METHODS OF DETERMINING GENOMIC HEALTH RISK

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of U.S. Provisional Application Serial No. 62/333,653, filed on May 9, 2016, and U.S. Provisional Application Serial No.62/410,783, filed on October 20, 2016, each of which is incorporated herein in its entirety.

BACKGROUND

[0002] There have been several recent large-scale efforts to gain insight into both common and rare human genetic variation. Historically, these efforts utilized two principal analytical methods to gather genetic information in large scale: high-density microarrays and whole exome sequencing. More recently, technological advances have allowed for the large-scale sequencing of the whole human genome.

[0003] Most studies have generated population-based information on human diversity using low to intermediate coverage of the genome (4x to 20x sequencing depth). The highest coverage (30x or greater) has been reported for the recent sequencing of 1,070 Japanese subjects, 129 trios from the 1000 Genome Project, and 909 Icelandic subjects. This shift in paradigm is only made stronger by the recent release of the Illumina HiseqX-Ten, which allows the sequencing of up to 160 genomes at 30x mean depth in 3-day cycles, at an average cost of $1,000 to $2,000 per genome.

[0004] These advances create new complications for the health care industry and health professionals. A whole genome sequence from an individual can possess several million nucleotide variations when compared to a reference genome. While, it is well appreciated that many different gene and nucleotide variants can have a significant impact on the risk to an individual's overall health, a significant problem arises when a health care worker is presented with a previously unannotated genetic mutation. This disclosure describes a novel method to determine the impact that any given nucleotide variation has on an individual's overall health risk.

SUMMARY

[0005] The genomic health risk metrics elaborated herein hold significant advantages for the health care industry. The likelihood that any given genomic sequence variant (GSV) will be deleterious is relatively small. Since every human genome sequenced may result in several million GSVs, the advantage of a health risk metric such as a tolerability score, an n-mer score, a context dependent tolerance score, or a protein tolerability score to clinicians is that it will allow them to focus on and prioritize deleterious mutations. Thus, the methods, systems and media of this disclosure solve significant problems that were created by virtue of advances in DNA sequencing and analysis. The methods described herein also describe a functional genomic sequencing assay that improves upon and is more efficient then previous methods such as whole-genome sequencing and exosome sequencing. The functional genomic sequencing assay described herein is allows targeted sequencing or analysis of GSV increasing the efficiency and reducing the cost of such analysis. This method is superior to other methods such as exosome sequencing in that it takes into account GSVs that occur in non-coding regions, and, thus, allows for greater sensitivity and accuracy of nucleic acid analysis.

[0006] In certain embodiments, described herein, is a method of identifying a relative genomic health risk of a genomic sequence variant in the DNA sequence of an individual, the method comprising: determining at least one genomic sequence variant in the DNA sequence of the individual; wherein the genomic sequence variant is a difference of at least one nucleotide in the individual when compared to a corresponding position in a reference genome; and comparing the at least one genomic sequence variant of the individual to a tolerability score at a

corresponding position within x nucleotides of a genetic element, wherein the tolerability score comprises a function of a nucleotide variation score and an allele proportion score, wherein the nucleotide variation score is the variance observed in a plurality of genomes at the

corresponding position, and the allele proportion score is the proportion of genomic variants that exceeds an incidence of 0.0001 in the plurality of genomes at the corresponding position. In certain embodiments, the plurality of genomes is at least 10,000 genomes. In certain

embodiments, the plurality of genomes is at least 100,000 genomes. In certain embodiments, the DNA sequence comprises at least 100,000 nucleotides. In certain embodiments, the DNA sequence comprises at least 90% of human haploid genome. In certain embodiments, at least 100 genomic sequence variants are determined in the DNA sequence of the individual. In certain embodiments, the reference genome is generated from at least 10,000 individual genomes. In certain embodiments, the reference genome is generated from at least 100,000 individual genomes. In certain embodiments, the genomic sequence variant is an insertion, a deletion, or a translocation. In certain embodiments, the genomic sequence variant is a point mutation. In certain embodiments, the nucleotide variation score is normalized. In certain embodiments, the genetic element is selected from any one or more of a gene promoter, gene enhancer, transcriptional start site, splice donor site, splice acceptor site, polyadenylation site, start codon, stop codon, exon/intron boundary, intron sequence, and an ex on sequence, TFBS, protein domain, non-coding RNA and a regulatory element. In certain embodiments, the genomic sequence variant is within 500 nucleotides of the genetic element.

[0007] In another embodiment, described herein, is a method of identifying a relative genomic health risk of a genomic sequence variant in the DNA sequence of an individual, the method comprising: determining at least one genomic sequence variant in the DNA sequence of the individual; wherein the genomic sequence variant is a difference of at least one nucleotide in the individual when compared to a corresponding position in a reference genome; and determining an ^-variant score for the at least one genomic sequence variant, wherein the ^-variant score comprises a function of a count score and an allele frequency score, wherein the count score is the ratio of the number of times any genomic sequence variant occurs in a unique sequence of n- nucleotides in length in the plurality of genomes to the number of times that the unique sequence of ^-nucleotides in length occurs in the reference genome, and the allele frequency score is the frequency of the proportion of genomic sequence variants that are fixed in the population, at an allele frequency greater than 0.0001 in the plurality of genomes. In certain embodiments, the unique sequence of ^-nucleotides in length is greater than 3 nucleotides. In certain embodiments, the unique sequence of ^-nucleotides in length is less than 100 nucleotides. In certain

embodiments, the unique sequence of ^-nucleotides in length is 7 nucleotides. In certain embodiments, the genomic sequence variant occurs in the center of the unique sequence of n- nucleotides. In certain embodiments, the plurality of genomes is at least 10,000 genomes. In certain embodiments, the plurality of genomes is at least 100,000 genomes. In certain

embodiments, the DNA sequence comprises at least 100,000 nucleotides. In certain

embodiments, the DNA sequence comprises at least 90% of human haploid genome. In certain embodiments, at least 100 genomic sequence variants are determined in the DNA sequence of the individual. In certain embodiments, the reference genome is generated from at least 10,000 individual genomes. In certain embodiments, the reference genome is generated from at least 100,000 individual genomes.

[0008] In another embodiment, described herein, is a method of identifying a relative genomic health risk of a genomic sequence variant of an individual, the method comprising: determining at least one genomic sequence variant in a DNA sequence of the individual; wherein the genomic sequence variant is a difference of at least one nucleotide in the individual when compared to a corresponding position in a reference genome; and determining if the at least one genomic sequence variant occurs within a region with a low context dependent tolerance score, wherein the context dependent tolerance score comprises a function of an observed context dependent tolerance score and an expected context dependent tolerance score, wherein the expected context dependent tolerance score is the overall probability to vary of a unique sequence of ^-nucleotides in length in a certain region of x nucleotides in length in a plurality of genomes, and the observed context dependent tolerance score is a number of genomic sequence variants in a certain region of x nucleotides in length actually observed and fixed in the plurality of genomes as a function of a length of the region. In certain embodiments, the plurality of genomes is at least 10,000 genomes. In certain embodiments, the plurality of genomes is at least 100,000 genomes. In certain embodiments, the DNA sequence comprises at least 100,000 nucleotides. In certain embodiments, the DNA sequence comprises at least 90% of human haploid genome. In certain embodiments, at least 100 genomic sequence variants are determined in the DNA sequence of the individual. In certain embodiments, the reference genome is generated from at least 10,000 individual genomes. In certain embodiments, the reference genome is generated from at least 100,000 individual genomes. In certain embodiments, the genomic sequence variant is an insertion, a deletion, or a translocation. In certain embodiments, the genomic sequence variant is a point mutation. In certain embodiments, the context dependent tolerance score comprises subtracting the expected context dependent tolerance score from the observed context dependent tolerance score.

[0009] In another embodiment, described herein, is a method of identifying a relative genomic health risk of a genomic sequence variant of an individual, the method comprising: determining at least one genomic sequence variant in a DNA sequence of the individual; wherein the genomic sequence variant is a difference of at least one nucleotide in the individual when compared to a corresponding position in a reference genome; determining if the at least one genomic sequence variant causes an amino acid variant in an expressed protein, wherein the amino acid variant is a difference of at least one amino acid when compared to a reference genome; and comparing the amino acid variant to a protein tolerability score at a corresponding position within a defined protein class, wherein the protein tolerability score comprises a diversity score, missense score, and a protein allele frequency score, wherein the diversity score is a normalized diversity metric, the missense score is the variance observed in a plurality of genomes at the corresponding position which leads to an amino acid mutation, and the protein allele frequency score is the proportion of genomic variants that leads to an amino acid variant that exceeds an incidence of 0.0001 in the plurality of genomes at the corresponding position. In certain embodiments, the plurality of genomes is at least 10,000 genomes. In certain

embodiments, the plurality of genomes is at least 100,000 genomes. In certain embodiments, the DNA sequence comprises at least 100,000 nucleotides. In certain embodiments, DNA sequence comprises at least 90% of human haploid genome. In certain embodiments, at least 100 genomic sequence variants are determined in the DNA sequence of the individual. In certain

embodiments, the reference genome is generated from at least 10,000 individual genomes. In certain embodiments, the reference genome is generated from at least 100,000 individual genomes. In certain embodiments, the genomic sequence variant is an insertion, a deletion, or a translocation. In certain embodiments, the genomic sequence variant is a point mutation. In certain embodiments, the defined protein class is selected from any one or more of a kinase, a phosphatase, a tyrosine kinase, a serine/threonine kinase, a G protein coupled receptor (GPCR), a nuclear hormone receptor, an acetylase, a chaperone, a protease, a serine protease, and a transcription factor. In certain embodiments, the diversity metric is a Shannon entropy, a Simpson diversity index, or a Wu-Kabat variability coefficient.

[0010] In another embodiment, described herein, is a non-transitory computer-readable storage media encoded with a computer program including instructions executable by a processor to create a program to identify a relative genomic health risk of a genomic sequence variant of an individual comprising: a DNA sequence for the individual; a software module to determine at least one genomic sequence variant in the DNA sequence of the individual; wherein the genomic sequence variant is a difference of at least one nucleotide in the individual when compared to a corresponding position in a reference genome; and a software module to compare the at least one genomic sequence variant of the individual to a tolerability score at a corresponding position within x-nucleotides of a genetic element, wherein the tolerability score comprises a function of a nucleotide variation score and an allele proportion score, wherein the nucleotide variation score is the variance observed in a plurality of genomes at the corresponding position, and the allele proportion score is the proportion of genomic variants that exceeds an incidence of 0.0001 in the plurality of genomes at the corresponding position. In certain embodiments, the plurality of genomes is at least 10,000 genomes. In certain embodiments, the plurality of genomes is at least 100,000 genomes. In certain embodiments, the DNA sequence comprises at least 100,000 nucleotides. In certain embodiments, the DNA sequence comprises at least 90% of human haploid genome. In certain embodiments, at least 100 genomic sequence variants are determined in the DNA sequence of the individual. In certain embodiments, the reference genome is generated from at least 10,000 individual genomes. In certain embodiments, the reference genome is generated from at least 100,000 individual genomes. In certain embodiments, the genomic sequence variant is an insertion, a deletion, or a translocation. In certain embodiments, the genomic sequence variant is a point mutation. In certain embodiments, the nucleotide variation score is normalized to the size of the genetic element. In certain embodiments, the genetic element is selected from any one or more of a gene promoter, gene enhancer, transcriptional start site, splice donor site, splice acceptor site, polyadenylation site, start codon, stop codon, exon/intron boundary, intron sequence, and an exon sequence. In certain

embodiments, the genomic sequence variant is within 50 nucleotides of the genetic element. In certain embodiments, the genomic sequence variant is within 500 nucleotides of the genetic element.

[0011] In another embodiment, described herein, is a non-transitory computer-readable storage media encoded with a computer program including instructions executable by a processor to create a program to identify a relative genomic health risk of a genomic sequence variant of an individual comprising: a DNA sequence for the individual; a software module to determine at least one genomic sequence variant in the DNA sequence of the individual; wherein the genomic sequence variant is a difference of at least one nucleotide in the individual when compared to a corresponding position in a reference genome in a unique sequence of n nucleotides in length; and a software module to determine an score for the at least one genomic sequence variant, wherein the ^-variant score is comprises a function of a count score and an allele frequency score, wherein the count score is the ratio of the number of times any genomic sequence variant occurs in a unique sequence of ^-nucleotides in length in the plurality of genomes to the number of times that the unique sequence of ^-nucleotides in length occurs in the reference genome, and the allele frequency score is the frequency of the proportion of genomic sequence variants that are fixed in the population, at an allele frequency greater than 0.0001 in the plurality of genomes. In certain embodiments, the unique sequence of n- nucleotides in length is greater than 4 nucleotides. In certain embodiments, the unique sequence of ^-nucleotides in length is less than 100 nucleotides. In certain embodiments, the unique sequence of ^-nucleotides in length is 7 nucleotides. In certain embodiments, the genomic sequence variant occurs in the center of the unique sequence of ^-nucleotides. In certain embodiments, the plurality of genomes is at least 10,000 genomes. In certain embodiments, the plurality of genomes is at least 100,000 genomes. In certain embodiments, the DNA sequence comprises at least 100,000 nucleotides. In certain embodiments, the DNA sequence comprises at least 90% of human haploid genome. In certain embodiments, at least 100 genomic sequence variants are determined in the DNA sequence of the individual. In certain embodiments, the reference genome is generated from at least 10,000 individual genomes. In certain embodiments, the reference genome is generated from at least 100,000 individual genomes.

[0012] In another embodiment, described herein, is a non-transitory computer-readable storage media encoded with a computer program including instructions executable by a processor to create a program to identify a relative genomic health risk of a genomic sequence variant of an individual comprising: a DNA sequence for the individual; a software module to determine at least one genomic sequence variant in a DNA sequence of the individual; wherein the genomic sequence variant is a difference of at least one nucleotide in the individual when compared to a corresponding position in a reference genome; and a software module to determine if the at least one genomic sequence variant occurs within a region with a low context dependent tolerance score, wherein the context dependent tolerance score comprises a function of an observed context dependent tolerance score and an expected context dependent tolerance score, wherein the expected context dependent tolerance score is the overall probability to vary of a unique sequence of ^-nucleotides in length in a certain region of x nucleotides in length actually observed and fixed in a plurality of genomes, and the observed context dependent tolerance score is a number of genomic sequence variants in a certain region of x nucleotides in length actually observed in the plurality of genomes. In certain embodiments, the plurality of genomes is at least 10,000 genomes. In certain embodiments, the plurality of genomes is at least 100,000 genomes. In certain embodiments, the DNA sequence comprises at least 100,000 nucleotides. In certain embodiments, the DNA sequence comprises at least 90% of human haploid genome. In certain embodiments, at least 100 genomic sequence variants are determined in the DNA sequence of the individual. In certain embodiments, the reference genome is generated from at least 10,000 individual genomes. In certain embodiments, the reference genome is generated from at least 100,000 individual genomes. In certain embodiments, the genomic sequence variant is an insertion, a deletion, or a translocation. In certain embodiments, the genomic sequence variant is a point mutation. In certain embodiments, the context dependent tolerance score comprises subtracting the expected context dependent tolerance score from the observed context dependent tolerance score.

[0013] In another embodiment, described herein, is a non-transitory computer-readable storage media encoded with a computer program including instructions executable by a processor to create a program to identify a relative genomic health risk of a genomic sequence variant of an individual comprising: a DNA sequence for the individual; a software module to determine at least one genomic sequence variant in a DNA sequence of the individual; wherein the genomic sequence variant is a difference of at least one nucleotide in the individual when compared to a corresponding position in a reference genome; a software module to determine if the at least one genomic sequence variant causes an amino acid variant in an expressed protein, wherein the amino acid variant is a difference of at least one amino acid when compared to a reference genome; and a software module to compare the amino acid variant to a protein tolerability score at a corresponding position within a defined protein class, wherein the protein tolerability score comprises a diversity score, missense score, and a protein allele frequency score, wherein the diversity score is a normalized diversity metric, the missense score is the variance observed in a plurality of genomes at the corresponding position which leads to an amino acid mutation, and the protein allele frequency score is the proportion of genomic variants that leads to an amino acid variant that exceeds an incidence of 0.0001 in the plurality of genomes at the corresponding position. In certain embodiments, the plurality of genomes is at least 10,000 genomes. In certain embodiments, the plurality of genomes is at least 100,000 genomes. In certain embodiments, the DNA sequence comprises at least 100,000 nucleotides. In certain embodiments, the DNA sequence comprises at least 90% of human haploid genome. In certain embodiments, at least 100 genomic sequence variants are determined in the DNA sequence of the individual. In certain embodiments, the reference genome is generated from at least 10,000 individual genomes. In certain embodiments, the reference genome is generated from at least 100,000 individual genomes. In certain embodiments, the genomic sequence variant is an insertion, a deletion, or a translocation. In certain embodiments, the genomic sequence variant is a point mutation. In certain embodiments, defined protein class is selected from any one or more of a kinase, a phosphatase, a tyrosine kinase, a serine/threonine kinase, a G protein coupled receptor (GPCR), a nuclear hormone receptor, an acetylase, a chaperone, a protease, a serine protease, and a transcription factor. In certain embodiments, the diversity metric is a Shannon entropy, a Simpson diversity index, or a Wu-Kabat variability coefficient. In another embodiment, described herein, is a method of creating a genomic health risk database comprising: populating a database with a tolerability score value for each of a plurality of positions in a genome;

wherein the tolerability score is determined for each of the plurality of positions in the genome within x nucleotides of a genetic element, wherein the tolerability score comprises a function of a nucleotide variation score and an allele proportion score; wherein the nucleotide variation score is the nucleotide variance observed in a plurality of genomes at each of the plurality of positions in the genome, and the allele proportion score is the proportion of genomic variants that exceed an incidence of 0.0001 in the plurality of genomes at each of the plurality of positions in the genome. In certain embodiments, the plurality of genomes is at least 10,000 genomes. In certain embodiments, the plurality of genomes is at least 100,000 genomes. In certain embodiments, the nucleotide variance is an insertion, a deletion, or a translocation. In certain embodiments, the nucleotide variance is a point mutation. In certain embodiments, the nucleotide variation score is normalized to the size of the genetic element. In certain

embodiments, the plurality of positions is greater than 1,000. In certain embodiments, the genetic element is selected from any one or more of a gene promoter, gene enhancer, transcriptional start site, splice donor site, splice acceptor site, polyadenylation site, start codon, stop codon, exon/intron boundary, intron sequence, and an exon sequence. In certain

embodiments, the tolerability score is determined for each of a plurality of positions in the genome within 500 nucleotides of the genetic element.

[0014] In another embodiment, described herein, is a method of creating a genomic health risk database comprising: populating a database with an score value for each of a plurality of positions in a genome; wherein the score is determined for each of the plurality of positions in the genome, wherein the ^-variant score comprises a function of a count score and an allele frequency score; wherein the count score is the ratio of the number of times any genomic sequence variant occurs in a unique sequence of ^-nucleotides in length in the plurality of genomes compared to a reference genome to the number of times that the unique sequence of ^-nucleotides in length occurs in the reference genome, and the allele frequency score is the frequency of the proportion of genomic sequence variants that are fixed in the population, in the plurality of genomes for each of the plurality of positions in the genome. In certain embodiments, the unique sequence of ^-nucleotides in length is greater than 4 nucleotides. In certain

embodiments, the unique sequence of ^-nucleotides in length is less than 100 nucleotides. In certain embodiments, the unique sequence of ^-nucleotides in length is 7 nucleotides. In certain embodiments, the genomic sequence variant occurs in the center of the unique sequence of n- nucleotides. In certain embodiments, the plurality of genomes is at least 10,000 genomes. In certain embodiments, the plurality of genomes is at least 100,000 genomes.

[0015] A method of creating a genomic health risk database comprising: populating a database with a context dependent tolerance score for each of a plurality of regions in a genome; wherein the context dependent tolerance score comprises a function of an observed context dependent tolerance score and an expected context dependent tolerance score; wherein the expected context dependent tolerance score is the overall probability to vary of a unique sequence of n- nucleotides in length in a certain region of x nucleotides in length actually observed and fixed in a plurality of genomes, and the observed context dependent tolerance score is a number of genomic sequence variants in a certain region of x nucleotides in length actually observed in the plurality of genomes. In certain embodiments, the plurality of genomes is at least 10,000 genomes. In certain embodiments, the plurality of genomes is at least 100,000 genomes. In certain embodiments, the genomic sequence variant is an insertion, a deletion, or a translocation. In certain embodiments, the genomic sequence variant is a point mutation. In certain

embodiments, the context dependent tolerance score comprises subtracting the expected context dependent tolerance score from the observed context dependent tolerance score.

[0016] In another embodiment, described herein, is a method of creating a genomic health risk database comprising: populating a database with a protein tolerability score value for each of a plurality of positions in a genome; wherein the protein tolerability score is determined for each of the plurality of positions in the genome, wherein the protein tolerability score comprises a function of a diversity score, missense score, and a protein allele frequency score; wherein the diversity score is a normalized diversity metric, the missense score is the variance observed in a plurality of genomes at each of the plurality of positions in the genome which leads to an amino acid variant, and the protein allele frequency score is the proportion of genomic variants that leads to an amino acid variant at each of the plurality of positions in the genome. In certain embodiments, the plurality of genomes is at least 10,000 genomes. In certain embodiments, the plurality of genomes is at least 100,000 genomes. In certain embodiments, the is an insertion, a deletion, or a translocation. In certain embodiments, the genomic sequence variant is a point mutation. In certain embodiments, the defined protein class is selected from any one or more of a kinase, a phosphatase, a tyrosine kinase, a serine/threonine kinase, a G protein coupled receptor (GPCR), a nuclear hormone receptor, an acetylase, a chaperone, a protease, a serine protease, and a transcription factor. In certain embodiments, the diversity metric is a Shannon entropy, a Simpson diversity index, or a Wu-Kabat variability coefficient.

[0017] In another embodiment, described herein, is a genomic assay comprising a plurality of polynucleotides bound to a substrate, wherein each of the plurality of polynucleotides possess a sequence corresponding to a genomic locus, wherein a sequence corresponding to the genomic locus possesses a tolerability score below 0.1, wherein the tolerability score comprises a function of a nucleotide variation score and an allele proportion score, wherein the nucleotide variation score is the variance observed in a plurality of genomes at the corresponding position, and the allele proportion score is the proportion of genomic variants that exceeds an incidence of 0.0001 in the plurality of genomes at the corresponding position. In certain embodiments, the plurality of genomes is at least 10,000 genomes. In certain embodiments, the plurality of polynucleotides is at least 1,000 polynucleotides. In certain embodiments, the plurality of polynucleotides is at least 10,000 polynucleotides. In certain embodiments, the plurality of polynucleotides comprises at least 4,000 distinct nucleotide sequences. In certain embodiments, the plurality of polynucleotides comprises at least 4,000 distinct nucleotide sequences. In certain embodiments, the plurality of polynucleotides comprises at least 8,000 distinct nucleotide sequences. In certain embodiments, the plurality of polynucleotides are covalently bound to the substrate. In certain embodiments, the plurality of polynucleotides are covalently bound to the substrate at their 5 prime ends. In certain embodiments, the plurality of polynucleotides are covalently bound to the substrate at their 3 prime ends. In certain embodiments, the plurality of polynucleotides further comprises a fluorescent molecule. In certain embodiments, the plurality of polynucleotides further comprises a fluorescent dye. In certain embodiments, the substrate comprises glass. In certain embodiments, the substrate comprises silicon.

[0018] In another embodiment, described herein, is a genomic assay comprising a plurality of polynucleotides bound to a substrate, wherein each of the plurality of polynucleotides possess a sequence corresponding to a genomic locus, wherein a sequence corresponding to the genomic locus possesses an score below 0.05 wherein the score comprises a function of a count score and an allele frequency score, wherein the count score is the ratio of the number of times any genomic sequence variant occurs in a unique sequence of ^-nucleotides in length in the plurality of genomes to the number of times that the unique sequence of ^-nucleotides in length occurs in the reference genome, and the allele frequency score is the frequency of the proportion of genomic sequence variants that are fixed in the population, at an allele frequency greater than 0.0001, in the plurality of genomes. In certain embodiments, the plurality of genomes is at least 10,000 genomes. In certain embodiments, the plurality of polynucleotides is at least 1,000 polynucleotides. In certain embodiments, the plurality of polynucleotides is at least 10,000 polynucleotides. In certain embodiments, the plurality of polynucleotides comprise at least 4,000 distinct nucleotide sequences. In certain embodiments, the plurality of

polynucleotides comprise at least 4,000 distinct nucleotide sequences. In certain embodiments, the plurality of polynucleotides comprise at least 8,000 distinct nucleotide sequences. In certain embodiments, the plurality of polynucleotides are covalently bound to the substrate. In certain embodiments, the plurality of polynucleotides are covalently bound to the substrate at their 5 prime ends. In certain embodiments, the plurality of polynucleotides are covalently bound to the substrate at their 3 prime ends. In certain embodiments, the plurality of polynucleotides further comprise a fluorescent molecule. In certain embodiments, the plurality of polynucleotides further comprise a fluorescent dye. In certain embodiments, the substrate comprises glass. In certain embodiments, the substrate comprises silicon.

