 7511309 2453737H1 SNP00144780 8 9 A A G noncoding n/a n/a n/a n/a 136 7511309 7611914J1 SNP00123174 378 391 A G A R104 n/a n/a n/a n/a 136 7511309 7638939J1 SNP00123174 366 381 G G A P100 n/a n/a n/a n/a 136 7511309 7677168H1 SNP00123174 370 407 G G A G109 n/a n/a n/a n/a I I I I. I I I I, I 136 7511309 8626384J1 SNP00144781 626 1666 A A C noncoding n/a n/a n/a rL/a 137 7511314 1348487H1 SNP00114445 182 1171 G G A R340 n/a n/a n/a n/a 137 7511314 1495867H1 SNP00044495 39 1821 T C T L557 n/a n/a n/a n/a 137 7511314 6391506H1 SNP00044495 199 1824 C C T H558 n/a n/a n/a n/a 138 7511316 002744H1 SNP00015750 181 1141 C T C noncoding n/a n/a n/a n/a l l l l l l l l l l l 138 7511316 1001477H1 SNP00113811 38 101 C T C noncoding n/a n/a n/a n/a 138 7511316 1335190H1 SNP00037569 45 88 G C G noncoding n/a n/a n/a n/a 138 7511316 1335190H1 SNP00037570 89 133 C C T noncoding n/a n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST CB 1 EST Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency 1381 7511316 1703707HI SNP00000525 149 399 c C T C66 n/a n/a n/a n/a 138 7511316 1728710H1 SNP00043742 6 256 C C T L19 n/a n/a n/a n/a 138 7511316 1821938F6 SNP00121237 116 795 C C T C198 n/a n/a n/a n/a 138 7511316 1821938F6 SNP00121238 196 875 C C T S225 n/d n/a n/a n/a 138 7511316 1821938H1 SNP00121237 117 796 C C T L199 n/a n/a n/a n/a 138 7511316 1821938H1 SNP00121238 197 876 C C T Y225 n/d n/a n/a n/a 138 7511316 1821938T6 SNP00121237 354 817 C C T R206 n/a n/a n/a n/a l l l l l 138 7511316 1821938T6 SNP00121238 275 896 C C T S232 n/d n/a n/a n/a 138 7511316 1984208R6 SNP00043742 256 257 C C T P19 n/a n/a n/a n/a I I I l I l I I 138 7511316 1984208T6 SNP00015750 24 1147 T T C noncoding n/a n/a n/a n/a 138 7511316 2354321T6 SNP00015750 51 1119 T T C noncoding n/a n/a n/a n/a 138 7511316 2356170H1 SNP00130926 3 246 A G A A15 n/a n/a n/a n/a 138 7511316 3107811H1 SNP00069722 67 318 T T C V39 n/a n/a n/a n/a 138 7511316 3402729H1 SNP00009424 220 618 G G C K139 n/a n/a n/a n/a I I I I, I I, I 138 7511316 7690092J1 SNP00138842 356 595 C C T L132 n/a n/a n/a n/a 139 7511391 1897002H2 SNP00031321 221 1424 A C A noncoding n/d n/a n/a n/a 139 7511391 1906985T6 SNP00031321 355 1425 C C A noncoding n/d n/a n/a n/a I I I I. I 140 7510144 1379965F6 SNP00114801 155 3858 A A G noncoding n/a n/a n/a n/a 140 7510144 2632730H1 SNP00146109 157 2271 A A G noncoding n/a n/a n/a n/a 140 7510144 2758103H1 SNP00019895 76 3132 T C T noncoding n/d n/d n/d n/d 140 7510144 2842560T6 SNP00114801 143 3864 A A G noncoding n/a n/a n/a n/a 140 7510144 348270T6 SNP00019895 193 3135 C C T noncoding n/d n/d n/d n/d 141 7510810 1304861H1 SNP00134028 220 2088 C C T noncoding n/a n/a n/a n/a 141 7510810 1643660T6 SNP00005543 191 1995 T T C S649 n/a n/a n/a n/a 141 7510810 1715725H1 SNP00136334 103 133 A A G H28 n/a n/a n/a n/a l l l l l l l l I I I. 141 7510810 1715725T6 SNP00136338 121 2065 C C T noncoding n/a n/a n/a a 141 7510810 1830980F6 SNP00005543 353 1989 T T C Y647 n/a n/a n/a n/a 141 7510810 1830980T6 SNP00136338'153 2035 C C T noncoding n/a n/a n/a n/a Table 8 SEQ PID EST ID SNP ID EST CB 1 EST l Allele Allele Amino Acid Caucasian African Asian Hispanic ID SNP SNP Allele 1 2 Allele 1 Allele 1 Allele 1 Allele 1 NO : frequency frequency frequency frequency t 141 7510810 2204112H1 SNP00005543 232 1988 T T C D646 n/a n/a n/a n/a 141 7510810 2243279H1 SNP00136337 17 483 T T C Y145 n/a n/a n/a n/a 141 7510810 2471394T6 SNP00005543 159 2019 T T C noncoding n/a n/a n/a n/a 141 7510810 2471410H1 SNP00136336 54 367 A A G E106 n/a n/a n/a n/a 141 7510810 2471487F6 SNP00136337 169 482 T T C F144 n/a n/a n/a n/a 141 7510810 2471487T6 SNP00005543 141 2043 T T C noncoding n/a n/a n/a n/a 141 7510810 2992338H1 SNP00136335 279 307 C C T T86 n/a n/a n/a n/a 141 7510810 6212318H1 SNP00136334 103 1285 T T C 1412 n/a n/a n/a n/a 141 7510810 6434947H1 SNP00134029 148 2124 A A C noncoding n/a n/a n/a n/a 141 7510810 7438371H1 SNP00136338 396 2034 C C T noncoding n/a n/a n/a n/a