[0019] In another embodiment, described herein, is a genomic assay comprising a plurality of polynucleotides bound to a substrate, wherein each of the plurality of polynucleotides possess a sequence corresponding to a genomic locus, wherein a sequence corresponding to the genomic locus possesses a low context dependent tolerance score, wherein the context dependent tolerance score comprises a function of an observed context dependent tolerance score and an expected context dependent tolerance score, wherein the expected context dependent tolerance score is the overall probability to vary of a unique sequence of ^-nucleotides in length in a certain region of x nucleotides in length actually observed and fixed in a plurality of genomes, and the observed context dependent tolerance score is a number of genomic sequence variants in a certain region of x nucleotides in length actually observed in the plurality of genomes. In certain embodiments, the context dependent tolerance score comprises subtracting the expected context dependent tolerance score from the observed context dependent tolerance score. In certain embodiments, the plurality of genomes is at least 10,000 genomes. In certain

embodiments, plurality of polynucleotides is at least 1,000 polynucleotides. In certain

embodiments, plurality of polynucleotides is at least 10,000 polynucleotides. In certain embodiments, the plurality of polynucleotides comprise at least 4,000 distinct nucleotide sequences. In certain embodiments, the plurality of polynucleotides comprise at least 4,000 distinct nucleotide sequences. In certain embodiments, the plurality of polynucleotides comprise at least 8,000 distinct nucleotide sequences. In certain embodiments, the plurality of

polynucleotides are covalently bound to the substrate. In certain embodiments, the plurality of polynucleotides are covalently bound to the substrate at their 5 prime ends. In certain

embodiments, the plurality of polynucleotides are covalently bound to the substrate at their 3 prime ends. In certain embodiments, the plurality of polynucleotides further comprise a fluorescent molecule. In certain embodiments, the plurality of polynucleotides further comprise a fluorescent dye. In certain embodiments, the substrate comprises glass. In certain embodiments, the substrate comprises silicon.

[0020] Any of the methods of this disclosure can be used to determine a section of the genome for targeted sequencing, resequencing, or S P analysis.

[0021] In another embodiment, described herein, is a functional genomic assay comprising: identifying a presence of at least one genomic sequence variant in the nucleic acid sequence of an individual; determining if the at least one genomic sequence variant occurs in a highly conserved genomic region; the highly conserved genomic region having an observed context dependent tolerance score greater than an expected context dependent tolerance score, wherein the expected context dependent tolerance score is the probability to vary of a unique nucleic acid sequence of ^-nucleotides in length in a certain region of x nucleotides in length in a plurality of genomes, and the observed context dependent tolerance score is a number of genomic sequence variants in the certain region of x nucleotides in length actually observed in the plurality of genomes. In certain embodiments, the nucleic acid sequence comprises a DNA sequence. In certain embodiments, the DNA sequence comprises a nuclear DNA sequence. In certain embodiments, the plurality of genomes is at least 10,000 genomes. In certain embodiments, the nucleic acid sequence comprises at least 100,000 nucleotides. In certain embodiments, the functional genomic assay comprises identifying the presence of at least 10 genomic sequence variants. In certain embodiments, the at least one genomic sequence variant comprises at least one of an insertion, a deletion, and a translocation. In certain embodiments, the at least one genomic sequence variant comprises a single nucleotide polymorphism. In certain embodiments, n equals 7. In certain embodiments, x is between 400 and 600. In certain embodiments, the functional genomic assay comprises determining if the at least one genomic sequence variant is in a non-coding genomic region that is highly conserved. In certain embodiments, the at least one genomic sequence variant is in a non-coding highly conserved genomic region within 1,000 base pairs of a known disease-associated gene. In certain embodiments, the highly conserved genomic region is a genomic region corresponding to a most conserved 1 ^st percentile of all genomic regions. In certain embodiments, the observed context dependent tolerance score is at least 10% greater than an expected context dependent tolerance score. In certain embodiments, at least one of the at least one genomic sequence variant in a non-coding genomic region that is highly conserved is selected from the list consisting of rs587780751, rs745366624, rs777251123, rs778796405, rs774531501, rs587776927, rs768823171, rs749303140, rs376829288,

rs750530042, rs587776558, rs372686280, rsl 11812550, rsl43144732, rsl93922699,

rs750180293, rs398122808, rs757171524, rs773306994, rs773306994, rs372418954,

rs762425885, rs397516031, rs397516022, rs730880592, rs730880592, rs397516020,

rs397516020, rs373746463, rs373746463, rs373746463, rs387906397, rs387906397,

rs587782958, rs730880718, rs730880667, rsl 13358486, rsl 11683277, rsl 12917345,

rs730880691, rs397515916, rs730880690, rsl l l437311, rs397515903, rs727503201,

rsl 12999777, rs397515897, rs727503204, rs397515893, rs397515891, rs587776699,

rs587776700, rs376395543, rs748486465, rsl49712664, rsl99683937, rsl44637717,

rs587776644, rs730880296, rs397515322, rs558721552, rs531105836, rs587777262,

rs267607302, rs387907354, rs398123750, rs727503988, rs587783714, rsl48622862,

rs763991428, rs761780097, rs770204470, rs387906521, rs387906520, rs79367981,

rs749160734, rs587776708, rs587776708, rs34086577, rsl99959804, rs587777290,

rs386834170, rs386834169, rsl44077391, rs386834164, rs386834166, rs770093080,

rs587777374, rs45517105, rs45517105, rs45488500, rs45517289, rs45517289, rsl37854118, rs45517358, rsl89077405, rs515726118, rs386833742, rs386833739, rs755127868,

rs200655247, rs376023420, rs747351687, rsl 13690956, rs376281637, rs765390290,

rs773401248, rs61750189, rs530975087, rs201978571, rs267604791, rs80358116, rs80358116, rs273899695, rs8035801 1, rs80358011, rs80358051, rs730880267, rs63751296, rs63750707, rs776442328, rs776820510, rs72653165, rs72667012, rs72667008, rs527398797, rs587780009, rs587776658, rs587782018, rs745620135, rs372651309, rs556992558, rsl37853932,

rs200253809, rs386833901, rs770882876, rs750550558, rs397507554, rs730880306,

rs201613240, rsl47952488, rs770241629, rs373494631, rs397517741, rs386833856, rs559854357, rs371496308, rs539645405, rsl87510057, rs41298629, rs536892777, rs747330606, rs748559929, rs770277446, rs201685922, rs767245071, rs730882032,

rs587776525, rs398123358, rs72659359, rsl37853943, rs267607709, rs267607710,

rs766168993, rs775288140, rs780041521, rsl45564018, rs775456047, rs587776879,

rs540289812, rs745832717, rs745915863, rs386833418, rsl99422309, rs431905514,

rs587784059, rs748086984, rs386833492, rsl99988476, rs281865166, rs587776515,

rs397518439, rsl93922258, rsl42637046, rs73717525, rsl45483167, rs587777285,

rs747737281, rsl83894680, rsl 16735828, rs574673404, rs386833563, rs768154316,

rsl 11033661, rs755363896, rs368953604, rsl80177319, rsl48049120, rsl50676454,

rs372655486, rs373842615, rs763389916, rsl l8203419, rs515726232, rs312262809,

rs312262804, rs281865349, rs281865338, rs281865337, rs281865334, rs281865336,

rs281865336, rs62638626, rs62638627, rs587784423, rsl 13951193, rs281874765, rsl04886349, rs398123247, rs74315277, rs200346587, rs398122908, rs727503036, rs397515747, and rs587776734. In certain embodiments, at least one of the at least one genomic sequence variant in a non-coding region that is highly conserved is selected from the list consisting of

rs778796405, rs8177982, rs376829288, rs4253196, rs750180293, rs757171524, rs727503201, rs397515893, rs587776699, rs397516083, rs201078659, rs750425291, rs558721552,

rs531105836, rs200782636, rs752197734, rs3093266, rs34086577, rsl99959804, rsl44077391, rs386834164, rs386834166, rsl89077405, rs746701685, rs386833721, rs376023420,

rs761146008, rs765390290, rs72648337, rs527398797, rs367567416; rs372651309,

rs200253809, rsl93922837, rs761737358, rsl 13994173, rs559854357, rsl 11951711,

rs371496308, rs368123079, rsl 18192239, rs41298629, and rs536892777. In certain

embodiments, the functional genomic assay is for use in determining a likelihood of the individual being diagnosed with a cancer. In certain embodiments, the functional genomic assay is for use in prognosing a cancer of the individual.

[0022] In another embodiment, described herein, is a computer-implemented system comprising: a computer comprising: at least one processor, a memory, an operating system configured to perform executable instructions, and a computer program including instructions executable by the at least one processor to create a functional genomic assay application, the functional genomic assay application configured to perform the following: receiving a nucleic acid sequence of an individual; identifying a presence of at least one genomic sequence variant in the nucleic acid sequence of the individual; and determining if the at least one genomic sequence variant occurs in a highly conserved genomic region, the highly conserved genomic region having an observed context dependent tolerance score greater than an expected context dependent tolerance score, wherein the expected context dependent tolerance score is the probability to vary of a unique nucleic acid sequence of n-nucleotides in length in a certain region of x nucleotides in length in a plurality of genomes, and the observed context dependent tolerance score is a number of genomic sequence variants in the certain region of x nucleotides in length actually observed in the plurality of genomes. The nucleic acid sequence may comprise a DNA sequence and in some cases, the DNA sequence comprises a nuclear DNA sequence. In some cases, the plurality of genomes is at least 10,000 genomes. In some cases, the nucleic acid sequence comprises at least 100,000 nucleotides. The functional genomic assay may comprise identifying the presence of at least 10 genomic sequence variants. In some cases, the at least one genomic sequence variant comprises at least one of an insertion, a deletion, and a translocation. In some cases, the at least one genomic sequence variant comprises a single nucleotide polymorphism. In particular embodiments of the functional genomic assay n equals 7. In some embodiments of the functional genomic assay x is between 400 and 600. The functional genomic assay may comprise determining if the at least one genomic sequence variant is in a non-coding highly conserved genomic region. In some cases, the at least one genomic sequence variant is in a non-coding highly conserved genomic region within 2 megabases of a known disease-associated gene. In some cases, the highly conserved genomic region is a genomic region corresponding to a most conserved 1st percentile of all genomic regions. In some cases, the observed context dependent tolerance score is at least 10% greater than an expected context dependent tolerance score. In various cases, at least one of the at least one genomic sequence variant in a non-coding genomic region that is highly conserved is selected from the list consisting of rs587780751, rs745366624, rs777251123, rs778796405, rs774531501, rs587776927, rs768823171, rs749303140, rs376829288, rs750530042, rs587776558, rs372686280, rsl 11812550, rsl43144732, rsl93922699, rs750180293, rs398122808, rs757171524, rs773306994, rs773306994, rs372418954, rs762425885, rs397516031, rs397516022, rs730880592, rs730880592, rs397516020, rs397516020, rs373746463, rs373746463, rs373746463, rs387906397, rs387906397, rs587782958, rs730880718, rs730880667, rsl 13358486, rsl 11683277, rsl 12917345, rs730880691, rs397515916, rs730880690, rsl 11437311, rs397515903, rs727503201, rsl 12999777, rs397515897, rs727503204, rs397515893, rs397515891, rs587776699, rs587776700, rs376395543, rs748486465, rsl49712664, rsl99683937, rsl44637717, rs587776644, rs730880296, rs397515322, rs558721552, rs531105836, rs587777262, rs267607302, rs387907354, rs398123750, rs727503988, rs587783714, rsl48622862, rs763991428, rs761780097, rs770204470, rs387906521, rs387906520, rs79367981, rs749160734, rs587776708, rs587776708, rs34086577, rsl99959804, rs587777290, rs386834170, rs386834169, rsl44077391, rs386834164, rs386834166, rs770093080, rs587777374, rs45517105, rs45517105, rs45488500, rs45517289, rs45517289, rsl37854118, rs45517358, rsl89077405, rs515726118, rs386833742, rs386833739, rs755127868, rs200655247, rs376023420, rs747351687, rsl 13690956, rs376281637, rs765390290, rs773401248, rs61750189, rs530975087,

rs201978571, rs267604791, rs80358116, rs80358116, rs273899695, rs80358011, rs80358011, rs80358051, rs730880267, rs63751296, rs63750707, rs776442328, rs776820510, rs72653165, rs72667012, rs72667008, rs527398797, rs587780009, rs587776658, rs587782018, rs745620135, rs372651309, rs556992558, rsl37853932, rs200253809, rs386833901, rs770882876, rs750550558, rs397507554, rs730880306, rs201613240, rsl47952488, rs770241629, rs373494631, rs397517741, rs386833856, rs559854357, rs371496308, rs539645405, rsl87510057, rs41298629, rs536892777, rs747330606, rs748559929, rs770277446,

rs201685922, rs767245071, rs730882032, rs587776525, rs398123358, rs72659359,

rsl37853943, rs267607709, rs267607710, rs766168993, rs775288140, rs780041521, rsl45564018, rs775456047, rs587776879, rs540289812, rs745832717, rs745915863, rs386833418, rsl99422309, rs431905514, rs587784059, rs748086984, rs386833492, rsl99988476, rs281865166, rs587776515, rs397518439, rsl93922258, rsl42637046, rs73717525, rsl45483167, rs587777285, rs747737281, rsl83894680, rsl 16735828,

rs574673404, rs386833563, rs768154316, rsl 11033661, rs755363896, rs368953604, rsl80177319, rsl48049120, rsl50676454, rs372655486, rs373842615, rs763389916, rsl l8203419, rs515726232, rs312262809, rs312262804, rs281865349, rs281865338, rs281865337, rs281865334, rs281865336, rs281865336, rs62638626, rs62638627, rs587784423, rsl l3951193, rs281874765, rsl04886349, rs398123247, rs74315277, rs200346587,

rs398122908, rs727503036, rs397515747, and rs587776734. In various embodiments, at least one of the at least one genomic sequence variant in a non-coding region that is highly conserved is selected from the list consisting of rs778796405, rs8177982, rs376829288, rs4253196, rs750180293, rs757171524, rs727503201, rs397515893, rs587776699, rs397516083, rs201078659, rs750425291, rs558721552, rs531105836, rs200782636, rs752197734, rs3093266, rs34086577, rsl99959804, rsl44077391, rs386834164, rs386834166, rsl89077405,

rs746701685, rs386833721, rs376023420, rs761146008, rs765390290, rs72648337,

rs527398797, rs367567416; rs372651309, rs200253809, rsl93922837, rs761737358, rsl 13994173, rs559854357, rsl 11951711, rs371496308, rs368123079, rsl 18192239, rs41298629, and rs536892777. The functional genomic assay may be for use in determining a likelihood of the individual being diagnosed with a cancer, for use in prognosing a cancer of the individual, and/or for use in determining longevity of the individual.

BRIEF DESCRIPTION OF THE DRAWINGS

[0023] FIGURE 1 illustrates a scheme, in the form of a metaprofile strategy, for determining a tolerability score for a genomic sequence variant (GSV).

[0024] FIGURE 2 illustrates a scheme, in the form of a heptameric variant score strategy, for determining an n-mer score for a GSV.

[0025] FIGURE 3 illustrates a scheme, in the form of a heptameric variant score expected versus observed strategy, for determining a context dependent tolerance score.

[0026] FIGURE 4 illustrates a scheme, in the form of a protein tolerance score strategy, for determining a protein tolerance score for a GSV.

[0027] FIGURE 5A illustrates a functional genomic scheme as applied to chromosome 1.

[0028] FIGURE 5B illustrates enrichment of genetic elements by a percentile ranking of conservation.

[0029] FIGURE 5C illustrates a distribution of the percentile ranking of conservation among selected genetic elements.

[0030] FIGURE 6A illustrates an analysis of the relationship of mean coverage with effective genome coverage uses 100 NA12878 replicates with coverage <30x, 200 replicates with mean coverage of 30x to 40x, and 25 replicates with >40x. Vertical grey lines highlight mean target coverage of 7x and 30x. Each sequencing replica is plotted at lOx (blue) and 30x (orange) effective minimal genome coverage.

[0031] FIGURE 6B illustrates an analysis of reproducibility uses NA12878 genomes at 30x- 40x mean coverage (two clustering chemistries, vl and v2, each n=100 replicas) to assess the consistency of base calling at each position in the whole genome. The analysis of reproducibility is then extended to 100 unrelated genomes (25 genomes per main ancestry group, African, European, Asian, and for 25 admixed individuals). The color bars represent degree of consistency (blue 100%, light blue >90%, orange >10-<90%, red <10%, black, no-PASS).

[0032] FIGURE 6C illustrates that false positive calls are concentrated in the region of GiaB that has <90% reproducibility of base calling. False negative calls are more evenly represented across GiaB; missingness (no-PASS) represents the bulk of error.

[0033] FIGURE 7A provides a genome view of a representative autosomal chromosome sequenced; Chr. l is the longest human chromosome. Each data point represents a Ikb window; the Y axis represents the number of SNVs per Ikb; dark blue are high confidence windows (the overlap of GiaB high confidence regions and regions with >=90% reproducibility in NA12878 replicates); light blue are extended confidence windows outside of GiaB; pink are GiaB only (low reproducibility with current technology); grey dots are regions outside of GiaB and extended confidence regions.

[0034] FIGURE 7B provides a genome view of a representative autosomal chromosome sequenced; Chr. 22 with the lowest proportion of sequenceable bases with the technology used, using the same color-coding as in FIGURE 7A.

[0035] FIGURE 7C provides summary statistics for all the chromosomes, using the same color- coding as in FIGURES 7 A and 7B.

[0036] FIGURE 8A illustrates the distribution of SNVs in selected genomic elements (genomic, protein-coding, RNA coding and regulatory elements). The genome average of 56.59 SNVs per kb is indicated by the horizontal dashed line. AE, alternative exon; AI, alternative intron; CE, constitutive exon; CI, constitutive intron; oriC, origin of replication.

[0037] FIGURE 8B illustrates the metaprofiles of protein-coding genes created by aligning all elements of 6 different genomic landmarks (TSS, start codon, SD, SA, stop codon and pA) for all 10,545 genomes. The y-axis in the upper representation describes the enrichment/depletion of SNVs occurrence per position, normalized to the mean (indicated by the horizontal dashed line); the y-axis in the lower representation describes the percent of SNVs at each position with an allelic frequency higher than 1 in a 1000. The x-axis represents the distance from the genomic landmark. The vertical line indicates the genomic landmark position. The SD and SA

metaprofiles highlight the strong conservation of the splice sites (upper panel) and the difference in SNV allele frequency between exons and introns (lower panel). TSS, transcription start site; SD, splice donor site; SA, splice acceptor site; and pA, poly adenylation site.

[0038] FIGURE 8C illustrates the metaprofiles of transcription factor binding sites (TFBS) created by aligning all the binding sites of four transcription factors (FOXA1, STAT3, NFKB1, MAFF) for all 10,545 genomes. The y-axis describes the normalized enrichment/depletion of SNVs occurrence per position, normalized to the mean (indicated by the horizontal dashed line). The x-axis represents the distance from the 5' end of the TFBS. The vertical lines indicate the 5' and 3' ends of the TFBS. TFBS, transcription factor binding site.

[0039] FIGURE 9A illustrates a Metaprofile of the transition between introns and exons expressed as Tolerance Score (TS). The TS is the product of the normalized SNV distribution value by the proportion of SNVs with allele frequency > 0.001 {see Fig. 3B). The exon sequence highlights the conservation of the first and second positions in codons and the tolerance to variation of the third position in codons (red). The pattern of higher tolerance to variation every third nucleotide is lost in introns. The TS is lowest at the splice donor and acceptor sites and highest in introns. [0040] FIGURE 9B illustrates the distribution of ClinVar and HGMD pathogenic SNVs (n=29,808 in SD; n=30,369 in SA metaprofiles) reflecting a significant enrichment of pathogenic variants at the sites of lowest TA. Consistently, the exon sequence highlights the enrichment for variation at the first position in codons (blue), as it results in amino acid change or truncation.

[0041] FIGURE 9C illustrates the relationship of tolerance score and enrichment for pathogenic variants. Represented on x-axis are the median TS values of 1200 positions (six protein-coding landmark positions +/- 100 bp) expressed in 100 bins. The y-axis presents the fold enrichment in pathogenic variants per bin. The LOESS curve fitting is represented by the solid line; the shaded area indicates the 95% confidence interval.

[0042] FIGURE 9D illustrates an orthogonal assessment of the impact of variation at sites with lowest TS values. The x-axis represents a gene essentiality score (the posterior probability of intolerance to truncation). The y-axis represents the fraction of genes with a given essentiality score or lower. Purple = genes with no variation in splice donor (SD) or acceptor (SA) sites, Orange = genes with variation only in SD sites, Blue = genes with variation only in SA sites, Green = genes with variation in SD and SA sites.

[0043] FIGURE 10A illustrates the SNV discovery rate for 8,137 unrelated individual genomes contributing over 150 million SNVs (blue line). The projection for discovery rates as more genomes are sequenced is represented without (dashed black line) and with correction for the empirical false discovery rate of 0.0025 (dashed orange line). The number of SNVs in dbSNP is represented by the horizontal straight grey line.

[0044] FIGURE 10B illustrates the number of newly observed variants, as more individuals' sequences are determined by the ancestry background and number of participants in the study. Shown are the rates of identification of novel variants for each additional African genome (13,539 SNVs), and for each additional genome of ad-mixed individuals (10,918 SNVs). The most numerous population in the study, Europeans, contribute the lowest number of novel variants (7,215 SNVs).

[0045] FIGURE IOC illustrates unmapped sequences from the analysis of 8,137 unrelated individual genomes contributing over 3.2 Mb of non-reference genome. The 4,876 unique non- reference contigs had matches in NCBI nucleotide database as human (1.89 Mb), or primate (0.189 Mb). There are contigs with human-like features that do not have a known match in databases. In addition, there are 0.82 Mb of sequence mapping to the alternate scaffolds of the hg38 assembly.

[0046] FIGURE 11 A shows that there is very limited overlap between human conserved regions assessed with context dependent tolerance score (CDTS) and interspecies conservation assessed with GERP. Boxes in the bar correspond to different element families. The coloring of the boxes is in the same order as the legend CDTS, context-dependent tolerance score. GERP, Genomic Evolutionary Rate Profiling.

[0047] FIGURE 11B shows that there is very limited overlap between human conserved regions assessed with CDTS and interspecies conservation assessed with GERP. Length of the first percentile regions of CDTS, GERP and the overlap region of CDTS and GERP. Bins without GERP score, due to insufficient multiple species alignments in the region, were not considered in the ranking process. This explains the total length difference between the first percentile regions of CDTS and GERP. CDTS, context-dependent tolerance score. GERP, Genomic Evolutionary Rate Profiling.

[0048] FIGURE 11C shows element family composition in the first 10 percentile regions of CDTS (the bar labelled as "CTDS l-10 ^th "), GERP ("GERP l-lO ¹¹¹ ") and the overlap region ("Intersection") shows that there is very limited overlap between human conserved regions assessed with CDTS and interspecies conservation assessed with GERP. CDTS, context- dependent tolerance score. GERP, Genomic Evolutionary Rate Profiling.

[0049] FIGURE 11D shows length of the first 10 percentile regions of CDTS, GERP and the overlap region of CDTS and GERP. CDTS, context-dependent tolerance score. GERP, Genomic Evolutionary Rate Profiling.

[0050] FIGURE 12A shows shared conservation of genes and cis or distal regulatory elements. Coordination of cis-elements. Each genomic bin within 15 kb of a gene (cis) is attributed the essentiality score of the closest gene. The median essentiality score of the closest genes is depicted on the Y-axis for each genomic element family throughout the CDTS spectrum (X- axis). The grey horizontal dashed line represents the median gene essentiality score genome- wide (0.028). Coordination of hypothetical gene-distal enhancer pairs. A scheme of a chromatin loop with the gene-enhancer pair is depicted in the right panel. Gene-enhancer pairs brought together by chromatin looping were assessed. The X-axis represent the enhancers median CDTS and Y-axis the essentiality of the associated gene. CDTS, context-dependent tolerance score. CDTS, context-dependent tolerance score.

[0051] FIGURE 12B shows shared conservation of genes and cis or distal regulatory elements. Distal coordination of anchor regions. A chromatin loop is depicted in the right panel. The median CDTS is extracted for each anchor region and binned in percentile slices. The X- and Y- axes indicate the median CDTS values for the upstream and downstream anchor regions, respectively. The anchor regions surrounding a loop share CDTS values. The whiskers extend from the 10th to the 90th percentiles of the data. The box spans the interquartile range. Outliers are not displayed. CDTS, context-dependent tolerance score.

[0052] FIGURE 12C shows shared conservation of genes and cis or distal regulatory elements. Coordination of hypothetical gene-distal enhancer pairs. A scheme of a chromatin loop with the gene-enhancer pair is depicted in the right panel. Gene-enhancer pairs brought together by chromatin looping were assessed. The X-axis represent the enhancers median CDTS and Y-axis the essentiality of the associated gene. CDTS, context-dependent tolerance score.

[0053] FIGURE 13A shows the distribution of pathogenic variants across the genome. The distribution of pathogenic variants across the different percentile slices identifies a strong enrichment at lower CDTS percentiles. The relative enrichment is calculated with regards to the 100 ^th percentile. Protein-coding pathogenic variants are shown in dark blue; non-coding pathogenic variants in red. The total number of pathogenic variants are N=l 17,257 protein- coding and N=12,996 non-coding variants. Exonic non-coding (e.g., lincRNA) are not displayed here as it contained only a very limited number of annotated pathogenic variants (N=514).

CDTS, context-dependent tolerance score. Vs, versus.

[0054] FIGURE 13B shows the distribution of pathogenic variants across the genome. Non- coding pathogenic variants associated with Mendelian traits. The total number of Mendelian associated non-coding pathogenic variants is N=550. Pathogenic variants are enriched at the lowest percentiles. CDTS, context-dependent tolerance score. Vs, versus.

[0055] FIGURE 14A shows the complementarity of scores for non-coding variants. The enrichment of pathogenic variant detection, as compared to random, is displayed at different percentile thresholds for Eigen non-coding, CDTS, CADD as well as for the union of the three metrics.

[0056] FIGURE 14B shows the complementarity of scores for non-coding variants. The barplot displays, at different percentile thresholds, the fraction of pathogenic variants identified exclusively by only one of the metrics. The Venn diagram displayed on top of each percentile threshold shows the overlap of pathogenic variant.

[0057] FIGURE 15 A and B Shows performance and complementarity of CDTS and other scores for non-coding variants. A. Receiver operating characteristic (ROC) curves for CDTS and six additional scores. The inset figure highlights the performance at the lowest false positive rate (x axis), which represents the most relevant segment for variant prioritization. B. Number of pathogenic variants identified by each metric at their first percentile. The darker hue represents the subset that is uniquely identified by a single metric. CDTS contributes a significant number of uniquely identified variants, demonstrating its complementarity to the other metrics. The plots and percentiles are computed on 1,369 non-coding pathogenic variants and over 5 million common variants (af>0.05) as controls. CDTS, context-dependent tolerance score. CADD, combined annotation dependent depletion. GERP, genomic evolutionary rate profiling.

[0058] FIGURE 16A illustrates the difference between a principal isoform (PI) and non- principal isoform ( PI)

[0059] FIGURE 16B show the characteristics of exon-intron junctions in terms of tolerance to variation as assessed by metaprofiling for principal isoforms.

[0060] FIGURE 16C show the characteristics of exon-intron junctions in terms of tolerance to variation as assessed by metaprofiling for non-principal isoforms.

[0061] FIGURE 17 shows a depiction of novel obesity related genomic sequence variants.

[0062] FIGURE 18 shows a non-limiting example of a digital processing device; in this case, a device with one or more CPUs, a memory, a communication interface, and a display. The devices and connectivity can be used to deliver reports accessible by health care professionals.

The reports can be generated by any of the methods of the current disclosure.

DETAILED DESCRIPTION

[0063] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Any reference to "or" herein is intended to encompass "and/or" unless otherwise stated.

[0064] As used herein "genomic sequence variant" refers to any nucleotide difference in an individual's genome sequence compared to a reference genome. The variant can be a single nucleotide variant (SNV or S P), insertion or deletion (Indel), or translocation. In certain embodiments, the indel comprises more than a single nucleotide. In certain embodiments, a genomic sequence variant excludes mitochondrial deoxyribonucleic acid (DNA) sequences. In certain embodiments, a genomic sequence variant excludes variants found on either of the non- autosomal human X or Y chromosomes. In certain embodiments, the genomic sequence variant is a human genomic sequence variant.

[0065] As used herein "reference genome" refers to any standard publicly available reference genome, for example GRCh38, the Genome Reference Consortium human genome (build 38). Alternatively, the reference genome can be one that is constructed de novo from sequencing a plurality of genomes. In certain embodiments, the plurality of genomes is greater than 10,000 different genomes. In certain embodiments, the plurality of genomes is greater than 100,000 different genomes. Nucleic sequences

[0066] Described herein, are methods, systems, and media useful for determining the health risk of a genomic sequence variant (GSV) in the nucleic acid sequence of an individual's genome. In certain embodiments, the DNA sequence comprises a sequence for an individual's whole genome. In certain embodiments, the DNA sequence comprises a sequence for only the high confidence regions of an individual's whole genome. In certain embodiments, the DNA sequence comprises a sequence for the high confidence region of an individual's whole genome as defined by the NA12878 Genome-In-A-Bottle call set (GiaB v2.19). In certain embodiments, the DNA sequence comprises a sequence for 90% of the high confidence region of an individual's whole genome as defined by the GiaB v2.19. In certain embodiments, the DNA sequence comprises a sequence for 80% of the high confidence region of an individual's whole genome as defined by the GiaB v2.19. In certain embodiments, the DNA sequence comprises a sequence for 70% of the high confidence region of an individual's whole genome as defined by the GiaB v2.19. In certain embodiments, the DNA sequence comprises a sequence of a plurality of contiguous nucleotides from an individual's genome. In certain embodiments, the DNA sequence comprises a sequence of at least 100 contiguous nucleotides from an individual's genome. In certain embodiments, the DNA sequence comprises a sequence of at least 1,000 contiguous nucleotides from an individual's genome. In certain embodiments, the DNA sequence comprises a sequence of at least 10,000 contiguous nucleotides from an individual's genome. In certain embodiments, the DNA sequence comprises a sequence of at least 100,000 contiguous nucleotides from an individual's genome. In certain embodiments, the DNA sequence comprises a sequence of at least 1,000,000 contiguous nucleotides from an

individual's genome. In certain embodiments, the DNA sequence does not comprise the sequence of ribonucleic acid (RNA). In certain embodiments, the DNA sequence does not comprise the sequence of cDNA generated from ribonucleic acid (RNA).

Genomic Health Risk

[0067] Described herein, are methods, systems, and media useful for determining the genomic health risk of a genomic sequence variant (GSV) in the DNA sequence of an individual's genome. Determining a genomic health risk encompasses several different or alternative steps. Further, the genomic health risk itself is with respect to an overall health risk or for specific diseases. In certain embodiments, determining the genomic health risk comprises determining a tolerability score for at least one GSV in an individual. In certain embodiments, determining the genomic health risk comprises determining an score for at least one GSV in an individual. In certain embodiments, determining the genomic health risk comprises determining a context dependent tolerance score for at least one region in which there is at least one GSV in an individual. In certain embodiments, determining the genomic health risk comprises determining a protein tolerability score for at least one GSV in an individual. In certain embodiments, the genomic health risk is determined using any single genomic health risk metric of this disclosure selected from the list consisting of: a tolerability score, an n-mer score, a context dependent tolerance score, and a protein tolerability score. In certain embodiments, the genomic health risk is determined using any two genomic health risk metrics of this disclosure selected from the list consisting of: a tolerability score, an n-mer score, a context dependent tolerance score, and a protein tolerability score. In certain embodiments, the genomic health risk is determined using any three genomic health risk metrics of this disclosure selected from the list consisting of: a tolerability score, an n-mer score, a context dependent tolerance score, and a protein tolerability score. In certain embodiments, the genomic health risk is determined using all of a tolerability score, an n-mer score, a context dependent tolerance score, and a protein tolerability score.

[0068] In certain embodiments, the genomic health risk is determined with respect to any single GSV of an individual. In certain embodiments, the genomic health risk is determined with respect to a plurality of GSVs of an individual. In certain embodiments, the genomic health risk is determined with respect to at least 10 GSVs of an individual. In certain embodiments, the genomic health risk is determined with respect to at least 100 GSVs of an individual. In certain embodiments, the genomic health risk is determined with respect to at least 1,000 GSVs of an individual. In certain embodiments, the genomic health risk is determined with respect to at least 10,000 GSVs of an individual. In certain embodiments, the genomic health risk is determined with respect to at least 100,000 GSVs of an individual.

[0069] In certain embodiments, the genomic health risk determined is an overall health risk defined as the increase or decrease in the likelihood of contracting any pathological condition. In certain embodiments, the genomic health risk is an arbitrary designation that communicates the increased risk of any given GSV. In certain embodiments, the genomic health risk is an arbitrary designation that communicates the increased risk of a plurality of GSVs. In certain embodiments, the genomic health risk is a percentage increase risk that any given GSV will be deleterious to the health of the individual. In certain embodiments, the genomic health risk is a percentage increase risk that a plurality of GSVs will be deleterious to the health of the individual. In certain embodiments, genomic health risk comprises the likelihood of contracting or being afflicted with diabetes, high blood pressure, cardiac arrhythmia, cardiovascular disease, atherosclerosis, stroke, non-alcoholic fatty liver disease, cirrhosis, dementia, bipolar disorder, depression, schizophrenia, anxiety disorder, autism, Asperger's syndrome, Parkinson's disease, Alzheimer's disease, Huntington's disease, cancer, breast cancer, prostate cancer, leukemia, melanoma, pancreatic cancer, colon cancer, stomach cancer, kidney cancer, liver cancer, an inborn error of metabolism, a genetically linked immunodeficiency, risk or protective alleles for the contraction. In certain embodiments, the genomic health risk is determined without GSVs known at the date of filing this disclosure that lead to a known disease, for example, known GSVs in the BRCA gene that lead to increased risk of breast cancer.

Generation of sequence data

[0070] In certain embodiments, DNA sequence data for use with the methods, systems and media, described herein, is generated by any suitable method. In certain embodiments, the DNA sequence data is generated by Sanger sequencing. In certain embodiments, the DNA sequence data is generated by any next-generation sequencing technology. In certain embodiments, the DNA sequence data is generated, by way of non-limiting example, pyrosequencing, sequencing by synthesis, sequencing by ligation, ion semiconductor sequencing, or single molecule real time sequencing. In certain embodiments, the DNA sequence data is generated by any technology capable of generating 1 gigabase of nucleotide reads per 24 hour period. In certain embodiments, the DNA sequence data is obtained from a third party.

Genomic sequence variants

[0071] In certain embodiments, GSVs for use with the methods, systems and media, described herein, are determined de novo during implementation of any of the methods. In certain embodiments, GSVs are determined by a third party and received by the party performing the method. In certain embodiments, determining a GSV encompasses receiving a list or file that comprises an individual's GSVs.

[0072] In certain embodiments, GSVs are determined by comparison with a reference genome. In certain embodiments, the reference genome is publicly available. In certain embodiments, the reference genome is NA12878 from the CEPH Utah reference collection. In certain

embodiments, the reference genome is the GRCh38, Genome Reference Consortium human genome (build 38). In certain embodiments, the reference genome is any previous or subsequent build of the Genome Reference Consortium human genome. In certain embodiments, the reference genome is constructed from at least 1,000 human genomes. In certain embodiments, the reference genome is constructed from at least 10,000 human genomes. In certain

embodiments, the reference genome is constructed from at least 100,000 human genomes. In certain embodiments, the reference genome is constructed from at least 1,000,000 human genomes. In certain embodiments, a GSV is a difference of a single nucleotide compared to a reference genome. In certain embodiments, a GSV is a difference of a plurality of contiguous nucleotides compared to a reference genome. In certain embodiments, a GSV is an insertion of one or more nucleotides compared to a reference genome. In certain embodiments, a GSV is a deletion of one or more nucleotides compared to a reference genome.

Tolerability score

[0073] In certain embodiments, the methods, systems and media, described herein comprise determining a tolerability score for at least one GSV. In certain embodiments, the methods, systems and media, described herein comprise determining a tolerability score for a plurality of GSV. The concept of determining a tolerability score is captured in Figure 1. A tolerability score is defined with regard to its position compared to a genetic landmark. In certain

embodiments, the landmark is an arbitrary sequence or position in the genome. In certain embodiments, the landmark is a functional genetic element. In certain embodiments, the functional genetic element is a transcriptional start site, an initiation codon, an mRNA splice acceptor site, an mRNA splice donor site, a promoter element, an enhancer element, a regulatory element, a transcription factor binding site, a stop codon, a poly-adenylation site, a protein domain, a non-coding RNA or an exon-intron boundary. All landmarks that fall within a class of functional genetic elements in a plurality of genomes sequenced are then aligned at their 5 or 3 prime ends. The tendency of the genome to vary at a position x nucleotides from the land mark (the nucleotide variation score) is determined. In certain embodiments, a tolerability score is calculated from a minimum of 10 aligned genetic elements. In certain embodiments, a tolerability score is calculated from a minimum of 50 aligned genetic elements. In certain embodiments, a tolerability score is calculated from a minimum of 100 aligned genetic elements. In certain embodiments, a tolerability score is calculated from a minimum of 500 aligned genetic elements. In certain embodiments, a tolerability score is calculated from a minimum of 1,000 aligned genetic elements. In certain embodiments, a tolerability score is calculated from a minimum of 5,000 aligned genetic elements. In certain embodiments, a tolerability score is calculated from a minimum of 10,000 aligned genetic elements.

[0074] The nucleotide variation score in the plurality of genomes is determined for a position x bases upstream or downstream of the above mentioned landmark. In certain embodiments, the position is less than 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1,000 bases, including increments therein, upstream or downstream from the landmark. The nucleotide variation score is then normalized to the average variability for all positions within x nucleotides of the landmark or genetic element. In certain embodiments, this normalization occurs in 100 to 1500 base pairs. The nucleotide variation score is then multiplied by the fraction of all alleles at that position x bases from the landmark that exceed 0.0001 (the allele proportion score, where the maximal allelic proportion is 0.5 in a population). In certain embodiments, the tolerability score is a function of the nucleotide variation score and the fraction of all alleles at that position x bases from the landmark that exceed 0.0001. This yields the tolerability score for a position x bases from a given landmark. In certain embodiments, the allele proportion score is determined as the fraction of all alleles at a position x bases from the landmark that exceeds 0.0001, 0.0002, 0.0003, 0.0004, 0.0005, 0.0006, 0.0007, 0.0008, 0.0009, 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, or 0.010. If an individual possesses a GSV x bases from a landmark the tolerability sore for that position is then correlated with the GSV.

[0075] In certain embodiments, a tolerability score that is below 0.01 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, a tolerability score that is below 0.02 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, a tolerability score that is below 0.03 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, a tolerability score that is below 0.04 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, a tolerability score that is below 0.05 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, a tolerability score that is below 0.06 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, a tolerability score that is below 0.07 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, a tolerability score that is below 0.08 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, a tolerability score that is below 0.09 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, a tolerability score that is below 0.10 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, a tolerability score that is below 1 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, a tolerability score that is below 0.12 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, a tolerability score that is below 0.13 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, the genomic health risk is increased by at least 20%. In certain embodiments, the genomic health risk is increased by at least 50%. In certain embodiments, the genomic health risk is increased by at least 100%. In certain embodiments, the genomic health risk is increased by at least 200%. In certain embodiments, the genomic health risk is increased by at least 300%. In certain embodiments, the genomic health risk is increased by at least 400%. In certain embodiments, the genomic health risk is increased by at least 500%. In certain embodiments, the genomic health risk is increased by at least 1000%.

Tolerability score examples

[0076] Position 117587738 on chromosome 7 has a tolerance score of 0.0159 and a variation at that position has been associated with Cystic fibrosis (ClinVar entry:

M_000492.3(CFTR):c. l585-lG>A AND Cystic fibrosis).

[0077] Position 32326240 on chromosome 13 has a tolerance score of 0.0137 and a variation at that position has been associated with Breast ovarian cancer (ClinVar entry:

NM_000059.3(BRCA2):c.476-2A>G AND Breast-ovarian cancer, familial 2).

[0078] Position 47480818 on chromosome 2 has a tolerance score of 0.0258 and a variation at that position has been associated with Lynch syndrome (ClinVar entry:

NM_000251.2(MSH2):c.2581C>T (p.Gln861Ter) AND Lynch syndrome).

^-variant score

[0079] In certain embodiments, the methods, systems and media, described herein comprise determining an score for at least one GSV. In certain embodiments, the methods, systems and media, described herein comprise determining an ^-variant score for a plurality of GSV. The concept of determining an is captured in Figure 2. Given 4 different nucleotides there are 4 ⁷ (16,384) different 7-mers (heptamers) possible. Every GSV will be situated, in this case, in the middle, of at least one of these 16,384 different heptamers, thus each GSV will create a heptameric variant from an existing heptamer. Since the variation at that GSV could theoretically be any of three different bases, the total variant heptamers possible are 16,384x3=49,152. Unexpectedly, not all variant heptamers are equally possible. First, a count score is determined, the count score comprises the number of instances a certain heptamer variant occurs in a plurality of genomes sequenced divided by the number of instances the non-mutated heptamer appears in the reference genome. This count score is then multiplied by the proportion of the specific GSV that gave rise to the variant heptamer that were present at an allelic frequency of more than 1 in a 1000. Since every nucleotide is a part of an timer, an ^-variant score can be calculated for each nucleotide in a haploid genome. In certain embodiments, n can be any number. In certain embodiments, n is equal to 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In certain embodiments, the GSV occurs in the center of the n-mer. In certain embodiments, the GSV occurs at a position that is not the center of the rimer. In certain embodiments, the GSV occurs at the 5 prime end of the n-mer. In certain embodiments, the GSV occurs at the three prime end of the n-mer.

[0080] In certain embodiments, an ^-variant score that is below 0.001 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, an ^-variant score that is below 0.002 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, an score that is below 0.003 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, an ^-variant score that is below 0.004 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, an ^-variant score that is below 0.005 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, an score that is below 0.006 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, an ^-variant score that is below 0.007 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, an ^-variant score that is below 0.08 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, ^-variant score that is below 0.009 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, score that is below 0.010 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, ^-variant score that is below 0.011 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, ^-variant score that is below 0.012 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, score that is below 0.013 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, the genomic health risk is increased by at least 20%. In certain embodiments, the genomic health risk is increased by at least 50%. In certain embodiments, the genomic health risk is increased by at least 100%. In certain embodiments, the genomic health risk is increased by at least 200%. In certain embodiments, the genomic health risk is increased by at least 300%. In certain embodiments, the genomic health risk is increased by at least 400%. In certain embodiments, the genomic health risk is increased by at least 500%. In certain embodiments, the genomic health risk is increased by at least 1000%). In certain embodiments, the score allows the identification of pathogenic variants (health risk associated) without the need for annotation.

n-variant score Examples

[0081] Position 43115730 on chromosome 17 has an heptamer tolerability score of 0.000397 for the variant T>A and this variant has been associated with Breast ovarian cancer (ClinVar entry: M_007294.3(BRCAl):c. l30T>A (p.Cys44Ser) AND Breast-ovarian cancer, familial 1).

[0082] Position 37028836 on chromosome 3 has an heptamer tolerability score of 0.000393 for the variant A>T and this variant has been associated with Lynch syndrome (ClinVar entry: NM_000249.3(MLHl):c. l462A>T (p.Lys488Ter) AND Lynch syndrome ).

[0083] Position 108335959 on chromosome 11 has an heptamer tolerability score of 0.000388 for the variant A>T and this variant has been associated with Hereditary cancer-predisposing syndrome (ClinVar entry: NM_000051.3 (ATM) :c.8266 A>T (p.Lys2756Ter) AND Hereditary cancer-predisposing syndrome).

Context dependent tolerance score

[0084] In certain embodiments, the methods, systems and media, described herein comprise determining a context dependent tolerance score (regional variation score) for the region in which at least one GSV occurs. In certain embodiments, the methods, systems and media, described herein comprise determining a context dependent tolerance score for the region in which at least one GSV occurs. As noted previously an score can be determined for each nucleotide in the genome. In Figure 3, the context dependent tolerance score is determined as an expected variation in a region of the genome versus the observed variation for that genome. Any given n-mer will have an overall probability to vary. In the case of a heptamer, there are 16,384 different possible heptamers. A variant at a given position in the heptamer will vary at a given frequency in a reference genome this is the global probability to vary. This global probability to vary is summed over the entire length of the region and divided by the length of the region, measured in nucleotides, giving the expected context dependent tolerance score. This number is then compared to the observed context dependent tolerance score, which is given by the number of single nucleotide variations in the plurality of genomes divide by the length of the region measured in nucleotides. The lower the context dependent tolerance (observed variation lower than expected variation) score the less tolerant the region is to variation and the greater the likelihood that a GSV located in this region will be deleterious. One of skill in the art will appreciate that the context dependent tolerance score is a function of the expected context dependent tolerance score and the observed context dependent tolerability score. By way of non- limiting example, the observed context dependent tolerance score may be divided by the expected context dependent tolerance score; the expected context dependent tolerance score may be subtracted from the observed context dependent tolerance score, the observed context dependent tolerance score may be subtracted from the expected context dependent tolerance score; the observed context dependent tolerance score may be added to the expected context dependent tolerance score.

[0085] In certain embodiments, the region for which the global probability to vary is between 10 and 10,000 nucleotides in length. In certain embodiments, the region is between 10 and 1,000 nucleotides in length. In certain embodiments, the region is between 10 and 500 nucleotides in length. In certain embodiments, the region is between 10 and 100 nucleotides in length. In certain embodiments, the region is between 100 and 200 nucleotides in length. In certain embodiments, the region is between 120 and 180 nucleotides in length. In certain embodiments, the region is between 140 and 160 nucleotides in length. In certain embodiments, the region is between 300 and 700 nucleotides in length. In certain embodiments, the region is between 400 and 600 nucleotides in length. The region can be any length that is able to be practically analyzed using computer aided means including lengths in excess of 1,000; 5,000; 10,000;

50,000; or 100,000 nucleotides.

[0086] In certain exemplary embodiments, if the context dependent tolerance score is

represented as an observed context dependent tolerance score divided by the expected context dependent tolerance score a context dependent tolerance score below 1 increases the genomic health risk of a given GSV. In certain embodiments, a GSV that occurs in a region with a context dependent tolerance score below 0.9 increases the genomic health risk of a given GSV. In certain embodiments, a GSV that occurs in a region with a context dependent tolerance score below 0.8 increases the genomic health risk of a given GSV. In certain embodiments, a GSV that occurs in a region with a context dependent tolerance score below 0.7 increases the genomic health risk of a given GSV. In certain embodiments, a GSV that occurs in a region with a context dependent tolerance score below 0.6 increases the genomic health risk of a given GSV. In certain embodiments, a GSV that occurs in a region with a context dependent tolerance score below 0.5 increases the genomic health risk of a given GSV. In certain embodiments, a GSV that occurs in a region with a context dependent tolerance score below 0.4 increases the genomic health risk of a given GSV. In certain embodiments, a GSV that occurs in a region with a context dependent tolerance score below 0.3 increases the genomic health risk of a given GSV. In certain embodiments, a GSV that occurs in a region with a context dependent tolerance score below 0.2 increases the genomic health risk of a given GSV. In certain embodiments, a GSV that occurs in a region with a context dependent tolerance score below 0.1 increases the genomic health risk of a given GSV. In certain embodiments, the genomic health risk is increased by at least 20%. In certain embodiments, the genomic health risk is increased by at least 50%. In certain embodiments, the genomic health risk is increased by at least 100%. In certain

embodiments, the genomic health risk is increased by at least 200%. In certain embodiments, the genomic health risk is increased by at least 300%. In certain embodiments, the genomic health risk is increased by at least 400%. In certain embodiments, the genomic health risk is increased by at least 500%. In certain embodiments, the genomic health risk is increased by at least 1000%).

[0087] The context dependent tolerance score is able to identify potentially pathogenic genomic sequence variants without any a priori knowledge about the genomic location of the sequence variant. In certain embodiments, the context dependent variation score allows the identification of pathogenic (health risk associated) variants without the need for annotation. In certain embodiments, the context dependent variation score allows the identification of pathogenic (health risk associated) variants without the need for functional annotation.

[0088] In certain embodiments, the genomic health risk of a particular variant is defined as pathogenic if it falls in a region of the genome in the top 10% of conserved regions. In certain embodiments, the genomic health risk of a particular variant is defined as pathogenic if it falls in a region of the genome in the top 5% of conserved regions. In certain embodiments, the genomic health risk of a particular variant is defined as pathogenic if it falls in a region of the genome in the top 2% of conserved regions. In certain embodiments, the genomic health risk of a particular variant is defined as pathogenic if it falls in a region of the genome in the top 1% of conserved regions.

[0089] In certain embodiments, the genomic health risk of a particular variant is defined as pathogenic if it in the top 10% of conserved genomic loci. In certain embodiments, the genomic health risk of a particular variant is defined as pathogenic if it falls in a region of the genome in the top 5% of genomic loci. In certain embodiments, the genomic health risk of a particular variant is defined as pathogenic if it falls in a region of the genome in the top 2% of genomic loci. In certain embodiments, the genomic health risk of a particular variant is defined as pathogenic if it falls in a region of the genome in the top 1% of genomic loci.

Context dependent variation score examples

[0090] In these examples, the expected context dependent tolerance score (CDTS) is subtracted from the observed context dependent tolerance score to yield the context dependent tolerability score. In this case the more negative the score the more potentially pathogenic the variant. In general, when the CDTS is a subtraction function, a number less than zero indicates an increased health risk of a given variant. In certain embodiments, a CDTS of less than 0, -1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -11, or -12 indicates an increased health risk.

[0091] ClinVar pathogenic variant (entry NM_000249.3(MLHl):c.2T>A (p.MetlLys) AND Lynch syndrome), position 36993549 on chromosome 3 is associated with Lynch syndrome and has a context dependent tolerance score of -12.0987.

[0092] ClinVar pathogenic variant (entry NM_000492.3(CFTR):c.350G>A (p.Argl 17His) AND Cystic fibrosis), position 117530975 on chromosome 7 is associated with Cystic fibrosis and has a context dependent tolerance score of -4.16129

[0093] ClinVar pathogenic variant (entry NM_006516.2(SLC2Al):c.377G>A (p.Argl26His) AND Glucose transporter type 1 deficiency syndrome), position 42930765 on chromosome 1 is associated with Glucose transporter type 1 deficiency syndrome and has a context dependent tolerance score of -9.09988. Protein tolerability score

[0094] In certain embodiments, the methods, systems and media, described herein comprise determining a protein tolerability score for at least one GSV. In certain embodiments, the methods, systems and media, described herein comprise determining a protein tolerability score for a plurality of GSV. The concept of determining a protein tolerability score is captured in Figure 4. The protein tolerability score is analogous to the tolerability score except that it accounts for conservation among proteins and not necessarily nucleotides. For the protein tolerability score a multiple sequence alignment is used to align proteins from a certain class or family. A diversity score is assigned to each vertically aligned amino acid column. In certain embodiments, the diversity score is calculated using the Shannon-Entropy, Simpson diversity index, WU-Kabat score, or any other amino acid diversity scoring algorithm. A missense score is determined. The missense score is determined by the variance observed in a plurality of genomes at the corresponding position, which leads to an amino acid mutation. Finally, a protein allele frequency score is determined. In certain embodiments, the protein tolerability score is the arithmetic product of the diversity score, the missense score and the protein allele frequency score. In certain embodiments, the protein tolerability score is an average of the diversity score, the missense score and the protein allele frequency score. In certain embodiments, the protein tolerability score is a weighted average of the diversity score, the missense score and the protein allele frequency score.

[0095] In certain embodiments, the protein family is any family of proteins that exhibit an evolutionary relationship, such as kinases. In certain embodiments, the protein family is any family of proteins that exhibit an evolutionary relationship and possess at least 95% similarity. In certain embodiments, the protein family is any family of proteins that exhibit an evolutionary relationship and possess at least 90% similarity. In certain embodiments, the protein family is any family of proteins that exhibit an evolutionary relationship and possess at least 85% similarity. In certain embodiments, the protein family is any family of proteins that exhibit an evolutionary relationship and possess at least 80% similarity. In certain embodiments, the protein family is any family of proteins that exhibit an evolutionary relationship and possess at least 75%) similarity. In certain embodiments, the protein family is any family of proteins that exhibit an evolutionary relationship and possess at least 70% similarity. In certain embodiments, a protein tolerability score that is below 0.1 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, a protein tolerability score that is below 0.05 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, a protein tolerability score that is below 0.01 indicates an increase in the genomic health risk for a given GSV. In certain embodiments, a protein tolerability score that is below 0.005 indicates an increase in the genomic health risk for a given GSV.

Functional genomic application for tolerability and variation metrics

[0096] There is an established relationship between functional units and sequence conservation.

Regions that are both functional and conserved are deemed essential for biology. Disclosed herein, are methods of using the regional score to enable the identification, and targeting for analysis and sequencing, of those parts of the human genome that are most functionally relevant, and, thus, most relevant for health.

[0097] The functional genome comprises regions that are known to have a biological role and share properties that assimilate them to probable functional units, despite being poorly annotated.

[0098] Referring to Figure 5A, presented is the pattern of enrichment and depletion of genomic elements in regions with marked context-based conservation (lowest regional score).

Specifically, in the 1 ^st percentile of regional scores (most conserved) we observe an enrichment of up to 10-fold in promoter sequences, and 5-fold in exonic sequences. In parallel, at the 1st percentile of regional score, there is up to 10 to 50-fold depletion in intronic and intergenic sequences.

[0099] Referring to Figure 5B, the analysis of pattern of enrichment allowed the detailed inspection of the genomic content for different levels of regional scores. For all genome elements, there are subsets of context-based conserved elements (lower range of regional score). For example, in the 1.76 Mb of sequence in the 1 ^st percentile 0.6 Mb of sequence represents conserved exonic sequences, and over 1.1 Mb contain other important genomics elements.

Discovery is facilitated - as illustrated by the identification of 8 Kb of intergenic region with features of profound context-based conservation.

[00100] Referring to Figure 5C, the most context-based conserved region is of particular interest for targeted analysis and detailed annotation. Figure 5C highlights the proportion of each genomic element that can be classified as functionally constrained at different percentiles of context-based conservation. For example, the 5 ^th percentile contains 18% of the promoters, 13% of the exonic regions, and decreasing proportions of other genomic elements.

[00101] Referring to Figures 5A-5C, any of the methods of this disclosure can be used in a method to identify functional genomic regions of the genome. These regions can be prioritized for sequence analysis or targeted sequencing. In certain embodiments any one or more of a tolerability score, an ^-variant score, a context dependent tolerance score, and a protein tolerability score can be used prioritize a part of the genome using a functional genomic approach. [00102] The methods of this disclosure can be used to develop a functional genomic assay. This functional genomic assay can integrate any of the methods described herein, including a context dependent tolerance score. The functional genomic assay comprises a step of obtaining a nucleic acid sequence from a biological sample from an individual; and determining a presence of at least one genomic sequence variant in a region that is highly conserved; wherein the region that is highly conserved is a region wherein an observed context dependent tolerance score is greater than an expected context dependent tolerance score, wherein the expected context dependent tolerance score is the overall probability to vary of a unique sequence of ^-nucleotides in length in a certain region of x nucleotides in length in a plurality of genomes, and the observed context dependent tolerance score is a number of genomic sequence variants in a certain region of x nucleotides in length actually observed and fixed in the plurality of genomes as a function of a length of the region. In a certain instance, the at least one genomic sequence variant is in a non- coding region.

[00103] Suitable biological samples can comprise oral swabs, whole-blood samples, peripheral blood mononuclear cells obtained from whole blood, plasma samples, serum samples, biopsy samples (both normal and malignant tissue), semen samples, fecal/stool samples. Nucleic acids can be isolated in these samples using methods well known in the art and appropriate

nucleotides for determining genomic sequence variants, can comprise RNA, mRNA, genomic DNA (including circulating cell-free DNA derived from nuclear DNA). In certain instances, the DNA does not comprise mitochondrial DNA or DNA derived from sex-chromosomes.

[00104] The step of the determining a presence of at least one genomic sequence variant in a region that is highly conserved can be greatly expanded. In some cases, greater than 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1,000 genomic sequence variants can be determined in greater than 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 highly conserved regions. In some cases genomic sequence variants can be determined in greater than 10,000; 20,000; 30,000; 40,000; 50,000; 60,000,; 70,000; 80,000; 90,000 or 100,000 highly conserved regions. In some cases genomic sequence variants can be determined in the most highly conserved 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% regions of the genome as determined by the method herein or the context dependent tolerability score. A list of exemplar highly conserved regions

corresponding to the most conserved 0.1% of genomic regions is shown in Table 5. Listed is the human chromosome number and the range of coordinates from X to X (e.g., chrl 902440 903230). Coordinates given are with regard to the Genome Reference Consortium GRCh38 build. Any one or more of these genomic regions are considered highly conserved for the purposes of functional genomic assay detailed herein.

[00105] The sequences can be determined using any method known inn the art that is sufficiently high throughput to enrich and identify a plurality of genomic sequence variants, such as, for example, next-generation sequencing (e.g., sequencing by synthesis, ion- semiconductor sequencing, or single molecule real-time sequencing) nucleotide array, massively-multiplex PCR, molecular inversion probes, padlock probes, or connector inversion probes. In certain instances the step of obtaining a nucleic acid sequence from a biological sample comprises receiving nucleotide sequence data from a third-party including commercial third parties such as 23andme. Additionally, the sequences may be received as raw data or as pre-called variants in a variant call format (.vcf) file. In certain instances greater than 10; 100; 1,000; 10,000; 100,000; 1,000,000; 2,000,000; or 3,000,000 GSVs, including increments therein, can be determined.

[00106] The genomic sequence variants (GSVs) determined include both germline and somatic mutations. For example, determining somatic GSVs from a biopsy sample, when compared to a normal germline control sample, can help to identify regions that are causative and contribute to an individual's malignancy allowing for rational selection of a treatment option. This treatment option can comprise specific drugs that target specific pathways or modalities that are associated with particular genomic mutations. The advantage of this functional genomic assay is that no previous knowledge concerning the potential pathogenicity of a particular locus is needed. The genomic sequence variant can include S PS, indels, translocations, repetitions, or copy number variations.

[00107] The pathogenicity of a GSV can be determined with respect to a candidate or known disease associated gene. In certain aspect the GSV can be within 2 megabases, 1 megabase, 1 kilobase, 200 base pairs, or 100 base pairs of a genomic feature of a known disease associated gene, such as a spice acceptor site, splice donor site, transcriptional start site, or promoter or enhance region.

[00108] Additional advantages of the functional genomic assay are that it is amenable to simultaneous analysis of GSVs without any pre-annotation. In certain instances greater than 10; 100; 1,000; 10,000; 100,000; 1,000,000; 2,000,000; or 3,000,000, including increments therein, can be analyzed without any appreciable additional cost from computing sources used.

[00109] For the described functional genomic assay, the unique sequence of ^-nucleotides in length can be any number larger than 2 and smaller than 20. In certain embodiments, n is equal to 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[00110] For the described functional genomic assay, the certain region of x nucleotides in length can be greater than 10, 20, 20, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1,000 base pairs, including increments therein. The certain region of x nucleotides in length can be less than, 20, 20, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1,000 base pairs, including increments therein. In certain embodiments, the certain region of x nucleotides in length can be between 10 and 10,000 nucleotides in length; between 10 and 1,000 nucleotides in length; between 10 and 500 nucleotides in length; between 10 and 100 nucleotides in length; between 100 and 200 nucleotides in length; between 120 and 180 nucleotides in length; between 140 and 160;

between 300 and 700; and between 400 and 600 nucleotides in length. The region can be any length that is able to be practically analyzed using computer aided means including lengths in excess of 1,000; 5,000; 10,000; 50,000; or 100,000 nucleotides, including increments therein.

[00111] The probability to vary is calculated from a plurality of genomes in some instance the plurality of genomes is greater than 10,000, 20,000; 30,000; 40,000; 50,000; 60,000; 70,000; 80,000; 90,000; 100,000; 200,000, 300,000; 400,000; 500,000; 600,000; 700,000; 800,000;

900,000; or 1,000,000 individual genomes, including increments therein. The probability to vary can be calculated from the allele frequency of all known alleles located in a certain region of x nucleotides in length, and optionally normalized to the length of the certain region of x nucleotides in length.

[00112] In certain instances, the functional genomic assay comprises determining the presence of genomic sequence variant of any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900 or more variants, including increments therein, in an individual given in Table 1. In certain instances, the functional genomic assay comprises determining the presence of genomic sequence variant of all variants given in Table 1. In certain instances, the functional genomic assay comprises determining the presence of a genomic sequence variant of any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200 or more variants, including increments therein, in an individual given in Table 2. In certain instances, the functional genomic assay comprises determining the presence of genomic sequence variant of all variants given in Table 2. In certain instances, the functional genomic assay comprises determining the presence of genomic sequence variant of any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110 or more variants, including increments therein, in an individual given in Table 3. In certain instances, the functional genomic assay comprises determining the presence of genomic sequence variant of all variants given in Table 3. In certain instances, the functional genomic assay comprises determining the presence of genomic sequence variant of any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 20, 30, 40 or more variants, including increments therein, in an individual given in Table 4. In certain instances, the functional genomic assay comprises determining the presence of genomic sequence variant of any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 20, 30, 40 or more variants, including increments therein, in an individual given in Table 4.

[00113] The functional genomic assay described is useful for determining a likelihood of a subsymptomatic disease, such as, a cancer, a metabolic disorder, a physiological disorder, or an autoimmune or inflammatory disorder. In addition, the assay is useful as a predictive measure to determine likelihood of developing a disease, such as, a cancer, a metabolic disorder, a physiological disorder, or an autoimmune or inflammatory disorder. This functional genomic assay can be used as a prognostic indicator for treatment and be performed multiple times on the same induvial to guide treatment. These methods can be applied to a biopsy or a cell-free nucleic acid isolated from the plasma, for example, determine a prognosis of a cancer or to determine the malignant potential of a biopsy. In a certain aspect, the cell-free nucleic acid is an mRNA or DNA. The DNA can be derived from a linear chromosome in the nucleus of a cell and in certain aspects is not derived from mitochondria or a sex-chromosome. The functional genomic assay can assign a certain GSV as high risk when the observed context dependent tolerance score is 5%, 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, or 200%), including increments therein, greater than an expected context dependent tolerance score for that GSV. In addition the functional genomic assay can determine a risk for a plurality of GSVs in some cases greater than 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000, including increments therein. The risk can be averaged or summed for the specific GSVs. The GSV can be in a certain part of the genome within lOObp, 500bp, lkb, 5kb, or lOkb, including increments therein, of a functional motif such as a splice acceptor site, splice donor site, transcriptional start site, a promoter, or an enhancer element. In certain cases these, functional motifs are associated with a gene known to play a role in cancer, such as, a rector tyrosine kinase (e.g., epidermal growth factor

receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR), HER2/neu, ROR1); cytoplasmic tyrosine kinases (e.g., Src- family, Syk-ZAP-70 family, and BTK family of tyrosine kinases, BCR/ABL);

cytoplasmic serine/threonine kinases and their regulatory subunits (e.g., Raf kinase and cyclin- dependent kinases); a regulatory GTPase (e.g., a Ras gene); a transcription factor (e.g., myc), or a tumor suppressor gene (e.g., p53, BRCA1, BRCA2, RB, PTEN, or pVHL, APC, CD95, ST5, YPEL3, ST7, and ST14).

Data structures

[00114] In certain embodiments, any of a tolerability score, an ^-variant score, a context dependent tolerance score, and a protein tolerability score can be pre-determined. In certain embodiments, a health care professional compares any one or more GSVs to a list, a spreadsheet or file with pre-determined health metrics. In certain embodiments, any of the health metrics are pre-determined for each nucleotide in the genome and accessible through a software program, on-line service or portal.

Systems

[00115] In certain embodiments, described herein, are systems to identify the relative genomic health risk of a genomic sequence variant of an individual comprising: a DNA sequence for the individual; a system to determine at least one genomic sequence variant in the DNA sequence of the individual; wherein the genomic sequence variant is a difference of at least one nucleotide in the individual when compared to a corresponding position in a reference genome; and a system to compare the at least one genomic sequence variant of the individual to a tolerability score at a corresponding position within x-nucleotides of a genetic element, wherein the tolerability score comprises a function of a nucleotide variation score and an allele proportion score, wherein the nucleotide variation score is the variance observed in a plurality of genomes at the

corresponding position, and the allele proportion score is the proportion of genomic variants that exceeds an incidence of 0.0001 in the plurality of genomes at the corresponding position.

[00116] In certain embodiments, described herein, are systems to identify the relative genomic health risk of a genomic sequence variant of an individual comprising: a DNA sequence for the individual; a system to determine at least one genomic sequence variant in the DNA sequence of the individual; wherein the genomic sequence variant is a difference of at least one nucleotide in the individual when compared to a corresponding position in a reference genome in a unique sequence of n nucleotides in length; and a system to determine an ^-variant score for the at least one genomic sequence variant, wherein the score is comprises a function of a count score and an allele frequency score, wherein the count score is the ratio of the number of times any genomic sequence variant occurs in a unique sequence of ^-nucleotides in length in the plurality of genomes to the number of times that the unique sequence of ^-nucleotides in length occurs in the reference genome, and the allele frequency score is the frequency of the proportion of genomic sequence variants that are fixed in the population, at an allele frequency greater than 0.0001 in the plurality of genomes.

[00117] In certain embodiments, described herein, are systems to identify the relative genomic health risk of a genomic sequence variant of an individual comprising: a DNA sequence for the individual; a system to determine at least one genomic sequence variant in a DNA sequence of the individual; wherein the genomic sequence variant is a difference of at least one nucleotide in the individual when compared to a corresponding position in a reference genome; and a system to determine if the at least one genomic sequence variant occurs within a region with a low context dependent tolerance score, wherein the context dependent tolerance score comprises a function of an observed context dependent tolerance score and an expected context dependent tolerance score, wherein the expected context dependent tolerance score is the overall probability to vary of a unique sequence of ^-nucleotides in length in a certain region of x nucleotides in length actually observed and fixed in a plurality of genomes, and the observed context dependent tolerance score is a number of genomic sequence variants in a certain region of x nucleotides in length actually observed in the plurality of genomes.

[00118] In certain embodiments, described herein, are systems to identify the relative genomic health risk of a genomic sequence variant of an individual comprising: a DNA sequence for the individual; a system to determine at least one genomic sequence variant in a DNA sequence of the individual; wherein the genomic sequence variant is a difference of at least one nucleotide in the individual when compared to a corresponding position in a reference genome; a system to determine if the at least one genomic sequence variant causes an amino acid variant in an expressed protein, wherein the amino acid variant is a difference of at least one amino acid when compared to a reference genome; and a system to compare the amino acid variant to a protein tolerability score at a corresponding position within a defined protein class, wherein the protein tolerability score comprises a diversity score, missense score, and a protein allele frequency score, wherein the diversity score is a normalized diversity metric, the missense score is the variance observed in a plurality of genomes at the corresponding position which leads to an amino acid mutation, and the protein allele frequency score is the proportion of genomic variants that leads to an amino acid variant that exceeds an incidence of 0.0001 in the plurality of genomes at the corresponding position.

EXAMPLES

[00119] The following examples are illustrative and not meant to limit this disclosure in any way.

High Quality sequencing of 10,000 genomes

[00120] In an effort to evaluate the capabilities of whole human genome sequencing on the HiseqX platform, we first measured accuracy and generated quality standards by replica analyses of the reference genome NA12878 from the CEPH Utah reference collection (also known as "Genome-In-A-Bottle", GiaB). We then assessed these quality standards across 10,545 human genomes sequenced to high depth. This allowed for the development of a reliable representation of human single nucleotide variation, and the reporting of clinically relevant single nucleotide variants (SNV) using new high throughput sequencing technology.

[00121] We first assessed the extent of genome coverage and representation using the data from 325 technical replicates of NA12878 at different depth of read coverage. We evaluated the accuracy and precision of the laboratory and computational processes to define quality metrics that might be applied to other samples to ensure consistent data quality. At the target mean coverage of 30x, 95% of the NA12878 genome is covered at least at lOx. In contrast, Figure 6A shows that at a target mean coverage of 7x used by several genome projects, only 23% of NA12878 is sequenced at an effective lOx.

[00122] We next assessed reproducibility on variant calling for the whole genome by restricting the analysis to a set of 200 samples of NA12878 that were sequenced at a mean coverage of 30x to 40x. Due to manufacturer's changes in clustering reagents, we analyzed 100 samples prepared with vl (original kit) and 100 with v2. In Figure 6B, after applying quality filters, passing genotypes (i.e., those with a PASS call in the variant call format [VCF] file) were compared for consistency. For v2 chemistry, 2.51 billion positions passed, and were called with 100% reproducibility in all replicates. Similarly, 2.44 billion positions passed for vl . An additional 210 Mb of genome positions yielded passing reproducible genotypes in more than 90% of samples for v2 chemistry and 258 Mb for vl chemistry. Only 184 Mb of genome positions were sequenced with lower reproducibility (<90%). The analysis of 100 unrelated genomes (25 individuals for each of the three main populations, African, Asian, European, and 25 admixed individuals) confirmed the consistency of calls across the genome.

[00123] The canonical NA12878 Genome-In-A-Bottle call set (GiaB v2.19) defines a set of high confidence regions that corresponds to approximately 70% of the total genome. The data for this GiaB high confidence region are derived from 11 technologies: BioNano Genomics, Complete Genomics, Ion Proton, Oxford Nanopore, Pacific Biosciences, SOLiD, 10X Genomics GemCode WGS, and Illumina paired-end, mate-pair, and synthetic long reads. Regions of low complexity (e.g., centromeres, telomeres and repetitive regions) as well as other regions that have proven challenging for sequencing, alignment and variant calling methods are excluded from the GiaB high confidence region. The above analysis of reproducibility addressed the whole genome of NA12878 - both in the GiaB high confidence region, and beyond those boundaries. We thus used the reproducibility metrics to define regions within GiaB with high (>90%) versus low (<90%) reproducibility at each position. The reproducibility metrics include the concordance in calls and missingness (defined in this disclosure as a measure of no-PASS calls). Figure 6C shows that a precise assessment of missingness is achieved by using a genomic variant call format file gVCF that informs every position in the genome regardless of whether a variant was identified at any given site or not. A total of 2,157 Mb (97.3%) of the GiaB high confidence region could be sequenced with high reproducibility, while 59 Mb (2.7%) were classified as less reliable. False positive, false negative and missingness rates were considerably lower in the GiaB region sequenced with high reproducibility. This suggests that, by defining high reproducibility sites, the false discovery rate is kept very low (FDR = 0.0025, or 0.25%). Other relevant metrics included a Precision of 0.998, Recall of 0.980 and a F- measure of 0.989. Overall, these first analyses indicate that the current technology and sequencing conditions generate highly accurate sequence data over a large proportion of the genome.

Defining high confidence regions for analysis

[00124] We next defined an extended confidence region (ECR) that includes the high confidence GiaB regions and the highly reproducible regions extending beyond the boundaries of GiaB. We also defined a low confidence region to include the regions within and beyond the boundaries of GiaB that could not be sequenced reliably with the technology in use. Figures 7A and 7B illustrate the noise we observed outside of the GiaB regions, both in terms of spurious variant calls and of apparent conservation. Of 3,088 Mb of sequence (autosomal, X- and Y- chromosomes), in Figure 7C the overlap of GiaB high confidence and highly reproducible regions represented 69.8% of the analyzed positions. Figure 7C shows the non-GiaB regions with high variant call reproducibility covered an additional 14.1% of the genome. Therefore, the newly defined ECR encompasses 83.9% of the human genome, and it includes 91.5% of the human exome sequence (Gencode, 96 Mb), which is consistent with recent reports on coverage of the human exome in whole genome analyses. We also examined the relevance for clinical variant calls: 28,831 of 30,288 (95.2%) unique ClinVar and HGMD pathogenic variant positions are found in the ECR.

Creating metaprofiles that capture human variation

[00125] The volume of data presented here provides unprecedented detail on the pattern of sequence conservation and SNVs across the human genome. In Figure 8A, we compared the rates of diversity in protein-coding, RNA coding, and regulatory elements. All protein-coding elements are more conserved than intergenic regions; as previously reported, alternative exons are the least variable. Alternative introns of IncRNAs are the most conserved and snoRNA the most variable of RNA coding elements. Figure 8A shows that among the analyzed DNA regulatory elements, repressed chromatin are the most conserved, and transcription start site loci are the least conserved.

[00126] In order to explore the pattern of variation in the human genome in depth, we built "SNV metaprofiles" by collapsing all members of a family of genomic elements into a single alignment. Metaprofiles of protein-coding genes used GENCODE annotated TSS (n=88,046), start codons (n=21, 147), splice donor and acceptor sites (n=137,079 and 133,702, respectively), stop codons (n=37,742) and polyadenylation sites (n=88,103). Figure 8B shows that for each nucleotide aligned against these landmark positions, all of the genomes in this dataset (n=10,545) were used to generate a precise representation of the pattern of conservation, and allele spectra. The pattern is built by incorporating up to 1.4 billion data points (number of aligned elements x 10,545 samples) per genomic position. For example, Figure 8B shows the analysis captures the decrease in variant allele frequency in exons, with the maximum drop occurring at the splice donor site. In addition, the metaprofiles reveal emerging patterns, including with great precision the periodicity of conservation in coding regions due to the degeneracy of the third nucleotide in the codon in every exon window.

[00127] A second example of functional inference from patterns of variation is provided in

Figure 8C. Here we highlight the unique SNV metaprofiles at transcription factor binding sites. For this analysis, we use the binding site core motifs for landmarking. Figure 8C shows metaprofile identify signatures that include both variation-intolerant and hyper-tolerant positions at the binding site. Positions that do not tolerate human variation can be interpreted as essential and possibly linked to embryonic lethality. While the identification of conserved, intolerant sites is expected, the biology behind unique hypertolerant positions at those sites remains to be investigated. Metaprofiles also register positions and domains that, while tolerant to rare variation, show limited possibility for fixation (allele frequencies are kept extremely low). We speculate that rare human variants in such domains carry a greater fitness cost, associate with greater phenotypic consequences and can be prioritized for clinical assessment.

Example validation of tolerability score for predicting harmful genomic sequence variants

[00128] To assess the value of a tolerability score for scoring of functional severity of GSV, we established a tolerance score Figure 9A that summarizes the rates and frequency of variation at a given position and for a given landmark. Using this approach, Figure 9B illustrates the accumulation of pathogenic variant calls at sites with the lowest metaprofile tolerance scores. To formalize this analysis, Figure 9C shows the tolerance score at 1,200 positions aligned to particular coding region landmarks: 100 positions upstream and downstream of the TSS, start codon, splice donor and acceptor, stop codon and polyadenylation site. At the lowest tolerance score, we observed up to 6-fold enrichment for pathogenic variants.

[00129] However, the assignment of pathogenicity or functional severity can be significantly biased by ascertainment (e.g., "it is at a splice site, it should then be a pathogenic variant"). In addition, variants are still observed at sites with very low metaprofile tolerance scores. In Figure 9D, to understand the characteristics of genes that tolerate variants at those privileged sites we used an orthogonal assessment of gene essentiality. See Bartha et al., The Characteristics of Heterozygous Protein Truncating Variants in the Human Genome. PLoS Comput Biol 11, el004647 (2015). The set of essential genes includes highly conserved genes that have fewer paralogs, and are part of larger protein complexes. Essential genes also display a higher probability of CRISPR Cas9 editing compromising cell viability, and knockouts in the mouse model are associated with increased mortality. Figures 9A-9D illustrate the concept that genes that tolerate variation at sites with low tolerance scores are less essential.

[00130] Figure 10A shows that a large number of genomes, and a broad coverage of human populations served to describe the rate of newly observed, unshared SNVs for each additional sequenced genome. We restricted the analysis to the 8, 137 unrelated individuals among the 10,545 genomes - as defined by an estimated kinship coefficient to exclude first degree relatives. In the absence of an earlier saturation of sites due to biological and fitness constrains, there is an expectation of 500 million variants identified after sequencing the genomes of 100,000 individuals.

[00131] In Figure 10B, unrelated individuals were assigned to five superpopulations as described by The 1000 Genomes Project, or to an admixed or "other" population group on the basis of genetic ancestry (EUR, n=5,596; AFR, n=962; SAS, n=62; EAS, n=148; AMR, n=12; ADMIX, n=l,288; other, n=57). Figure 10B shows that each subsequently sequenced genome contributes on average 8,579 novel variants. For the three populations represented by >900 individuals, the number of newly observed unshared variants per sample varied from 7,214 in Europeans and 10,978 in admixed, to 13,530 in individuals of African ancestry This reflects the current understanding of Africa as the most genetically diverse region in the world. Of the 150 million SNVs observed in the ECR, 82 million (54.7%) have not been reported in dbSNP of the National Center for Biotechnology Information.

[00132] Much of the non-reference sequence is shared with hominins. In Figure IOC, the unmapped contigs were compared to Neanderthal and Denisovan sequencing reads that did not map to hg38. There were 809 contigs (0.96 Mb) covered by Neanderthal reads and 999 contigs (1.18 Mb) covered by Denisovan reads. In addition, we identified 608 contigs (0.82 Mb) that are not in hg38 primary assembly, but in the "alt" sequences or subsequent patches. Those contigs are not included in the above estimates of non-reference sequence. Collectively, we observed over 3Mb of sequence that is not represented in the main hg38 build and "alt" sequences. CDTS defines pathogenic sequence variance better than methods that use inter species conservation

[00133] Traditionally, conservation in the genome has been identified through the comparison among species: if a segment of genome is conserved across many species, then it is assumed that it is important. Therefore, to compare the conserved human genomics regions as defined by a context dependent tolerability score (CDTS) with findings in the larger context of interspecies conservation, we assessed the extent of overlap of conserved regions assessed with CDTS (i.e., context-dependent conservation in the current human population) and Genomic Evolutionary Rate Profiling (GERP) across 34 mammalian species (i.e., interspecies conservation). From the 1 ^st to 10 ^th percentile levels, the overlap between both scores is limited and heavily enriched for protein-coding regions. Figures 11A and 11B show results from these experiments. Figure 11A shows the composition in the first percentile regions by CDTS (the bar labelled as "CTDS 1 ^st "), GERP ("GERP 1 ^st ") and the overlap region of CDTS and GERP ("Intersection"), as defined by functional genomic elements. The data shows that there is little overlap between highly conserved regions as defined by CDTS and GERP, outside of protein-coding exons. Figures llC and 11D show that the overall length of the genome that falls into the 1 ^st percentile by CDTS and GERD overwhelming indicates that there is very little overlap between the two methods in identifying highly conserved sequences outside of protein-coding exons. Figure 11C shows an analysis as in Figure 11A except the 1 ^st to the 10 ^th percentile is analyzed. Figure 11D shows an analysis as in Figure 11B except the 1 ^st to the 10 ^th percentile is analyzed. Surprisingly, these results suggest that the least variable non-coding regions in human populations are primarily revealed by CDTS and not by an interspecies evolutionary relationship.

Genomes

[00134] The analysis used deep sequence genome data of 11,257 individuals. Analysis was limited to the high confidence region of the genome (as defined in Telenti, A. et al. "Deep sequencing of 10,000 human genomes," Proc Natl Acad Sci USA) a region covering

approximately 84% of the genome and closely overlapping with the high confidence region as described in the most recent release of Genome in a Bottle (GiaB v3.2).

Metaprofiles

[00135] Metaprofiles comprise the massive alignment of elements of the same nature in the genome. These genomic elements can be chosen based on their structure (e.g., exonic, intronic, intergenic, etc.), function (e.g., transcription factor binding sites, protein domains, etc.) or sequence composition (&-mers). Genetic diversity is assessed at each nucleotide position of the alignment of genomic elements, by monitoring both the occurrence of variation in the population (reported as a binary - presence or absence) and the allelic frequency. More specifically, 3 metrics are computed at each position: (i) the percent of elements with SNVs,(ii) the percent of SNVs with an allelic frequency higher than 0.001 or 0.0001, and (iii) the product of both scores. Each score is calculated using between 10 ⁶ and 10 ¹⁰ values, a value provided by the number of elements present in the genome and aligned multiplied by the number of genomes sequenced; therefore, the metaprofile strategy massively increases the power to compute variation rate at nucleotide resolution with high precision. A priori knowledge of genomic landmarks is required for constructing metaprofiles based on similarity in structure or function. In order to remove potential biases through the use of this a priori knowledge, we developed a strategy to construct metaprofiles based on all possible heptameric sequences found in the genome (4 ⁷ =16384) and scored the middle nucleotide for each of these sequences as described above. As every nucleotide in the genome is part of an heptamer, every single position can be attributed to the corresponding genome-wide computed scores. Scores are computed separately for autosomes and chromosome X. To account for the difference in effective population size over history for chromosome X, the allelic frequency threshold is adjusted by a factor of 0.75. In a certain aspect, indels are not used to compute the score. When testing the score on smaller study populations the allelic frequency threshold was adjusted to retain only non-singleton positions.

Expected versus observed

[00136] The variation rates computed through heptamer metaprofiles reflect the chemical propensity of a nucleotide to vary depending on its surrounding context and can be interpreted as an expectation of variation. We rationalized that functional regions would vary significantly less than they would be expected to, as assessed genome-wide through the heptamer tolerance score. To evaluate the departure from expectation, we compared the observed and expected tolerance score obtained in defined genomic regions.

[00137] The observed regional tolerance score is the number of SNVs present at an allelic frequency higher than 0.001 in the studied population in a defined region. The expected regional tolerance score is the sum of the heptamer tolerance scores in the same region.

[00138] The difference between the observed and expected scores is further referred to as context-dependent tolerance score (CDTS). The regions are then ranked based on their CDTS. The regions with the lowest rank are the regions with the lowest context-dependent tolerance to variability and the regions with the highest rank are the regions with the highest context- dependent tolerance to variability. Genomic regions are ranked based on their CDTS. Regions with the lowest rank (1 ^st percentile) have the lowest context-dependent tolerance to variation. Regions with the highest rank (100 ^th percentile) have the highest context-dependent tolerance to variation.

Region definition and annotation

[00139] To avoid any use of a priori knowledge and any biases due to the differing size of the regions (i.e., more power to detect difference between observation and expectation in longer elements), the genome was chopped irrespective of genomic annotations into sliding windows of the same size. The window size was 1050 bp sliding every 50 bp and the calculated CDTS across the 1050 bp window was attributed to the middle 50 bp bin. Only regions with at least 90% of the nucleotides in the 1050 bp window present in high confidence regions were used. To evaluate the element distribution across those size defined windows, we built a new annotation model by combining sources of annotation from GenCode (v.23) and ENCODE (annotated features and multicell regulatory elements, Ensembl v84 Regulatory Build). In order to avoid conflicting and overlapping annotations from the two different sources and thereby use the score of the same region multiple times, we prioritized element annotation as follows, such that only the highest order element would be used: exonic, then multicell, then intronic and then annotated features. We assessed the element composition of the different percentiles, using the above mentioned combined GenCode/ENCODE annotation, by computing the number of nucleotides of an element in each percentile. The following categories were used: "Exon - protein coding ", referring to nucleotides in exonic regions contained in protein-coding genes (including UTR) as annotated in GenCode; "Exon - non-coding", referring to nucleotides in exonic regions contained in non-coding RNAs (e.g., snRNA, snoRNA, lincRNA, etc.) as annotated in GenCode; "Intron", referring to nucleotides in intronic regions contained in either protein-coding or non- coding genes as annotated in GenCode; "Promoter", "Promoter Flanking" and "Enhancer", referring to the nucleotides contained in the respective elements as annotated in ENCODE multicell regulatory elements; "H3K9me3" and "H3K27me3", referring to the nucleotides overlapping with (and only) the respective elements as annotated in ENCODE annotated features; "Multiple Histone marks", referring to the nucleotides overlapping with a combination of histone marks, as annotated in ENCODE annotated features; "Others", referring to the remaining nucleotides with ENCODE annotated features that did not cover a substantial part of the genome individually, which notably encompasses transcription factor binding sites as well as other regulatory element combinations (e.g., nucleotides annotated as both Promoter and

Enhancer); and "Unannotated", referring to nucleotides in regions that had no annotated features in either GenCode or ENCODE.

Essentiality and CDTS coordination

[00140] We used gene essentiality (pLI score from ExAC ² ) as an orthogonal proxy for functionality to assess whether genomic bins, annotated with the same genomic element, have different biological importance depending on their CDTS ranking. Each genomic bin present within lOkb of a gene is attributed the essentiality score of its closest or overlapping gene, with the exception of genomic bins annotated as "Promoters," that have the mandatory constraint of being upstream of the closest gene. The median essentiality score is then assessed per genomic element annotation and per percentile slice. To assess distal CDTS coordination, we used an external chromatin loop dataset. The loop and anchor coordinates were extracted from previous Hi-C experiment. The median CDTS percentile is computed for every anchor region. To pair distal enhancers with their hypothetically associated genes, for each loop we extracted the genes and enhancers that were the closest to both loop-anchor points. We then kept only meaningful pairs, where an enhancer was annotated in the upstream anchor and a gene in the downstream anchor, or vice versa. In addition, the 5 prime end of the gene had to be facing the loop. A maximum of one pair per gene was retained; in the cases of several possible pairs, the pair was kept that had the smallest total distance between the enhancer to the gene after subtracting the loop size. We computed the median CDTS of the enhancers associated in such a distal gene- enhancer pair and compared it to the essentiality score of the associated gene.

Interspecies conservation

[00141] We used Genomic Evolutionary Rate Profiling (GERP++) to capture the interspecies conservation. GERP++ provides conservation scores through the quantification of position specific constraint in multiple species alignments. We calculated and attributed the mean GERP scores to the same set of 50 bp bins as mentioned in the section "Region definition and annotation." Bins were ranked based on the GERP score from the most (percentile 1) to the least conserved (percentile 100). Bins without GERP score, due to insufficient multiple species alignments in the region, were not considered in the ranking process.

CDTS reveals a previously unknown additional novel level of conservation in the human genome

[00142] A surprising result emerges from the mapping of all human conserved regions as represented by CDTS. The genome structure that is revealed is one of coordination of genes with the respective regulatory regions. For example, a very important gene ("essential gene") will use a very conserved promoter, cis enhancer, distal regulatory elements and other regulatory signals. This new data provides enhanced ability to pair the genes with the generally under- or un-recognized regulatory units, which is key to understanding function in health and disease. This also allows for using CDTS to identify pathogenic variants, and to build a targeted sequencing and genotyping array for diagnostics. As expected, Figure 12A shows exons in essential genes were enriched in the conserved regions of the genome as defined by CDTS. We first assigned the essentiality score of the gene to the corresponding upstream promoter. This analysis confirmed that promoters in the conserved part of the genome associate with essential genes. We then observed that cis enhancer regions also shared sequence conservation with genes (within lOkb) that were putatively regulated by those elements as shown in Figure 12 A. Next, we searched for evidence that functional constraints could be shared over greater distances. Topological associated domains were defined using information from Hi-C and 3D genome structure data. We observed that the regions brought together through these long-distance interactions shared similar levels of conservation as reflected by the CDTS values. Figure 12B shows that this this coordination was maintained at distances as long as one megabase. In addition, and despite the complexity to associate distant regulatory regions with a particular gene, Figure 12C shows that we observed a correlation between conservation of the distal enhancer, and the essentiality of the putative target gene. Finally, we assessed other cis non- coding elements (e.g., chromatin histone marks, transcription factor binding sites), and unannotated and intronic regions, and consistently identified a pattern of correlation between conservation scores of non-coding or regulatory regions with gene essentiality. Strikingly,

Figure 12A confirms that even genomic elements that were depleted in the most conserved part of the genome (e.g., H3K9me3 and H3K27me3) are associated with essential genes when present in the lower CDTS percentiles. More generally, regions of low CDTS appear clustered in the genome. Overall, the data support the concept of conserved and coordinated regulatory and coding units in the genome over large genome distances.

Distribution of pathogenic variants across the genome

[00143] The description of the conserved genome raises the issue of its relevance to human disease. We assessed whether CDTS ranking was a good proxy to score functional constraint and the consequences of mutations. For this purpose, we investigated the distribution of annotated pathogenic variants across the genome. Figure 13A shows that the pattern of enrichment was marked for pathogenic variants in the 1 ^st versus the 100 ^th percentile for both protein-coding (73-fold) and, more importantly, for non-coding (79-fold) pathogenic variants. Of note, the enrichment of non-coding pathogenic variants is even more striking after accounting for the size of the non-coding territory covered in each percentile slice and reaches > 100-fold enrichment. To confirm these findings, we further investigated 550 manually curated non-coding variants associated with 118 Mendelian disorders. We confirmed that Mendelian non-coding variants are highly enriched in the regions with the lowest CDTS values as shown in Figure 13B. Table 1 lists the 1,000 lowest percentile (most conserved) non protein-coding variants by genomic position as defined by CDTS. Table 2 lists the lowest percentile (most conserved) non protein-coding known S Ps by genomic position as defined by CDTS.

Pathogenic variants

We assessed the distribution of known annotated pathogenic variants, defined as either HGMD high DM 14 (Version: HGMD 2016 R1) or ClinVar variants consistently annotated as pathogenic or likely pathogenic and with at least 1 entry with star 1 or more 15, 16 (Version: ClinVarFullRelease_2016-07.xml.gz) for a total N=130,767, by counting the number of variants present in each percentile of the genome. For variants in indel regions, the left most coordinate was used to establish in which genomic bin they fell. Pathogenic variants with conflicting annotations were removed, defined here as variants having a high DM in HGMD and a consistent annotation of benign or likely benign with at least 1 entry being star 1 or more in ClinVar. The non-coding variants associated with Mendelian traits were extracted from ClinVar (copy number variants were excluded from analysis) and manually curated with a filter of >5bp from any splice acceptor or splice donor site, and additional variants were collected by literature review 17-20.

CDTS identifies pathological variants

[00144] We explored how CDTS compared to other functional predictive scores used to prioritize variants, such as CADD and Eigen. We focused on the performance of these metrics on the non-coding genome. The combination of the three metrics provides the best detection, while the three metrics used alone provide similar ranges of detection as shown in Figure 14A. As shown in Figure 14B shows that CDTS is the functional predictive score that has the highest fraction of specific variant detection at any percentile threshold (barplot) providing high complementarity to the other metrics, while Eigen and CADD capture more redundant information (Venn diagrams). In addition, CDTS is the functional predictive score that detects the highest number of pathogenic variants, as the scores are computed for the whole genome, including sex chromosomes, and can be used for both SNVs and indels. Overall, CDTS requires no prior knowledge such as annotation or training sets, and captures a very specific set of pathogenic variants that are not detected by other metrics. Thus, CDTS complements other functional predictive scores in the analysis of the non-coding genome. Table 3 lists genomic positions that fall within the lowest 1 ^st percentile (most conserved) as defined by CDTS, and are unique to the CDTS method. Table 4 lists known SNPS that fall within the lowest 1 ^st (most conserved) percentile as defined by CDTS, and are unique to the CDTS method.

Functional predictive scores

[00145] The CDTS metric was compared to the most widely used metrics for variant prioritization: CADD (Kircher, M. et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46, 310-5 (2014)) and Eigen (lonita-Laza, I,

McCallum, K., Xu, B. & Buxbaum, J.D. A spectral approach integrating functional genomic annotations for coding and non-coding variants. Nat Genet 48, 214-20 (2016)). A "control" set of variants relative to the previously defined pathogenic variants was created using variants from dbSNP (June 2015 release). A control variant was defined as having the "COMMON" and

"G5A" tag (>5% minor allele frequency in each population and all populations overall) and, similar to the tested pathogenic variant set, not be present in an exonic region and appear more than 5bp from any splice site. The remaining working set of non-coding pathogenic and control variants were ranked according to their CDTS, CADD or Eigen non-coding scores and the ranking was normalized from 0 to 100 (for CADD and Eigen, the PHRED scores were converted into probabilities before this step, so that for all metrics the lower the ranking the more likely pathogenic a variant would be). To compare the different metrics, the precision

(TP/(TP+FP)) was computed at each step of the new ranking. TP are the true positives, in this case the number of pathogenic variants with a ranking <threshold, and FP are the false positives, in this case the number of control variants with rank <threshold; where threshold can be any step in the new ranking (from 0 to 100). The precision was further normalized by the general prevalence of pathogenic variant in the set studied (∑ pathogenic/^pathogenic+I ontrol)). This step was done in order to account for the fact that not all variants were scored by the other metrics (e.g., no scores on chromosome X for Eigen, conversion conflicts from hgl9 to hg38, not all indel have a CADD score, etc.). The prevalence normalized precision provides the enrichment of a metric pathogenic variant detection compared to random.

CDTS identifies unique pathological variants compared to other metrics for determining pathogenicity

[00146] We explored how CDTS compared to other functional predictive scores used to prioritize variants in the non-coding genome, CDTS, Eigen, CADD, DeepSEA, GERP, funseq2, and LINSIGHT. To avoid the contribution of pathogenic variants in the proximity of exons, we focused the analysis to the stringent set of 1,369 non-coding pathogenic variants that were further than 10 bp from any splice site. Eigen and CDTS had the best performance of the metrics as represented by ROC curves as sown in Figure 15A. Of the set of 1,369 non-coding

pathogenic variants, 713 were identified by at least one of the metrics as being in their top 1st percentile score as sown in Figure 15B. CDTS captures the highest proportion of variants only detected by a single metric (Figure 15B). Other metrics capture more redundant information because they were developed or trained on similar datasets. In contrast, CDTS requires no prior knowledge such as annotation or training sets, and thus captures a very specific set of pathogenic variants.

Methods

[00147] The CDTS metric was compared to other metrics used for variant prioritization: CADD, Eigen, GERP, DeepSEA, LINSIGHT and FunSeq2. A control set of variants relative to the previously defined pathogenic variants (N=l,369, detailed in the above paragraph) was created using variants from dbS P ³³ (June 2015 release). The control variants were defined as having the "COMMON" and "G5A" tag (>5% minor allele frequency in each population and all populations overall, as well as in our own study population), being in high confidence region ¹ and, similar to the tested pathogenic variant set, not be present in an exonic region and more than 10 bp from any splice site. The remaining working set of non-coding pathogenic and control variants were ranked according to their CDTS, CADD, Eigen, GERP, DeepSEA,

LINSIGHT or FunSeq2 scores and the ranking was normalized from 0 to 100 (the direction of values of the scores were modified so that, for all metrics, the lower the rank would represent the pathogenic state. Of note, the CDTS ranking might differ slightly as only variant positions (control + pathogenic) are used here. To compare the different metrics, the true positive rate (TP/(TP+FN)) and false positive rate (FP/(FP+TN)) was computed at each step of the new ranking. TP are the true positives, in this case the number of pathogenic variants with a ranking <threshold; FP are the false positives, in this case the number of control variants with rank <threshold; FN are the false negatives, in this case the number of pathogenic variants with a ranking > threshold TN are the true negatives, in this case the number of control variants with rank > threshold, where threshold can be any step in the new ranking (from 0 to 100). Given the fact that the control set of variants (N>5mio) is order of magnitudes bigger than the pathogenic set (N=l,369), a false positive rate of 0.01 (threshold used in Fig. 15A for the zoom in view) corresponds approximately to the 1 ^st percentile of the data. Of note, not all variants were scored by all the metrics (e.g., no scores on chromosome X, conversion conflicts from hgl9 to hg38, indels are not scored by all metrics, not in high confidence region, etc.). The number of non- coding pathogenic variants scored per metric are the following: CDTS (N=l,226), Eigen (N= 1,000), CADD (N=l,283), DeepSEA (N= 1,324), LINSIGHT (N=l,350), GERP (N=l,354) and FunSeq2 (N=l,203).

CDTS identifies misidentified genomic features

[00148] This example shows how metaprofiles and heptamer content analysis identifies new genomic elements that were misannotated so far. In short, we investigated 3 sets of splice sites described in Figure 16A: (1) sites used only by the principal isoforms; (2) sites used by both principal (PI) and non-principal isoforms (NPI); and (3) sites used only by non principal isoforms We used CTDS tools to investigate whether the 3 groups behave differently (in reality represent different genomic elements)

[00149] Results: While the 2 first sets (present in the principal isoforms) behave similarly, the set of sites that are present only in non-principal isoforms do not show the characteristics of ex on-intron junctions in terms of tolerance to variation as assessed by metaprofiling (Figure 16B principal isoforms and Figure 16C non-principal isoforms). In addition, the 3'UTR of the non-principal isoform, as well as their intronic region adjacent to the splice donors seem to display a different heptameric content than the respective regions in principal isoforms.

Compared to other genomic features, the closest elements (in terms of heptamer content) to the 3'UTR of not-principal isoforms are long non-coding RNAs (IncRNAs). This could indicate that genome wide, there might be thousands of unannotated IncRNAs.

CDTS identifies novel pathogenic variants

[00150] We assessed 6 candidate genes (POMC, LEP, LEPR, SMI, MC4R, and PC SKI) that have previously been associated with early onset of obesity due to deficiency in the MC4R pathway, based on existing literature. To identify new pathogenic SNVs, we started by extracting all variants from a population of unrelated individuals (N=7794) that were found in the genes or vicinity (15kb upstream and downstream) as well as in distal regulatory elements, as assessed by Hi-C and promoter-capture Hi-C. The criteria for an SNV to be candidate were the following: (i) the minimum BMI of the individual(s) carrying the alternative allele must be >=35; (ii) when applicable, individual(s) homozygous for the alternative allele must have a median Body mass index (BMI) higher than the median BMI of individual(s) heterozygous for the alternative allele; (iii) the SNV must be present in the population at an allelic frequency lower than 1/100; finally, (iv) the SNV must be "likely functional" as assessed by either one or more of the following metrics: CDTS, percentile <=2; CADD, score >=15; Eigen or Non-coding Eigen, score >=15; GERP, score >=5; Linsight, score >=0.8. The remaining SNVs are kept as candidates.

[00151] Figure 17 illustrates candidate SNVs in MC4R gene and associated regulatory regions. The candidate variants associated with high BMI in the single exon gene, MC4R, are depicted as circles. The boxes represent genomic elements annotated in this genomic locus. The arrow indicates the transcription start site. Red colored circles are candidate variants that have previously been associated with high BMI (true positives) while yellow colored circles are candidate variants that are not known to be associated with high BMI (new candidates). Circles with a thicker edge weight indicate that the candidate variants are identified solely by CDTS. The coordinates indicate the distance (bp) between genomic elements. Reports 2enerated and delivered to health care professionals and/or consumers

[00152] Referring to Figure 18, in a particular embodiment, an exemplary digital processing device 1801 is programmed or otherwise configured to calculate and/or organize a plurality of tolerability scores, scores, context dependent tolerability scores, or protein tolerability score s. The device 1801 can regulate various aspects of calculating and delivering the health risk metrics of the present disclosure, such as, for example, calculating one or more context dependent variability scores. In this embodiment, the digital processing device 1801 includes a central processing unit (CPU, also "processor" and "computer processor" herein) 1805, which can be a single core or multi core processor, or a plurality of processors for parallel processing. The digital processing device 1801 also includes memory or memory location 1810 (e.g., random-access memory, read-only memory, flash memory), electronic storage unit 1815 (e.g., hard disk), communication interface 1820 (e.g., network adapter) for communicating with one or more other systems, and peripheral devices 1825, such as cache, other memory, data storage and/or electronic display adapters. The memory 1810, storage unit 1815, interface 1820 and peripheral devices 1825 are in communication with the CPU 1805 through a communication bus (solid lines), such as a motherboard. The storage unit 1815 can be a data storage unit (or data repository) for storing data. The digital processing device 1801 can be operatively coupled to a computer network ("network") 1830 with the aid of the communication interface 1820. The network 1830 can be the Internet, an internet and/or extranet, or an intranet and/or extranet that is in communication with the Internet. The network 1830 in some cases is a telecommunication and/or data network. The network 1830 can include one or more computer servers, which can enable distributed computing, such as cloud computing. The network 1830, in some cases with the aid of the device 1801, can implement a peer-to-peer network, which may enable devices coupled to the device 1801to behave as a client or a server. Reports can be delivered from for example a sequencing lab to a health care provider or consumer over the network 1830, or alternatively through the mail or a secure download site such as an FTP site.

[00153] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. 229431720 C A 3 48593536 C T

229431903 C A 3 48593697 c G

229431993 CCG CTT 3 48593699 G C

229432190 G T 3 48595346 G A

229432269 C T 3 48595347 G A

229432432 C T 3 49122703 C T

14953901 C A 3 49129836 T A

43105194 G A 3 49129838 C T

43114478 A G 3 49130730 TCTCA T

72007170 AGG ACC 3 49419255 C G

92639901 G A 3 49722971 C T

93796966 A G 3 49723475 G C

117545628 G T 3 52406909 T C

117545631 G A 3 52407318 T c

125789036 A C 3 52407398 C T

534210 A ACCT 3 128483288 G A

819906 G A 3 128486802 C T

6390917 G T 3 136327256 GTGAGGACC G

17407131 T c 3 169765118 G C

17407138 C T 3 169765159 G C

17407139 G T 3 184170317 A G

17442719 C A 3 184170318 G A

17442719 C T 3 193593410 G A

17476966 G c 4 1002162 G A

17544271 C A 4 1002163 T C

31800857 C G 4 1002265 G A

31800857 C T 4 1004011 G C

31810826 A T 4 1004259 G A

32428625 G T 4 88075456 A G

32434699 C T 4 102869188 G A

46899386 C T 4 110621370 C A

47332563 TA T 4 110621370 C G

47332564 A T 4 177442248 C CCCGCAT

47332565 C A 5 1294770 C T

47332565 C T 5 1416097 C T

47332703 c T 5 36975774 A G

47332704 T A 5 36975775 G A

47332705 G c 5 41870274 ACTTTAC A

47332705 G T 5 90653207 A G

47332813 C A 5 132557455 T A

47332813 C T 5 149960981 T C

47333189 C A 5 150378903 A G

47333189 C G 5 150378903 AG A

47333189 C T 5 150388089 G A 47333192 A c 5 173234749 C A

47333192 A G 5 177280562 CA C

47333552 C T 5 177402460 C T

47333552 CGCA C 5 180620170 CA c

CCAA CAAC CT

47333553 GC G 6 2948700 C T

47333555 A C 6 31860041 C G

47333556 C T 6 31860438 C T

47341986 C G 6 35512638 C T

47341990 c G 6 43045403 C G

47342157 c T 6 43576441 G C

47342158 T C 6 45422958 G A

47342162 G T 6 45422958 G C

47342573 C T 6 45546826 G C

47342574 T A 6 116877784 A G

47342575 c G 6 157174118 G C

47342576 A G 6 162727661 C A

47342577 c T 6 162727661 C T

47342745 c G 6 168441455 G T

47342745 c T 7 40134228 C T

47342804 CCAT C 7 44145281 C A

GCCC CGTG CTTC TGGA

A

47342828 A G 7 44145281 C G

47342936 C T 7 44145282 T C

47343019 A G 7 44145496 C A

47343020 C T 7 44145496 c G

47343158 C T 7 44145731 c G

47343264 T C 7 44147645 c A

47343281 c T 7 44147648 A T

47347030 c G 7 44147649 c G

47351507 T C 7 44147649 c T

47441822 c A 7 44147834 c A

47441923 T C 7 44147834 c T

62691423 T C 7 44147835 T A

62691424 G c 7 44147835 T C

64746809 C T 7 44147839 G T

64747221 C G 7 66082878 AG A

64754026 C A 7 66083175 G A

64755268 c T 7 74036585 G A

64755272 c G 7 74036585 G T 64755357 T A 7 74036586 T c

65532806 G A 7 74048502 G c

66849229 C T 7 74053160 C G

66870301 C T 7 74063229 G C

66871686 C A 7 74063309 G A

67519792 C A 7 94655985 C G

67611982 A C 7 94655989 C A

68039120 G c 7 94655989 C T

68039120 G T 7 117479846 G c

68043912 G A 7 117479869 G T

68043912 G c 7 117479930 G A

68049299 G A 7 120838776 C T

68049426 T C 7 130440932 A c

68049436 T A 7 150947880 T A

68049440 G A 7 150951442 A G

68049443 C T 7 150951447 C T

68049954 T c 7 150952424 C G

68049961 G A 7 150952424 c T

68050135 A C 7 150974709 A T

68050255 G A 7 150974710 c CCAT

68050255 G T 7 150974942 c T

72195749 T c 7 155806295 c T

72195749 T G 7 155806576 c T

72240199 C T 7 157005875 T C

72243787 C T 7 157006478 c T

77147796 A G 7 157006478 CCTGGGT c

77190017 C G 8 38413915 T c

77190019 GT G 8 38414028 G T

112086961 T G 8 38414558 C T

118340370 C T 8 38418375 T c

119085735 A G 8 41797691 C T

119101146 C T 8 60781432 T A

119101490 C T 8 60781432 T c

124739465 A G 8 60844862 A G

124739507 C G 8 60844862 A T

124739741 G A 8 89984520 C T

130208685 G A 8 89984522 T TA

6075330 C T 8 89984524 c T

6075333 A G 8 118110078 CACTT C

6075334 C T 8 118110083 A G

48980693 A G 8 118110084 C A

49022152 C G 8 118110084 C G

49022279 C A 8 118110084 c T

49022279 c G 9 6645244 c T 49022355 T C 9 34647078 T G

49022589 c A 9 34647086 c G

49026181 c T 9 34647259 G A

49027324 T c 9 34647490 A G

49027325 G c 9 35074217 C G

49042880 T c 9 35074217 C T

49046425 C A 9 35075755 c A

49050885 c T 9 35075755 c G

49053206 c A 9 35075957 c T

49053322 c T 9 35079242 c T

49054306 c T 9 35090061 c T

49054419 T c 9 37424831 CCCTTTCCCC CTT

49054527 c G 9 37424831 CCCTTTCCCC CTTT

49054527 c T 9 37424843 A G

49054753 T G 9 37430647 G A

51915223 A G 9 69035948 G A

51915501 G A 9 69035952 G C

51915505 G A 9 83971880 A AC

51915505 G T 9 95478049 C T

53321870 G A 9 97697119 A C

56042170 G A 9 126693743 CA C

56042170 G C 9 126693745 G A

56042170 G T 9 127502773 G A

57628264 T c 9 127819661 C G

57765296 C T 9 127819661 C T

57766006 C T 9 127819662 T C

57766845 A c 9 127824975 C A

65171119 G A 9 127824975 C G

76348161 C A 9 127824976 T A

110281908 G c 9 127824977 A C

110340652 ATTT A 9 127824981 G C

TAGA CCAA TCTG ACC

114398572 C A 9 127825226 C G

114398721 C A 9 127825229 A G

114398725 A G 9 127825229 A T

120978231 G C 9 127825358 C T

120994162 A G 9 127825359 T A

120994163 G A 9 127825693 A G

32315668 G A 9 127825694 C A

48303701 G A 9 127825861 c G

48303715 G A 9 127825862 T C

48303715 G T 9 130479801 G A 48303716 G A 9 130479801 G GT

48303720 T A 9 130479849 C T

48303720 T G 9 132921818 C T

48303721 G A 9 136199883 G C

48303724 G T 9 136515289 C T

48303763 G c X 630463 C A

48303764 G T X 631175 G A

48304050 G A X 644388 C T

48304050 G T X 8731829 C A

48304051 T G X 8731829 C G

50910141 G A X 13735348 T C

52011779 C T X 13735349 A G

99983141 T A X 17721439 A G

113110851 G A X 17721440 G A

113110851 G C X 18642157 C G

113110851 G T X 18642158 T C

113110855 G A X 18672012 C G

113110855 G T X 18672014 T TA

113113749 C G X 18672014 T TACCTTCA

113113750 A G X 18672015 A G

113148915 G A X 18672016 c A

24259703 C T X 18672016 c T

36518021 C T X 19354461 G A

36518022 T A X 19354489 AGGT A

36518022 T C X 20172745 C T

36518022 T G X 24726579 A G

36518029 G T X 25010259 C G

36518978 CACT C X 25015540 A G

T

36518980 C G X 37727634 A G

36518981 T C X 37727635 G A

36518984 c T X 38327335 C T

36662094 G T X 38327338 A c

49586052 G T X 38327339 C T

56804187 C CCTG X 40057322 C T

60648627 T A X 40062394 c A

73136191 C G X 40063072 c G

73136796 G A X 43973299 c T

74241181 G A X 43973302 A C

93787624 A G X 43973303 c T

94769660 C G X 46837203 G A

102928424 A G X 46837205 A G

102928425 G C X 46837205 A T

102929087 G A X 47179165 T C 102930400 C T X 48509957 GT G

102930503 C T X 48511936 G A

40405972 G T X 48512280 T A

43058441 T C X 48512311 G A

43058442 T C X 48512325 G A

43105937 C G X 48512588 G C

43105939 T TA X 48515715 A C

44711614 G T X 48515716 G c

72375719 C T X 48515888 A G

89649739 A G X 48520373 AGGGCTACGGC A

ATG

96334604 G A X 48520374 GGGCTACGGCA G

T

2048066 G C X 48684281 A G

2054295 G A X 48684282 G C

2054295 G T X 48684424 G A

2054441 G T X 48684425 T C

2079429 G A X 48685545 A C

2079429 G C X 48685546 G A

2086190 CAG C X 48685634 G A

2086192 G A X 48685634 G C

2092479 C G X 48685634 G GT

2277878 C T X 48685634 G T

2283456 G A X 48685636 A T

23641108 A C X 48688052 AG A

23641109 C G X 48688052 AGGCATGTCAG A

CCACGTGGG

28482199 C A X 48688053 G A

28482324 T A X 48688454 G A

28482472 c T X 48688455 T A

28936152 G T X 48688455 T C

30756589 GATC G X 48688455 T G

T

30980736 CAG C X 48689067 G A

31464391 C A X 49075135 C T

31489049 G C X 49075282 C G

67436156 C T X 49075360 TCA T

67942609 A G X 49075362 A G

68645751 G A X 49075363 C T

68738295 A C X 49075862 TCAC T

68738295 A G X 49076429 C A

71570677 A C X 49076525 C T

74774483 T A X 49076526 T G

7220198 G A X 49209761 T C

7223238 G A X 49210404 c T 7223240 G T X 49210588 A T

7223629 A G X 49211482 C G

7223731 G A X 49217752 CACTT C

8003851 G T X 49218454 C T

8004157 G A X 49218881 C G

8015845 A T X 49218942 CTG C

8110091 C A X 49230611 T C

15260645 C T X 49251768 G C

15260647 CACG c X 49253121 C T

CTG

15260649 C A X 49253122 T c

15260649 C G X 49253913 T c

15260649 C T X 49254068 C T

18143622 G A X 49255422 c G

18143797 G A X 49255424 c T

31206221 G A X 49255425 T C

31206238 A C X 49255426 CA C

31206238 A G X 49255510 C T

31206239 G T X 49255511 T G

31206372 G A X 53198975 A G

31206372 G T X 53405492 C A

31206373 T A X 53413140 T C

35107364 A G X 53548953 c T

37731832 T G X 68838616 G A

37731834 G C X 68839958 A G

41819452 G T X 68840240 A G

42422626 C A X 70033397 G GATTT

42695516 TGCA T X 70033529 G A

43104262 C G X 70033529 G T

43104262 C T X 70033530 T c

43104262 CT C X 70033532 AG A

43104263 T C X 70033533 G A

43104263 T G X 70033536 C A

43104264 G C X 70033536 C G

44006527 A G X 71107922 C T

44006527 A T X 74422068 G A

44007322 G C X 74524358 G C

44254490 TCTC TTTCAT X 77520784 T C

AC

44351362 G C X 77618986 G c

44351362 G T X 77618991 A T

44351461 G A X 78023559 T G

44351797 T C X 78031398 A C

44352339 A G X 78031398 A G 44374761 C G X 78031399 G A

44376303 c G X 80023047 C A

44380385 c T X 86047473 GCTACACAT GAAGC

44383489 T C X 86047479 C A

44384587 T A X 86047481 T TA

44384587 T C X 86047483 C T

44385284 G T X 101348532 C A

44385546 C G X 101348532 C T

44385550 C T X 103786463 A G

44385813 G T X 103786463 A T

44386003 GACT G X 108440207 G C

C

44386009 C T X 108440207 G T

50188902 C A X 108440210 A c

50188902 C T X 108440210 A G

50189011 C T X 108559154 G A

50189012 T c X 108695441 T C

50189164 T G X 108695442 A G

50189278 T C X 129553302 A G

50199553 T A X 136208453 A T

50199554 A G X 136208642 G A

50199554 ACC AGA X 149496345 C T

50199555 C A X 149496518 T A

50199555 C T X 149496518 T C

50199591 C G X 149505034 c G

50199591 C T X 149505034 CCTGTGGTCGA C

GTTGGCCTGCG

TTTCGGATCCG

AGGGCGACGCA

GACGGAGCTCA

GAACCAGACCC

AGCCAGAGAAG

GCCTCGGCCGG

TCCGGGGTGGC

GGCATTTCGGC

TTCGACGCGGC

CGCTTCAGAGC

GGCGGGGACAG

GCTGCAGCAGG

TGGCGCAGTTA

GCAGCCGCCGC

CGCAGCCACAG

AGACCTCCTCG

TCGGGAACCCA

TGAAGACTGCG

CAACACAGCCG

CCGCCCGGGCC

CGCAGGCCCGG

GCGCTGGCCGC AGCGCGAGTGC

GTCCGTGCGAC

TCTTCCCTGCGT

CCCTCCCCTCCG

GGGCGGGTTCT

50199592 T C X 153726167 G A

50201410 c G X 153726167 G T

50201410 c T X 153729227 C A

58692789 G T X 153729229 C G

61398941 G C X 153729230 A C

72122717 A C X 153729231 G A

72122717 A G X 153736256 T C

72122973 G A X 153736256 T G

75727507 T A X 153736343 A C

80108829 G A X 153736343 A G

22176953 A G X 153736514 G A

57586548 A C X 153737155 A G

57586549 C T X 153737252 G A

57586551 T G X 153863550 C G

57586552 A C X 153863550 C T

57586553 C A X 153864019 T C

57586553 c G X 153864320 A G

57586553 c T X 153864583 A T

57586871 c G X 153864584 CCT C

79988603 CGCG C X 153864705 c T

CGCG CTAG CGCC GTGC GTGC TGAC GGCA TGT

855795 G A X 153865087 c T

855795 G C X 153865838 T G

855795 G T X 153867554 c T

855797 A T X 153867795 c T

855799 G A X 153867799 c T

855799 G T X 153867911 c G

920280 AC A X 153868123 c T

1207204 G A X 153868197 c A

1207204 G T X 153868460 T A

1207205 T A X 153868559 A G

1220367 CCGC CTGCA X 153868559 A T

AGG C

1220369 G A X 153868836 c T

1220371 A G X 153868953 c T 1220371 AGG AC X 153868954 T A

1220372 G A X 153869664 c G

1220506 G A X 153869664 c T

1220506 G T X 153869802 c T

1220507 T A X 153870785 c T

1220579 A T X 153870961 c T

1220718 G A X 153870962 T G

1220718 G GT X 153871045 G A

1220718 G T X 153871052 C T

1220719 T C X 153872587 C G

1220722 G A X 153872591 C T

2250761 G A X 153872698 C T

3586494 G T X 153872699 T C

3586681 G A X 153971810 A G

6712507 C A X 154092175 GTTAC G

6712625 T A X 154351698 T C

7550431 T G X 154359234 CCACCTCCT C

11021968 G C X 154359244 A C

11105217 C T X 154361788 C T

11105218 A C X 154362416 A C

11105219 G A X 154362417 C G

11105219 G GC X 154364525 C T

11106688 G A X 154364721 T C

11106688 G T X 154364819 A C

11106689 T c X 154364959 T C

11107389 C G X 154365487 c A

11107390 A G X 154370872 c T

11107391 G A X 154379567 G T

11107391 GTGA G X 154379571 G c

CACT

C

11129671 G A X 154379795 G A

12648404 T C X 154379795 G T

12656947 A C X 154380231 A G

12656947 A T X 154380232 A G

12656948 C G X 154380233 G C

12806801 G C X 154412216 T G

12887264 A G X 154419541 A G

12887294 G A X 154419624 G A

12891400 G T X 154419624 G T

12891829 A T X 154419697 CTCACCAGGGA c

AAG

12896426 G A X 154419748 T c

12938404 C T X 154419751 G A

12938561 G c X 154420265 G T 15192300 T C X 154420656 A c

18599564 c T X 154420657 G A

34399554 A C X 154420657 G GA

35844099 TCA T X 154420736 G A

35844249 G c X 154420737 T A

35844317 A G X 154420901 A G

35846006 A C X 154420902 G T

40605654 T G X 154532464 T C

45363914 G T X 154534034 CCG CAT

49862180 C CTT X 154547746 G T

3575685 G A X 154765429 T C

3575889 G A X 154765439 C G

3575889 G T X 154863076 CACTT C

11785078 T c X 154863078 C G

26263480 G c X 154863080 T G

26263483 A T X 154863082 c A

26473569 T G X 154863082 c G

26483461 c A X 154863082 c T

27312679 c A X 154863228 c G

27312992 A G X 154863229 T C

27312993 c A X 154863230 G C

32064247 G A X 154863234 GGAGAGATTA G

32064247 G T X 154863241 T C

32127023 G A X 154901369 AC A

47403403 G C X 154901370 C T

61853858 C A X 154904525 C T

73927053 G A X 154904526 T A

96293315 C A X 154904526 T C

127422915 A T X 154904617 G A

127422942 G A X 154906414 A C

127422947 T G X 154906418 A C

127423006 T G X 154906419 C A

127423030 G A X 154906419 C G

127423033 G A X 154906419 c T

127423409 GTGA G X 154928568 T C

GA

151524617 C T X 154928568 T G

171435079 TTAG TAA X 154928569 A C

176093672 G A X 154928569 A G

178553911 TACC T X 154928570 c A

202377551 G T X 154928570 c T

202377552 T c X 155264073 c T

218661308 G T Y 2787733 c G

968139 C T 3082975 AC A

3229016 AGCA ACCGG

GACG CCGGC GGCA C

3229094 C T

3889730 T G

8132751 G A

10639957 T C

10641245 C G

10641246 T C

10641251 CGAT C

TTT

18057908 A C

18057941 A G

18058004 A G

18507416 A G

21708712 G A

23049806 G T

34955722 C T

46709745 G A

49936342 C A

49936344 C A

58909948 TA T

58909949 A G

26171136 G C

26171301 C T

34886842 C A

34886842 C T

19755950 C T

19756055 C T

19756212 A c

20431017 C A

20994728 GT G

29604113 G A

29604114 T C

29674835 G A

36284091 A T

41515536 G T

50526241 C T

50526244 A T

50526478 TGCG T

G

50526575 C T

50529339 C G

10142188 G A 10142188 G C

10142188 G T

10142189 TACG TCG

GGCC

C

10142194 G A

33097008 T TA

33097009 ACGC A

GCAA GCCG

33097010 C G

33114549 G C

33114550 C A

33114550 C G

36993664 G A

36993668 G C

Table 2

Table 3

66526640 C G X 20173150 A c

68049426 T C X 20195156 T c

68049436 T A X 24726579 A G

68049440 G A X 31209490 ATACGTAC AAT

68049443 C T X 31444636 A T

68049954 T c X 37782077 T G

119084613 G A X 48512280 T A

119084703 C T X 48512311 G A

119084764 G A X 48685939 T G

119085735 A G X 49255422 C G

119101146 C T X 50081633 A G

124739465 A G X 73852757 G C

124739741 G A X 77618991 A T

53425642 C T X 78011443 T TAT

AAG

56092977 A G X 78023559 T G

65963237 TGTTCCAG T X 80023047 c A

88068657 A T X 85900715 A C

110339493 A G X 86047473 GCTACACAT GAA

GC

120978231 G C X 101354702 GCAAA G

120978307 G A X 101354717 T C

120999262 G A X 101358705 AC AAG

TTT TCC CCT

52011547 T A X 101358707 G T

113118403 T C X 108570694 G A

73136191 C G X 108595489 T A

73136796 G A X 108601867 A G

102929087 G A X 108695042 T C

102930400 C T X 120470223 T G

102930503 C T X 129553302 A G

43038157 G c X 134377997 A G

43058441 T c X 134491434 A G

43058442 T c X 134494792 T A 1362442 G A X 139548353 CTTCT c

2093103 G T X 139548354 T G

2283456 G A X 139548355 T G

2308643 C T X 139548504 A G

28486663 C G X 150649703 T A

50779517 A G X 153865838 T G

67436156 C T X 153868197 c A

83914942 A G X 153871045 G A

1400568 C A X 154359234 CCACCTCCT C

3648823 T C X 154765429 T C

7223629 A G X 154863234 GGAGAGATTA G

31161118 T G X 154863241 T C

31206221 G A X 154902965 C T

31334559 A G X 154904122 T A

31337600 A G X 154904617 G A

41819452 G T X 154931683 ATGAGGAAGAA A

TAAGACTC

44386003 GACTC G X 154947686 A T

50189549 A C X 154961183 G T

50194840 C T X 154969566 A c

50199462 T C X 154987311 A G

61398941 G C X 154987316 A C

80108689 G A X 154987337 T C

22181443 C G X 154991304 c T

51078250 T C X 154999606 T c

57586871 C G X 154999611 A c

79988603 CGCGCGCGCTAGCGC C X 154999626 T A

CGTGCGTGCTGACGG CATGT

855556 C A Y 2787733 c G

920280 AC A

1220367 CCGCAGG C

T G C

A c

1399509 C A

12887294 G A

35844249 G C

38523211 C G

45364557 C T

69245213 A G

97733464 G A

108930249 ACAAAGGGGGGTGTT A

GTGG

127423006 T G

227303992 A G

10641251 CGATTTT C

18507416 A G

18546201 A G

21708712 G A

21709456 A C

49936342 C A

49936344 C A

63408542 G T

19755950 C T

19756055 C T

19756212 A c

10142194 G A

46858471 G A

48565083 C T

48575248 A c

48576781 A c

48592705 C T

122275793 A c

1001672 G A

42963153 A T

110618699 T c Table 4

Table 4. SM's l aned in (Ί ⁾ Ί S Γ cavnlilo non-coding r gions thai arc highly consmed I

(Ί) I S as annotated In ii niimliLT

rs778796405; rs8177982; rs376829288; rs4253196; rs750180293; rs757171524; rs727503201; rs397515893; rs587776699; rs397516083; rs201078659; rs750425291; rs558721552;

rs531105836; rs200782636; rs752197734; rs3093266; rs34086577; rsl99959804; rsl44077391; rs386834164; rs386834166; rsl89077405; rs746701685; rs386833721; rs376023420;

rs761146008; rs765390290; rs72648337; rs527398797; rs367567416; rs372651309;

rs200253809; rsl93922837; rs761737358; rsl 13994173; rs559854357; rsl 11951711;

rs371496308; rs368123079; rsl 18192239; rs41298629; rs536892777

Table 5 genomic regions in the most conserved 0.1%

Chromosome 1905050-905600;999480-1001030;1001440-1002080;1020370-102098 0;1032860-

1033410;1033830-1034400;1040180-1040880;1059000-1060030;1 069480-1070170;1116280-

1117110;1201130-1201690;1231370-1232040;1232950-1233700;1 246340-1246890;1273100-

1274150;1294220-1294810;1308590-1309290;1324250-1325330;1 354310-1355790;1374670-

1375560;1398930-1399560;1406600-1407620;1539370-1539930;1 540670-1541230;1574090-

1574680;1614810-1615890;1616160-1616730;1778710-1779300;1 908380-1909570;1918690-

1919650;2044640-2045370;2050500-2051050;2205360-2206100;2 226580-2227160;2228960-

2229860;2314470-2315210;2390980-2392160;2412020-2412940;2 525540-2526210;2529850-

2530730;2643080-2643790;2789250-2789940;2790000-2790640;3 063380-3064280;3067560-

3068540;3070630-3071330;3073230-3074230;3453960-3454570;3 624070-3625040;3652060-

3653210;3746520-3747080;3795670-3796570;4653750-4654530;4 656010-4656850;6205700-

6206820;6208470-6209730;6241770-6242940;6245090-6246130;6 393360-6393930;6418600-

6421050;6424700-6425390;6461150-6462060;6470390-6471970;6 490000-6490650;6601480-

6602880;6612690-6613400;6625020-6625570;6701410-6701960;7 770920-7771990;7954030-

7954580;8025590-8026620;8217180-8217790;8317520-8318580;8 877920-8878500;8878580-

8879370;9039160-9039720;9128310-9129090;9182030-9183560;9 198400-9199080;9539700-

9540420;9651630-9652690;9823030-9823600;9824280-9824870;9 996930-9998160; 10032400-

10033360;10210120-10210670;10430150-10430720;10472060-104 72900;10639380-

10640190;10795970-10796900;11059070-11059740;11273110-112 73680;11478820-

11479870;11501260-11502140; 11653970-11654640; 11663890-11664480;11691040-

11691600;11691730-11692360;12063160-12063950;12166720-121 67900;12229880-

12230670;12616790-12617520;13512840-13513400;13892790-138 93430;14598400-

14599120;14599150-14599700;15154380-15154950;15409220-154 09810;15410040-

15410670;15617120-15618130;15758840-15759590;15847330-158 47880;15848350-

15848910:15943200-15945400:16155350-16156440:16206610-162 07430:16227490- 16228040; 16367170 -16367800; 16440500 ^■ 16441250; 17011170-17011740; 17119110- 17119750; 18482250 -18483220; 18636150■18637100; 18643650-18644200; 18645140- 18645690; 18646330 -18646880; 18956960■18957540; 19209620-19210590; 19644770- 19645380; 19665340 -19666460; 19882220■19883310;20366080-20367100;20483970- 20484820;20552400 -20553580;20731440■20732010;20732040-20732960;20786040- 20787080;21176690 -21177480;21659050■21659910;21668640-21669970;21782460- 21783300;21814090 -21814930;22142060■22142610;22576290-22577050;22784330- 22785090;22953570· -22954200;23019210■23020240;23177430-23178300;23216830- 23217860;23424180 -23425000;23483490·■23484270;23530480-23531260;23568220- 23568770;23742880· -23744440;23778160■23779040;23799770-23801030;23867530- 23868400;24186980 -24187610;24642960■24643530;24745110-24745770;24847980- 24849060;24902080 -24902690;24929010■24929880;24931970-24932540;25246260- 25247430;25429830· -25430550;25543300·■25544340;25615980-25616560;25617760- 25618430;25922370· -25923340;26045660■26046670;26111670-26112580;26161410- 26162070;26169660 -26170340;26279780■26280550;26360410-26361060;26472580- 26473250;26500950· -26501530;26529910■26530550;26695330-26695890;26697040- 26697720;26863060 -26863910;26889390■26890440;26921570-26922130;26959860- 26960820;27006090 -27006650;27234170·■27235110;27321850-27322680;27349420- 27350670;27356580· -27357190;27360300·■27361290;27392080-27392890;27528100- 27528680;27549990 -27550660;27633950·■27634660;27659520-27660560;27726080- 27726640;27830640 -27831190;27959890■27960540;28259210-28260140;28369530- 28370080;28736370· -28737440;28812370■28813030;28862680-28863690;28887190- 28888100;28914210 -28914820;29121850■29123460;29124310-29124860;29181310- 29182310;29237050 -29237600;29238100■29238880;29259710-29260440;30718630- 30719180;31065450 -31066200;31238910■31239460;31588660-31589610;31617840- 31618500;31760450 -31761210;31762590■31763290;31772130-31772830;31788320- 31788900;32013500 -32014660;32072550■32073270;32179390-32180460;32240990- 32241710;32275060· -32275800;32291670·■32292680;32336110-32336820;32351470- 32352160;32361260 -32362580;32393960·■32394580;32464760-32465530;32650970- 32651680;32753630 -32754630;32885920·■32887010;32893020-32893660;33180950- 33181850;33350040 -33350630;34163620■34164530;34165040-34165600;34176870- 34177430;34781140 -34781930;34865490■34866730;34885100-34886440;34929770- 34930570;35268590 -35269330;35557610■35558530;35573050-35573940;35707580- 35708570;35882830· -35883710;35930540■35931660;36088500-36089640;36156300- 36156870;36178190 -36179100;36306130■36307020;36322120-36323920;36385480- 36386070;37032760· -37034090;37034520·■37035120;37514300-37514880;37633760- 37635210;37761300 -37762190;37793310■37793910;37808110-37808930;37931110- 37931820;38004660 -38005220;38047020·■38048080;38559430-38560040;38872670- 38873470;38991060■38991670;39105510■39106200;39408290-39 408850;39409080- 39409680;39639220■39640260;39671440■39672420;39683650-39 684250;39691900- 39692750;39900670■39901690;39954790■39955360;40096760-40 097570;40161180- 40162210;40303480■40304090;40316490■40317630;40373570-40 374510;40476950- 40477750;40665170■40665800;40883910■40884740;41241090-41 241870;41360740- 41361320;41361690■41362710;41381400■41382060;42035020-42 035710;42456240- 42457180;42682160■42682720;42766270■42767370;42958550-42 959120;43068110- 43068910;43171810■43172360;43304650■43305410;43349060-43 349630;43358440- 43359450;43707200■43708160;43946120■43947200;43974470-43 975670;44029960- 44031500;44213310■44213880;44405190■44406100;44406550-44 407120;44417620- 44418500;44616870■44617820;44775280■44775830;44783950-44 785080;44786050- 44786970;44800490■44801150;44805850■44806580;44812770-44 814110;44842670- 44843230;45326680■45328000;45339760■45340530;45622780-45 623380;45686590- 45687140;46203140■46203700;46301890■46303430;46393940-46 394760;46448150- 46448700;46466180■46467430;46489460■46491160;47225380-47 226020;47231700- 47232280;47437010■47438060;47439200■47439860;47444640-47 445380;47709300- 47710290;47710360■47711120;47983920■47984500;47996200-47 996940;48776260- 48776930;50047730■50048650;50332850■50333500;50419230-50 419860;50420610- 50421870;50968030■50968880;50968970■50970000;51344620-51 345470;51729350- 51730180;51990280■51990920;52032920■52033980;52141490-52 142850;52365590- 52366570;52552580·■52553150;52601920■52602540;52632760- 52633850;52697850- 52698530;52842610■52843170;53196480■53197230;53326300-53 327280;53438710- 53439310;5373762O■53738410;53738490■53739050;54800520-54 801170;54886770- 54887400;55039420■55039970;55215190■55215800;56578410-56 579560;58249440- 58250460;58576220·■58577780;58781770·■58783910;5878411 0-58785350;58816010- 58816740;59814680■59815270;61042900■61043850;61050200-61 050780;61056880- 61057450;61082970■61083750;61742880■61743440;62318760-62 319730;62436180- 62437400;62687580■62688220;63317060■63317760;63322570-63 323760;63324190- 63324860;64470510■64471130;65002450■65003050;65066410-65 067140;65147250- 65149060;65265560■65266110;65420550■65421120;65525360-65 526100;65792450- 65793470;66924750■66925360;66929830■66930740;67307400-67 308110;67429680- 67430560;67685240■67686690;68496420■68496970;70221290-70 222020;70354140- 70355110;71046480■71047890;77281560■77282520;77682520-77 683070;78045830- 78046780;83998610■83999560;84505560■84506220;84574120-84 575000;84690480- 84691060;84892600■84893560;84998130■84998720;85047840-85 048980;85200440- 85201980;85259270■85259820;85464230■85465480;85576320-85 577320;85580600- 85581820;87131840■87132730;87331650■87332230;89632460-89 633020;89821190- 89821770:89995130■89995700:90716370■90716940;90718310-90 719090;90719540- 90720120;90835780-90836590;90850980-90851750;91021680-910224 40;91500600-

91501580;91885190-91886340;92298800-92299380;92480170-924 80800;92480930-

92481510;92484160-92485000;92784300-92785280;93345800-933 46520;93448020-

93448900;93680740-93681450;93846180-93846910;94236870-942 38160;94418220-

94418850;94541130-94542210;94819920-94820830;94926160-949 27030;94927040-

94927880;95116980-95117670;95234010-95234620;96721630-967 22470;98045320-

98045900;98661620-98662270;99004110-99004670;99849850-998 50670;100037860-

100038420;100352130-100353280;100538770-100539510;1012395 30-101240090;107056570-

107057580;108876780-108877430;109041470-109042290;1090904 20-109091010;109100190-

109100850;109113470-109114380;109213830-109214430;1092584 10-109259320;109466520-

109467590;109619500-109620340;109739580-109740570;1099846 10-109985500;110067710-

110068610;110150370-110151310;110210680-110212450;1103384 90-110339060;110339260-

110340160;110673220-110675510;111140100-111140660;1112040 90-111204700;111448470-

111449420; 111738800-111739800; 111981560-111982830; 111988810-111989450; 112508390-

112509760; 112674770-112675580;112714660-112715750;112718630-112719360; 112743830-

112744400; 112955670-112956460;113390040-113391530; 113758790-113759690;113929090-

113929640;114152400-114153460; 114510180-114510900;114669670-114670390; 114780220-

114780790;115337490-115338740; 115642320-115642940;115828070-115828700; 115837560-

115839410;116372430-116373580; 116909580-116910220;117366330-117367340;117605770-

117606440;118987540-118988090;119006670-119007220;1193273 10-119327910;145858770-

145859340;145957450-145958120;145960130-145962160;1459643 70-145964920;146019160-

146019730;147171790-147172680;147907770-147908660;1498875 50-149888230;150149260-

150149860;150234370-150235570;150268350-150268920;1503209 80-150321990;150549520-

150550070;150578800-150579680;150629220-150629770;1509748 60-150975860;151048000-

151048700;151059290-151059950;151146000-151146930; 151281470-151282120; 151282560-

151283260;151399520-151400290;151510880-151511810;1516118 10-151612580;151838600-

151839410;152107640-152108420;153678300-153680120;1537753 90-153776370;153945840-

153946970;153957940-153958660;153966990-153967910;1539771 30-153978070;154221170-

154221770;154272210-154272780;154325120-154326280;1543281 60-154329180;154405000-

154406090;154501370-154503220;154558780-154559380;1545711 40-154572380;154607600-

154608380;154961420-154962260;155003600-155004320;1550502 90-155051390;155063750-

155064370;155070030-155070800;155070960-155071660;1550786 50-155080970;155081620-

155082670;155084960-155085850;155125910-155126720;1551274 10-155128140;155173730-

155174830;155193620-155195080;155208510-155209200;1552728 20-155273810;155276960-

155277900;155294570-155295460;155322630-155324280;1553243 90-155325170;155933990-

155934590;155977990-155978800;156053830-156054400;1560544 40-156055190;156076530-

156077830;156114370-156115610;156193490-156194050;1562454 00-156246370;156388300-

156388990;156420240-156421970;156436220-156436940;1565000 80-156500690;156623740- 156625720; 156646670■156647430;156676260■156677550;156705000-156705 670;156728000- 156729050;156750680■156751370;156751800■156752490;156767 610-156768290;156813430- 156814480;156845470■156846100;156848720■156849460;156893 420-156893970;156920310- 156921110;156923650■156924450; 156927240■156928170;157993540-157994320;158113190- 158113960;159780970■159781600;159924450■159925190;159929 630-159930190;160083690- 160085290;160098160■160098720;160205130■160206020;160261 980-160262540;160342890- 160343550;161097960■161099040;161389520■161390110;161725 870-161727120;161749740- 161750290;162023450■162024320; 162069790■162070460; 162366820-162367760; 162497890- 162498470;162561360■162562260;164576080■164576720;165827 360-165827920;166165020- 166165570;166165600■166166290;166875860■166876480;166920 420-166921750;167121190- 167121790;167454640■167456150;167553170■167554000;167935 690-167936340;167936690- 167937390;168135970■168136520;168178720■168179510;169485 200-169486150;171841070- 171841980;172532860■172533460;173824080■173825080;174159 280-174159910;175599100- 175599670;176206340■176207100;177164310■177164980;178093 800-178094840;179586240- 179586920;179591630■179592370;179743190■179744330;179882 180-179883060;179954520- 179955500;180154860■180155590;180230030■180230580;180231 020-180231680;180234690- 180235680;180631920■180632760;180912060■180913040;180934 850-180935730;181105500- 181106050;181482590■181483150;182056280■182057310;182390 730-182391700;182789170- 182790080;182839070■182839810;182952540■182953230;183022 500-183023050;183472490- 183473090;183635100■183636090;183804750■183805710;184386 120-184386810;184387300- 184387850;184973880■184974700;185045390■185046280;185156 910-185157670;185316680- 185317240;186374780■186375710;193059040■193060230;197201 140-197201690;197917630- 197918520;198156920■198157750;200028990■200029780;200039 220-200039780;200042450- 200043100;200739010■200739600;200873510■200874260;200890 920-200891470;201022780- 201023460;201114820■201115410;201283340■201283910;201399 410-201399980;201468340- 201469330;201506590■201507420;201538790■201539630;201648 430-201649470;201828850- 201829690;201888590■201889190;202348420■202349420;202709 880-202710780;202806820- 202807400;202807710·■202808390;202811260■202811940;2028 60920-202861780;202957960- 202958620;203305100·■203306150;203629110■203629910;2040 73060-204075370;204151120- 204151910;204377510■204378150;204494100■204494810;204684 800-204685380;204828180- 204828910;205210670■205211530;205343300·■205344630;2054 56460-205457420;205774640- 205775210;205812930·■205813530;206506900■206508160;2066 35110-206636150;207050610- 207051320;207751950·■207752580;208243000·■208244580;20 9805670-209806220;210233310- 210233870;211133500■211134540;211577730■211579970;211830 500-211831260;212285350- 212286520;212558350·■212559220;212606800■212607460;2126 07490-212609370;212699930- 212700850;212858140■212859180;213015120■213015810;213985 190-213985910;213997670- 213998280;215567080■215568010;217135220■217136000;218164 380-218165820;218345500- 218346300:219927700■219928820;220046000■220047020;220094 080-220094840;220690220- 220691000;220877060-220877770;220879490-220880470;220881960- 220882520;221742740- 221743360;222711740-222712480;223363240-223363910;223712070- 223712760;223748590- 223749350;224183000-224183990;224356940-224357640;224433800- 224434400;224616720- 224617620;225427110-225428670;225653450-225654090;225923590- 225924500;226062650- 226063270;226083010-226083610;226121680-226122790;226186100- 226186990;226407460- 226408050;226548350-226549640;226736960-226738840;226870450- 226871330;227541810- 227542860;227558550-227559130;227560610-227561570;227734940- 227735580;227787390- 227788240;227946700-227947270;228007170-228008130;228008140- 228008840;228037560- 228038550;228058670-228059630;228082140-228083400;228102280- 228103910;228109020- 228109730;228139530-228140960;228165560-228166280;228378580- 228379610;228405880- 228406680;228416090-228416710;228457220-228457860;228471180- 228471780;228486880- 228487450;228734960-228735660;229270630-229271270;229342290- 229343500;229431260- 229432510;229558600-229559210;229594320-229594940;230067980- 230068530;230425140- 230425740;230867800-230868350;231039190-231039960;231162850- 231163740;231336790- 231338010;231420820-231421540;231422150-231422760;232630210- 232630940;233295170- 233295850;233327800-233328370;234213920-234214980;234599740- 234600380;235128300- 235129150;235326930-235328090;235503830-235504380;235650300- 235651050;235866150- 235867150;236064220-236065570;236142650-236143530;236281150- 236282520;236395070- 236396220;237041550-237042170;237042450-237043360;237783810- 237784470;239387120- 239387670;240091610-240092250;240092550-240094090;240492560- 240493520;242523690- 242524440;243254800-243255620;243482950-243483610;244451160- 244452480;244653180- 244653820;244834850-244835520;244863560-244864730;245154100- 245155090;245155430- 245156660;246566000-246566760;247007520-247008080;247111110- 247112420;247331080- 247331650;247332060-247332700;247518170-247518740;247856990- 247857950;248811760- 248812490;248838210-248839210;248847260-248848820

Chromosome 10 988130-988680;1048210-1049280; 1056340-1056900;3067210-3068950;3172550-

3173150;3784580-3785270;4825970-4826680;5412300-5412890;5 524870-5525530;5684910-

5685490;5889270-5890240;5976920-5977980;6144400-6145650;6 200660-6201470;7407670-

7408250;7412700-7413560;7666460-7667030;7818280-7819040;8 055610-8056360; 11610760-

11611380; 11823380-11824130; 12068650-12069320; 12195610-12196420; 12349980-

12350590; 13299620-13300540; 14837660-14839130; 14878650-14879440; 15719400-

15719950; 17229110-17230180; 17454510-17455060; 17616660-17617610; 19816560-

19817250;21173080-21174640;21494390-21495230;21496280-214 97530;21499640-

21500910;21510030-21510780;21517390-21518000;21525820-215 26790;21533830-

21534500;22002930-22003670;22252270-22253630;22334940-223 37040;22340210-

22341650;22344980-22346070;22475990-22478150;22713680-227 14270;23173330-

23174940;23191440-23192050;23194740-23195700;23694740-236 95570;25174790-

25175370;25175390-25176320;26216190-26216950;26217260-262 18060;26391600- 26392360;26697570■26698250;27240530·■27241270;27742960- 27743900;27744530- 27745080;27745290·■27746380;28532360·■28533320;2866835 0-28669010;28677690- 28678240;28721980■28722600;29409470■29410240;29734930-29 735520;29735590- 29736140;29736310■29736990;30058640■30059190;30433980-30 434670;32055470- 32056410;32346330■32347250;33336700·■33337260;35089840- 35090470;35127000- 35127740;35337090·■35337650;35607630·■35608190;3564114 0-35642300;35642840- 35643710;43104730■43105840;43229330■43230170;43408800-43 409350;43455350- 43456200;43573860■43574680;43606470■43607020;43648210-43 649060;43690010- 43690790;44384670■44385660;44959210■44960080;45443010-45 444040;45594320- 45594870;47300280■47300860;47309720■47310640;48450490-48 451060;48523320- 48523880;49610700■49612490;49761480■49762580;49768430-49 769280;50623260- 50624220;51074460■51075240;59176800■59177440;59362270-59 362840;59709110- 59710420;59905870■59907210;60732950■60733670;60944010-60 944610;61662780- 61663550;62268570■62269220;62373940■62374730;62804600-62 806090;62813290- 62813910;62814950■62816170;62818260■62819310;63630220-63 630790;68074640- 68075220;68230950·■68231520;68406520■68407080;68560260- 68561290;68988560- 68989650;69318090■69319640;69572360■69573400;69577680-69 578230;69630050- 69630630;69802340■69803050;70052560■70053520;70053720-70 054450;70132480- 70133080;70145250■70146860;70382050■70382600;70403850-70 404870;70440650- 70441970;70458110■70458840;70478200■70479230;71212190-71 213320;71396120- 71396720;71397270·■71397920;71963880■71964920;72007110- 72008430;72087300- 72088420;72273260·■72273940;72354460·■72355050;7269239 0-72692950;73167660- 73168620;73495330■73495900;73625710■73626280;73647780-73 648340;73772120- 73773500;73781670·■73782560;73785390·■73786330;7381092 0-73812050;73910810- 73911500;73997540■73998900;74176360■74177270;74813140-74 813740;74824800- 74825350;75043510■75044280;75111170■75112010;75234330-75 235340;75398550- 75400390;75403360 75404140;75407140■75407920;77636630-77637660;78973780- 78974410;79070200■79070790;79243730·■79244310;79347270- 79348270;79981710- 79982340;80206690■80207470;80356350·■80356960;80408160- 80409190;81875560- 81876210;84139370■84139930;84328850■84329420;86363120-86 363910;86365660- 86366290;86366920■86367470;86399850■86401870;86521380-86 522450;86631800- 86632500;86943110■86943660;86968320■86969200;87093830-87 094690;87095280- 87095970;87504570·■87505760;87659490■87660160;88879940- 88881000;89207600- 89208440;89535290■89536250;89644250■89645310;90856990-90 857870;91163370- 91164130;91908030■91909040;92045510■92046380;92239180-92 240320;92420400- 92421100;92573090■92574710;92592830■92593740;92690090-92 690950;92848720- 92849290;93060450■93061400;93062520■93063510;93065570-93 066650;93068100- 93069180:93073500■93074080:93074090■93074740;93074920-93 075560;93566470- 93567390;93601140-93601830;93893720-93894640;93994040-939945 90;94402260-

94403890;95183280-95184080;95290300-95290850;95560650-955 61220;95656060-

95657050;95907490-95908330;96043020-96044050;96369900-963 70630;96513230-

96514130;96833010-96833720;97185310-97186380;97196090-971 96650;97319890-

97320460;97333520-97334150;97425930-97426980;97445730-974 46280;97498200-

97499940;97578220-97578810;97714010-97715070;97737050-977 37610;97974890-

97975480;98031030-98031660;99231930-99232480;99329050-993 31000;99430200-

99431490;99536660-99537430;99540200-99540900;99620400-996 21600;99659030-

99659870;99732110-99732690;100346910-100347990;100482100- 100483010;100562430-

100563070;100670780-100671620;100730410-100731370;1007350 90-100735930;100744450-

100745010;100749540-100750140;100826290-100828270;1009868 10-100987660;100996940-

100998110;100998950-100999650;101018580-101019370;1010479 50-101048770;101062350-

101063360;101131300-101132380;101133820-101134850;1011363 60-101137040;101139900-

101140690;101217110-101217910;101224330-101225040;1012267 40-101227970;101229430-

101230620;101566200-101567230;101693890-101695340;1017752 10-101775850;101778720-

101780170;101840480-101841480;102054700-102055280;1020652 60-102066010;102132740-

102133740;102152010-102152610;102230230-102232130;1022412 20-102242000;102393900-

102395260;102399180-102400190;102408470-102409040;1024104 50-102411150;102418820-

102420070;102420630-102422460;102432060-102432810;1024507 80-102451350;102461070-

102461770;102503920-102504560;102642040-102642710;1026441 70-102645600;102917270-

102918070;102918180-102920220;103276670-103278380;1033506 00-103351370;103367700-

103368640;103493240-103493940;103494060-103494740;1035840 80-103584630;103692370-

103692920;104231830-104232700;104254730-104255530;1043376 30-104338610;104639880-

104640430;104641450-104643020;107163900-107164560;1089119 60-108912510;110210110-

110211100;110497090-110497860;110643890-110644800;1110766 90-111077750;111077870-

111078560;113854340-113855280;114044210-114044900; 114239230-114240120;114404110-

114404810;114938100-114938830;115093520-115094290; 116270710-116271540;116272380-

116273440; 117004580-117005450;117134500-117135100; 117136480-117138050; 117138140-

117138710;117139990-117140590;117162880-117163650;1171680 30-117168810;117175240-

117175840;117241110-117241780;117374240-117375100; 117375410-117376180;117534950-

117535670;117543540-117544460;117545400-117545950;1180462 60-118046880;118594130-

118595360;118754310-118755120; 119030560-119031170;119165230-119166230;119541900-

119542730;119542980-119543690; 119651390-119652420; 119726000-119726850;120457350-

120457900;121597040-121598150;121608560-121609240;1219272 80-121927970;121928060-

121928880;122112560-122113400;122374390-122375650;1228796 10-122880530;122953720-

122954630;122980160-122981020;123008140-123009130;1231350 90-123136070;123136960-

123138000;123147940-123148710;123150750-123151720; 123154420-123155330; 123666510-

123667150;123991860-123992410;124091690-124093220;1240934 70-124094400;124418180- 124418880; 124449180-124450080; 124742840-124743780; 124801530-124802380; 125161710-

125162530; 125822610-125823430; 126388260-126388990; 127736500-127738240; 128125670-

128126330; 128150220-128150900; 128210430-128211130; 129958570-129959470; 129964710-

129965470; 129967010-129967770; 129968190-129968800; 129969420-129970020; 129970210-

129971080; 129972250-129972820; 130136310-130137180; 130190030-130190730; 132395830-

132396460; 132536710-132537540; 132784190-132785470; 132786450-132787970; 132787990-

132788820; 133087430-133088890; 133160430-133161080; 133236020-133237610; 133308390-

133309640; 133325070-133326410; 133335840-133337220; 133357300-133358110; 133378250-

133378990; 133459450-133460390; 133464980-133465840; 133527710-133528700

Chromosome 11 208310-209390;279050-281890;288200-288870;376900-377700;3790 80-

380620;407370-407960;416190-417730;420260-421210;449980-4 51060;506440-507340;507430-

508030;555380-556610;694990-696260;705720-706740;720420-7 21010;747090-748200;789610-

790480;797630-798530;804650-805200;818910-820520;826650-8 27630;830480-831310;842380-

843450;911030-911590; 1309590-1310280; 1336910-1337790; 1382830-1383580; 1389180-

1389810; 1546270-1547760; 1572540-1573390;2140440-2141370;2144080-2144740;2166210-

2167070;2269040-2270910;2271020-2271650;2885050-2885820;2 901880-2902580;2928500-

2929500;2991420-2991990;3057010-3057600;3667070-3667830;3 855770-3856340;4187080-

4187630;6270580-6271560;6418440-6419120;6456210-6457000;6 570730-6571570;6611550-

6612100;6629630-6630250;7251510-7253050;8019250-8020070;8 262390-8263150;8267730-

8268930;8870570-8871260;9003330-9004850;9384480-9385220;9 574560-9575220;9613760-

9614640; 10293390-10294450; 10305480-10306600;10450390-10451410; 11620790-

11621840; 12008060-12008700; 12110120-12110740; 13009240-13010760; 13668110-

13669180; 13962260-13963740; 14380920-14381660; 14643890-14644950; 14891320-

14892260; 14905610-14906350; 16605040-16605610; 16606580-16607760; 16613290-

16613970; 16924870-16925890; 17013620-17014170; 17351260-17352040; 17476250-

17477160; 17544190-17544770; 17719590-17720650; 17721140-17721910; 17735660-

17736950; 17771780-17772580; 18012550-18013480; 18394140-18395090; 18698390-

18699490; 18721050-18721700; 18791140-18792220; 19240970-19241790; 19712130-

19712680; 19713170-19713800;20387210-20388240;20596640-20597300;206695 60-

20670110;22192510-22193350;24496640-24497380;27699870-277 00450;27701150-

27701930;27719000-27719620;30585130-30586690;31798810-317 99540;31809770-

31810750;31816040-31816600;31816640-31817630;32090830-320 91800;32332870-

32333490;32434540-32435830;32893370-32893980;33015780-330 16550;33039240-

33040110;33257410-33258650;33700500-33701100;33735870-337 36480;34356680-

34357960;35138910-35139460;35418720-35420130;35618910-356 20050;35662630-

35663680;43547200-43547780;43575400-43576000;43579090-435 79990;43581070-

43581670;43943120-43944150;44308960-44310200;44950070-449 50860;44950880-

44951460;45285840-45286600;45649440-45650880;45803930-458 04920;45847080- 45848130;45885770■45886360;45899710■45900800;45917420-45 917970;45922570- 45923670;46237620■46238560;46277600■46278690;46332400-46 333780;46380860- 46381530;46381790■46382840;46385340■46386240;46389150-46 390200;46390600- 46391160;46391980■46393090;46704880■46705450;46845530-46 846550;46917640- 46918370;47185420■47186270;47187200■47187790;47269620-47 270480;47355070- 47355870;47552880·■47553440;47565060■47566270;47578550- 47579370;47589470- 47590100;47590540■47591110;47641880■47642740;47848140-47 848860;47981070- 47981730;57335120■57336040;57459690■57460500;57476000-57 477100;57482670- 57483220;57499110■57499660;57514000■57514860;57515010-57 516040;57567250- 57568270;57667590·■57668860;59755160■59755730;60841820- 60842580;60853090- 60853650;60905980■60906800;60913870■60914850;60924260-60 925390;60934180- 60934780;60950700■60951390;61007310■61008250;61160910-61 161900;61294150- 61295620;61332450■61333460;61361610■61362420;61429690-61 430250;61508170- 61508740;61509090■61510190;61567310■61567980;61777000-61 778160;61815070- 61816060;61816080■61817410;61827280■61829310;61890820-61 891470;61891650- 61892200;61955190■61956210;61967060■61967870;62545380-62 546020;62546140- 62547240;62591220■62591960;62600770■62603430;62612160-62 612780;62621320- 62622390;6268757O■62688520;62726970■62727560;62786410-62 787550;62839130- 62839680;62880890■62881930;62925740■62926970;63613520-63 614470;63671060- 63671610;63769150■63770140;63812820■63813370;63838270-63 839310;63908720- 63909410;63916210■63916880;63938460■63939150;63974440-63 974990;63985920- 63986740;63999100■63999680;63999780■64001210;64036120-64 036680;64165230- 64166730;64185060■64185660;64233880■64234440;64240510-64 241390;64241470- 64242510;64247010■64247960;64269260■64270180;64284990-64 286290;64291240- 64292710;64299100■64300200;64300310■64301100;64304440-64 305380;64316780- 64317520;64359840■64360390;64368270■64370430;64607120-64 607970;64630000- 64630730;64723130■64723860;64742540■64743480;64743650-64 744340;64745080- 64745650;64809500■64810730;64827210■64827780;64844010-64 845050;64877790- 64879160;64916810■64917660;64924460■64925300;64971610-64 972170;65013970- 65015100;65040680■65042050;65047390■65047940;65083630-65 084450;65095970- 65096650;65107370■65108060;65108110■65108780;65116940-65 117850;65121490- 65122200;65134040■65134750;65181110■65181970;65184010-65 184730;65314410- 65315950;65525010■65525850;65539900■65540800;65546060-65 547040;65547410- 65548080;65553660■65554220;65569930■65571210;65574480-65 575040;65576040- 65576750;65607070·■65608180;65615310■65615860;65642010- 65642820;65646130- 65646720;65652220■65653230;65662910■65663460;65719960-65 721000;65786030- 65786990;65817790■65818720;65857780■65858340;65859380-65 859940;65860510- 65861270:65887930■65888870:65890210■65891720;65898990-65 900830;65961300- 65962450;66002140-66002690;66011480-66012490;66043070-660437 30;66048730-

66049560;66069540-66070140;66070620-66071280;66257080-662 58850;66268340-

66269010;66282150-66282910;66288590-66289570;66294270-662 95670;66311900-

66312520;66344510-66345570;66346590-66347610;66371090-663 72090;66408400-

66409240;66420620-66421670;66545620-66546180;66567940-665 68690;66592440-

66593030;66616360-66617570;66643410-66644170;66744140-667 44700;66842840-

66843900;66857700-66858850;66958090-66958940;67056330-670 57430;67250170-

67250790;67288390-67289090;67303030-67303980;67317200-673 18540;67391390-

67392260;67420270-67421380;67443370-67443920;67464410-674 65120;67468790-

67469460;67482830-67483380;67493240-67494100;67504390-675 05590;67507330-

67508990;67629090-67630090;68003120-68003790;68684100-686 85560;68749850-

68750790;68839120-68839970;68855520-68856070;68903530-689 04360;69048760-

69049380;69443450-69444010;69636220-69636920;69641320-696 41970;69642020-

69644070;69702820-69704420;69704430-69705250;69774090-697 75900;69817510-

69818270;69818280-69819060;70270000-70270560;70398320-703 98890;70486120-

70487630;71452470-71453410;72102910-72103700;72239350-722 40590;72240940-

72241570;72243470-72244520;72434010-72434570;72584070-725 85040;72751830-

72752550;72814030-72815070;72821580-72822660;73141420-731 42120;73217930-

73219040;73308250-73309640;73376310-73377300;73597740-735 98490;74311080-

74312070;74397800-74398950;74493030-74493880;75240450-752 41070;75561840-

75562780;75668230-75669120;76206170-76206940;76207190-762 08020;76209090-

76211140;76380100-76380880;76444470-76445220;76670750-766 71410;76783510-

76784060;77039680-77040730;77473020-77473740;77473960-774 74510;77820000-

77821160;79069630-79070220;82732650-82733240;82970490-829 71250;83156950-

83157800;85663560-85664710;86671580-86672400;86954720-869 55460;88508490-

88509520;92224600-92225500;92226180-92226960;92882740-928 83630;93197510-

93198260;93330410-93331090;93661330-93662120;94401030-944 01940;94543770-

94545780;94740300-94740940;94768290-94769290;94973110-949 73730;95066850-

95068040;95089600-95090630;95230350-95231120; 100687140-100687970; 101127080-

101127630; 101127760-101128620; 102109910-102110570; 102110710-102111500; 102346820-

102347590; 102452450-102453230; 103091550-103092250; 107928170-107928910; 108008550-

108009380; 108121420-108121970; 108222630-108223320; 110093520-110094070; 110295890-

110296460; 110430130-110430720; 111299020-111300040; 111512250-111513080; 111601790-

111603300; 112289920-112290480; 112962380-112963890; 114059550-114060210; 114060630-

114061190; 114400450-114401130; 116579940-116580680; 116580740-116581420; 116772740-

116773370; 116787680-116788330; 117231710-117232260; 118145440-118146330; 118153000-

118153610; 118530330-118531380; 118572480-118573070; 118607970-118609020; 118609500-

118611330; 118634720-118635370; 118998020-118998690; 119056530-119057130; 119094210- 119095570; 119107720-119108280; 119121220-119121940; 119148760-119149900; 119168520-

119169520; 119316470-119317100; 119339240-119340700; 119381170-119381720; 119727440-

119728040; 120137120-120138160; 120324980-120325850; 120335700-120336350; 120336420-

120337180; 120564310-120565160; 120985700-120986540; 122655800-122656920; 122979020-

122979570; 123430300-123431580; 124739760-124740860; 124745350-124746070; 124761960-

124763350; 124799540-124800780; 124839460-124840230; 124865180-124865740; 124868810-

124869360; 124875890-124876770; 124920730-124921710; 125062810-125063650; 125165300-

125166210; 125495230-125496220; 125568970-125569960; 125904040-125905000; 128521830-

128522730; 128692690-128693510; 128693970-128694520; 128890760-128891320; 130002850-

130003670; 130070300-130070870; 130208320-130208870; 130448870-130450090; 133955650-

133957650; 134068800-134069540; 134224510-134225590; 134253460-134254030; 134275560-

134276130; 134276150-134277090; 134332120-134332740; 134383380-134384470

Chromosome 12 138070-139500;460510-461120;752570-754240;990490-991050; 1690910-

1691520; 1796110-1796790; 1796930-1797650; 1907820-1908750;2690880-2691960;2876700-

2877490;2890540-2891220;3200230-3201220;3490710-3491510;3 491980-3492550;4269790-

4270370;4273840-4274420;4649000-4649560;4809260-4810850;4 810870-4811730;4909790-

4910380;4911180-4912230;5043990-5044760;5494490-5495040;6 200330-6200880;6278380-

6278990;6310260-6311070;6328940-6329960;6554800-6555890;6 619850-6621330;6766990-

6767590;6773390-6774160;6828730-6829600;6851910-6852790;6 914030-6915090;6937470-

6938430;7017980-7019060;8032100-8033240;9064330-9065180; 10212830-10213500; 12716810-

12717800; 12723780-12724630; 12724800-12725350; 12786780-12787350; 12890980-

12891750; 13001420-13002080; 13044090-13045020; 13100750-13101770; 13563440-

13564420; 13980660-13981440; 14567010-14567570; 14774370-14775070; 15322340-

15323150; 15788600-15789970; 19439730-19440580;22046110-22046720;22334000-

22334750;22335190-22335790;22624940-22625660;24562010-245 62690;24902700-

24903640;25250680-25251700;26114010-26114620;26125230-261 26170;26126220-

26127050;26226530-26227210;26832470-26833070;27013800-270 14850;27333040-

27333900;27780180-27780980;29782940-29783620;30201050-302 01600;30754420-

30755260;31323660-31325890;31589800-31590750;32399290-323 99880;32679150-

32680100;32755090-32756040;39442410-39443110;40105060-401 06010;42482690-

42483620;42588970-42589570;43550760-43551440;43551490-435 52150;43805790-

43806750;43835570-43836470;45050400-45051130;45216050-452 16640;45728690-

45729290;46268580-46270000;46371480-46372350;47705320-477 06180;47904520-

47905140;48001540-48002220;48004200-48004990;48156970-481 57590;48183510-

48184080;48329530-48330110;48350360-48351040;48814330-488 15360;48817860-

48818710;48969680-48970710;48971310-48971870;48977890-489 78980;48979470-

48981940;48996680-48997830;48997840-48999000;49059430-490 60010;49069390-

49070360;49089620-49090720;49090850-49091400;49094380-490 94930;49294970- 49295950;49296080■49297780;49322530■49323330;49335800-49 337060;49341730- 49342300;49345080■49345640;49366700■49367670;49537710-49 539040;49548910- 49549720;49706790■49707510;49827570■49828130;49903560-49 904120;49960840- 49961490;50032500■50033320;50084720·■50085570;50166920- 50167610;50400850- 50401420;50763750■50764390;51025980■51026530;51082860-51 083820;51217040- 51217700;51269600■51270520;51323820·■51324370;51391440- 51392240;51424520- 51425220;51721320·■51722170;51821210■51822400;51846930- 51847540;51849010- 51849570;51907180■51907830;52006910■52007970;52050790-52 051860;52151980- 52152690;52232900·■52233720;52308120·■52308790;5294890 0-52949520;53180130- 53180900;53197440■53198080;53324520■53325830;53344650-53 345350;53500830- 53501840;53750770·■53752220;53938770·■53940060;5395465 0-53955810;53972990- 53974070;53985150■53985720;53999900■54001070;54030800-54 031370;54033160- 54034440;54047240■54047930;54053740■54054290;54126060-54 126870;54369790- 54370830;54418660■54419480;55707330■55708140;55743590-55 744280;55931600- 55932490;56079780■56080840;56128370■56128930;56257680-56 258960;56266690- 56267550;56449040■56449710;56634420■56635440;56687870-56 688540;57078360- 57078920;57088510·■57089440;57215850■57216570;57216950- 57217630;57224760- 57225630;57226720·■57227360;57229580·■57230190;5723863 0-57239380;57240020- 57241130;57461250■57461970;57475310■57476410;57549830-57 550610;57591010- 57591610;57610850■57611420;57619310■57620180;57627310-57 628200;57631900- 57633340;57726780·■57727990;57736020·■57736660;5773731 0-57737910;57751910- 57752650;57764780·■57765850;57845050·■57846920;5786499 0-57865870;58919560- 58920590;59596030■59596980;62190900■62191860;62260240-62 260810;62466450- 62467260;62602630■62603960;62934280■62934850;62934890-62 935450;63149780- 63151060;63843690■63844840;64221780■64222650;64390180-64 390730;64404580- 64405200;64759010■64759760;64780380■64781090;64824330-64 825370;65169510- 65170650;65823710■65824300;65824750■65825420;65825680-65 826430;66130710- 66131280;66188750■66189770;67269290■67269900;67649400-67 650200;68807760- 68808970;68933170■68933800;70366730■70367430;71439910-71 440850;71662970- 71663750;72271710■72272270;72272460·■72273840;75207200- 75208090;76030870- 76031690;76083890■76084920;76558880■76559900;79689530-79 691000;79934400- 79935260;80708320·■80709000;80937190■80937800;81077710- 81078450;82687020- 82687630;88580100■88580750;89351330■89352330;89524960-89 525510;90953960- 90954570;92145040■92145720;92145840■92146570;92929050-92 929890;93377910- 93378730;93441550■93442380;93569970■93571660;93571700-93 572500;93572530- 93573080;94147770■94148490;94149140■94150200;94459720-94 460620;94649360- 94650310;94872990■94873580;95216720■95217370;95217460-95 218370;95547950- 95548610:95943130■95943780:96399570■96400540;98515250-98 516520;98593570- 98594450;98745470-98746430;100142050-100142950;100199410-100 200120;100717410-

100717960;101877070-101878150;102958060-102959150;1038405 70-103841370;104064190-

104065380;104215500-104216520;104456590-104457200;1044579 20-104458700;105107560-

105108160;105330880-105331430;106138190-106138920;1061392 80-106139840;106246990-

106247540;106583450-106584150;106585860-106586720;1067742 80-106775160;106955310-

106956190;107092830-107093690;107318490-107319640;1073199 20-107320650;107580910-

107581650;107775060-107775850;108562210-108562990;1087685 10-108769320;109477200-

109477900;109714340-109715110;109899990-109901070;1099990 50-110000010;110281470-

110282260;110468280-110469340;110501620-110502470; 110582310-110583010; 110613720-

110614550;110688590-110689160;110742680-110743230;1110332 10-111033760;111319860-

111320870;111368440-111369480;111405710-111406840;1115980 00-111598620;111685670-

111686220;111766460-111767510;111841790-111842820; 112013110-112014190;112108560-

112109110;112125290-112126420;112184150-112185520;1124183 10-112419730;112575120-

112575820;113056550-113057460;113103660-113104510;1131351 80-113135860;113153050-

113153780; 113334630-113335470; 113463220-113464190; 113465200-113465890; 113466810-

113468690;113475570-113476740;113591460-113592070;1136377 20-113638290;114674190-

114674740; 114682530-114683360; 114684150-114685010; 114735400-114736140; 116879290-

116880060;116910690-116911390; 117098990-117099790;117360560-117361380;117760800-

117761620;117968760-117969470;118103520-118104620;1181358 70-118136650;118371400-

118372240;118372360-118373220;118375970-118377210;1189814 60-118982060;119667670-

119668330;120086920-120087570;120116950-120117690;1201941 80-120195210;120446060-

120447110;120469340-120470090;120534520-120535310;1206401 10-120640670;120641190-

120641800;120686850-120687940;120710130-120711280;1212100 10-121210760;121295930-

121296600;121400030-121400770;121441910-121442580;1214527 50-121453670;121467670-

121468240;121578650-121579410;121626870-121627420;1217128 00-121713360;121792940-

121794090;121888370-121889220;122022870-122023490;1221829 00-122183670;122203660-

122204500;122226350-122226940;122421710-122422370;1225002 60-122501230;122752250-

122753090;122774110-122774680;122895440-122896360;1229801 60-122981390;122985760-

122986590;123151330-123151880;123233500-123234140;1233640 80-123364630;123383700-

123384500;123389680-123390290;123532920-123533490;1237120 70-123713110;123761750-

123762800;123973570-123974210;124863410-124864110;1258613 60-125861950;127145910-

127146460;127455430-127456270;129903020-129903630;1301607 40-130161890;130162850-

130164310;130338900-130339480;130872430-130873040;1310447 30-131045440;131829960-

131830690; 131908280-131909240; 131928270-131930440; 131949500-131950670; 132083850-

132084520;132143410-132143980;132328740-132329310;1324891 90-132489820;132560240-

132560870;132619330-132619880;132907910-132908500;1329863 10-132986870;133037130-

133038030;133235800-133236440 Chromosome 13 19781860-19782960;20127610-20128530;20141960-20143390;201921 40-

20193130;20193140-20193830;20525280-20526140;20702990-207 03600;20717930-

20718500;20721230-20722120;20998760-20999310;21060190-210 60760;21061050-

21061860;21176080-21176730;21458650-21459440;21669840-216 70740;23160130-

23160710;23466130-23467010;23578410-23579060;24160650-241 61510;24680350-

24681150;24745930-24746490;24747560-24748150;25170380-251 71970;25287060-

25287650;26050280-26051270;26051340-26052010;26254000-262 54900;27270450-

27271410;27620050-27620940;27792220-27793210;27793450-277 94290;27794500-

27795190;27919730-27920460;27924590-27925140;27953500-279 54570;27960690-

27961480;27966430-27967180;27968030-27969410;27975610-279 76190;27977710-

27978810;28099840-28100940;28494550-28495600;28532490-285 33190;28718410-

28719060;29594660-29595500;30408110-30408730;30617140-306 17720;30906320-

30906870;31846230-31847330;32426970-32427700;32585890-325 86570;33016620-

33017320;33349940-33350750;33542400-33543070;35475380-354 76120;36346180-

36346960;36431680-36432440;36673940-36674570;36819090-368 19990;37059200-

37059750;38687230-38688250;40665030-40665710;40667080-406 67810;40789660-

40790250;41132000-41132690;41193840-41194560;41311360-413 11960;41456780-

41458760;41960480-41961410;42047970-42049050;43785720-437 87710;43878790-

43880250;44373220-44374170;44577640-44578270;45340310-453 41140;45464690-

45465630;45783490-45784090;45975070-45975920;46386940-463 87720;46552830-

46554130;48233140-48233860;48303230-48304440;48975520-489 76420;49219640-

49220200;49220370-49221530;49495700-49496570;49585190-495 85960;49935750-

49937080;50123720-50124450;50124610-50125290;50125670-501 26290;50130380-

50130950;50133030-50134040;50909680-50910480;51452450-514 53150;51584510-

51585220;51803410-51804700;52449700-52450980;52738940-527 39700;52845650-

52846820;52848190-52848740;52850840-52851940;57629370-576 30200;57632380-

57635040;60163520-60164160;71865700-71866320;73058830-730 59390;74135480-

74136040;75480890-75482120;75636240-75636850;76885020-768 86650;77326100-

77327290;77918070-77918720;78601260-78601860;79405550-794 06190;79480860-

79481780;80341410-80341960;87677140-87677910;94702300-947 02930;94710680-

94711360;94712930-94713590;95300640-95302020;95552220-955 53290;95641400-

95642360;95643930-95644910;95676960-95677810;96053050-960 53690;96091180-

96091960;99087110-99087780;99959630-99960320;99968010-999 68570;99979950-

99980630;99982390-99983470;99984660-99985320;99996970-999 97830; 100532170-

100532780; 100588410-100589340; 102772870-102773880; 102799000-102800030; 102800040-

102800930; 106534000-106534970; 106535840-106536770; 106567120-106568380; 106917550-

106918220; 107865670-107866230; 108218310-108219070; 109781940-109782810; 110561150-

110561780; 110615430-110616390; 110705650-110706350; 110714110-110714840; 110718890- 110719950; 110914420-110915010; 111114390-111114950; 111892920-111893690; 112053800- 112054490; 112056290-112057390; 112057710-112058260; 112072820-112073550; 112104650- 112105540; 112587230-112588550; 112943210-112944020; 113096210-113096930; 113109910- 113110960; 113207960-113208730; 113354950-113355520; 113393800-113394460; 113490000- 113490700; 113490740-113491380; 113862790-113863650; 114048510-114049070; 114131640- 114132660; 114281470-114282190

Chromosome 14 20455400-20455970;20460980-20461790;20469450-20470010;210244 60-

21025220;21070260-21070850;21090530-21091390;21091910-210 93530;22837110-

22838030;22886400-22887490;22928860-22929640;22956750-229 57300;22980440-

22981040;22981070-22982500;23094650-23095380;23301090-233 02970;23351710-

23352710;23364930-23365960;23575340-23575920;23576230-235 77780;24081070-

24081980;24094130-24094860;24114050-24114630;24135880-241 36800;24140940-

24141520;24171760-24172590;24188150-24188920;24195120-241 95800;24232180-

24232920;24241850-24242490;24310810-24311790;24315820-243 16520;24398810-

24399730;25049600-25050330;28767760-28768760;28774110-287 74700;31025550-

31026710;31206810-31208260;32077260-32077940;32201320-322 01930;32932870-

32933710;33799460-33800340;33800680-33801350;33950250-339 51320;34059750-

34060820;34539250-34539940;34713940-34715030;34873610-348 74820;35404360-

35404920;35533200-35533980;35534160-35536080;35808560-358 09270;35826190-

35827020;36517550-36518370;36518480-36519550;36580610-365 81860;36655790-

36656760;36662670-36663590;37197380-37197930;37591330-375 92810;37594240-

37594800;38208950-38210720;38255400-38256240;39267150-392 67730;41607870-

41608660;47674260-47674880;47675360-47676000;49620640-496 21780;49633690-

49635360;49687710-49688580;49768090-49768730;50531790-505 32770;50831270-

50831820;50943880-50944520;51094070-51095230;51239930-512 40520;51989270-

51989820;52314390-52315530;52553310-52553900;52695070-526 96090;52790870-

52791630;52950380-52950960;53152100-53153200;53953180-539 54140;53963570-

53964150;54397010-54397600;54565200-54566070;54566430-545 68140;54902210-

54902760;55051400-55052160;55128810-55129860;56797890-567 98860;56817220-

56817830;57268280-57269180;57390210-57391460;57865530-578 66500;58298880-

58299770;58395570-58396500;59188940-59189780;59463770-594 65530;59483510-

59484390;59630200-59630940;59727010-59727610;59870080-598 70980;60164880-

60165460;60327490-60328050;60509020-60510030;60648440-606 49410;60721290-

60721940;60723150-60724180;61279980-61281290;61321790-613 22590;61812830-

61813420;63542800-63543390;63727170-63727730;63853410-638 54240;64387570-

64388270;64464970-64466030;64504640-64505630;64540840-645 42770;64704040-

64704980;64879360-64880440;64971410-64971970;65412270-654 13600;66508190-

66508890;67241010-67241930;67411650-67412550;67473260-674 74040;67514740- 67515370;67532670-67533790;67674320-67675250;68789510-687905 40;68795450-

68796410;68816330-68816880;68978310-68980130;69151610-691 52510;69259310-

69260150;69260170-69261590;69484270-69485420;69571320-695 72970;69573130-

69573690;70808740-70809300;70907820-70908800;71931840-719 32930;72893060-

72893630;73237340-73238570;73245650-73246200;73458180-734 58730;73490960-

73491920;73591850-73592540;73612450-73613270;73633760-736 34580;73713360-

73714540;74018620-74019240;74240400-74241020;74493640-744 94360;74611170-

74612560;74763090-74763890;74955200-74956270;75126420-751 27130;75175860-

75176800;75276710-75277870;75278540-75279490;75982200-759 83130;76138780-

76139400;76376810-76377600;76761450-76762560;76775720-767 76340;76812420-

76813060;77025470-77026040;77026270-77027240;77097710-770 98700;77140460-

77141810;77270280-77271520;77498030-77499490;77615980-776 17000;81435690-

81436240;88323670-88324280;88562740-88563440;88791910-887 93360;89026880-

89027470;90060260-90061710;90061750-90062800;90383480-903 84300;91234070-

91234950;91417020-91417660;91509320-91509870;91510280-915 11050;91573930-

91574630;91835840-91836410;92106100-92106830;92121680-921 22260;92323490-

92324130;92513760-92515080;92687280-92688630;92793740-927 94620;92922790-

92923820;93114430-93115130;93206740-93207720;93787420-937 88350;93788580-

93789150;93938940-93940020;94026310-94026980;94080430-940 81150;94768260-

94770280;94773050-94773660;95876250-95876810;96038750-960 40180;96363480-

96364050;96391270-96391880;96423740-96424300;96501690-965 02480;96797000-

96797930;97033230-97033830;99173770-99174460;99175190-991 76560;99271700-

99272560;99604460-99605680;99644720-99645670;99675350-996 75950;99683440-

99684050;99684280-99684870;99730080-99730680; 100159110-100159680; 100214180-

100214750; 100284950-100286030; 100292100-100292950; 100305470-100307100; 100538000-

100539090; 100708780-100709330; 100825540-100826140; 101457640-101459730; 101559400-

101560290; 101561470-101562560; 101564650-101565400; 101628390-101629070; 101705520-

101706170; 101781340-101781890; 102139580-102140460; 102362580-102363660; 102506530-

102507140; 102509940-102510550; 102516500-102517910; 102555040-102555750; 102928340-

102930780; 103075190-103076020; 103104140-103105360; 103123100-103123650; 103189000-

103189660; 103207310-103208180; 103220200-103220770; 103273110-103274100; 103384680-

103385420; 103520890-103521830; 103522880-103523630; 103528640-103529330; 103562200-

103562800; 103629380-103630330; 103716250-103716870; 103847810-103848690; 104116490-

104118260; 104136590-104137140; 104137360-104138170; 104138570-104139180; 104604190-

104604750; 104723930-104724480; 104752030-104753470; 104800960-104801700; 104815400-

104816830; 104826760-104827430; 104864100-104865000; 104865610-104866320; 104931710-

104932360; 104932400-104933430; 104977670-104978250; 105020600-105021150; 105045380-

105046280; 105299890-105300590; 105315160-105315750; 105414690-105415600; 105474900- 105475720; 105478240-105479410; 105486920-105487730; 105489830-105491790; 105527930- 105528630; 105528780-105530190

Chromosome 15 22979060-22979790;25438040-25439200;25862400-25862970;268831 10-

26883770;27541360-27542190;28095570-28097460;28106500-281 07550;29674810-

29675370;29822150-29822750;31215600-31216210;31440600-314 41300;31484120-

31484790;32717860-32719640;33310530-33311300;34337370-343 38320;34754390-

34755410;37097630-37098180;38252430-38253210;38564680-385 65420;39919690-

39920840;39976240-39977050;40108530-40109270;40252380-402 53320;40282080-

40283520;40290940-40291770;40323000-40323600;40367670-403 68690;40435680-

40436610;40471190-40472150;40511100-40511990;40763680-407 64540;40843580-

40844620;40873570-40874350;40925540-40926590;40929420-409 30250;40930340-

40930990;40952710-40953510;41115570-41116670;41230710-412 31270;41416990-

41417680;41486080-41487060;41493140-41493690;41494180-414 95080;41495170-

41496110;41501300-41503380;41511630-41513320;41585110-415 85730;41621270-

41622270;41659830-41661170;41774280-41774980;41881680-418 82270;41971650-

41972950;42490750-42491330;42574910-42575650;42736710-427 37310;42919970-

42920830;43133530-43134100;43329910-43330650;43370410-433 71350;43776520-

43777580;43791700-43793070;44194270-44195480;44536940-445 37900;44711710-

44712270;45112540-45113430;45129470-45130190;45378140-453 79070;45402430-

45403430;45430020-45431060;45522080-45522660;47184080-471 84720;47184950-

47185510;47718010-47718940;48177750-48178470;48331870-483 32670;48644510-

48645100;48645110-48645890;48645900-48646690;48877780-488 78650;50181820-

50183100;50765330-50766080;51093640-51094360;51341440-513 42140;51751110-

51751700;52111870-52113030;52295030-52295680;52788310-527 89010;52790760-

52791520;52805570-52806120;55289370-55290440;55742480-557 43030;56733140-

56733780;56919150-56919760;58932930-58933780;60004250-600 06180;60591520-

60592130;61227950-61228510;62163770-62164320;62391230-623 92050;63042490-

63043290;63048110-63048860;63121770-63122520;63189270-631 89820;63503930-

63504860;63505080-63505770;63601090-63601730;63833280-638 33930;64151750-

64152800;64823670-64824590;64841860-64842410;64989260-649 90200;65067440-

65068060;65077340-65078230;65102310-65102940;65132690-651 33240;65355720-

65356270;65395600-65396250;65396510-65397230;65530320-655 31220;65791570-

65792190;66252790-66253980;66386660-66387720;66621740-666 22310;66700570-

66701130;66702100-66702680;66780840-66781790;67066220-670 66770;67521280-

67521860;67542250-67543030;67823560-67824130;67825730-678 27170;67827280-

67828320;67828800-67829380;68053740-68054500;68229320-682 30260;68277570-

68278750;68578230-68578950;68817410-68818030;68818040-688 19670;68819860-

68820590;68821170-68821820;69160440-69161010;69414100-694 15030;69452900- 69453450;70096530-70097940;70098560-70099530;72117550-721183 30;72197090-

72197650;72229910-72230670;72288780-72290260;72319380-723 20010;72320040-

72320830;72473840-72475210;72783100-72784310;72796880-727 97430;73051360-

73052010;73368590-73369850;73632490-73633560;73684180-736 85020;73927280-

73928140;73997900-73998680;74022630-74023610;74127320-741 28210;74130150-

74131090;74132430-74135190;74136060-74136650;74365660-743 66230;74432730-

74434380;74615030-74615990;74621650-74622270;74826160-748 26970;74842800-

74843810;74906040-74907190;74937440-74938150;74955750-749 57070;74957130-

74957970;75201330-75202760;75347140-75348310;75368170-753 68910;75455700-

75456350;75578230-75579390;75639500-75640550;75647020-756 48560;75842700-

75843330;75843390-75843940;75903710-75904310;76059070-760 59700;76337470-

76338760;76339800-76340650;76341690-76342240;76342600-763 43390;76345980-

76346990;76904930-76905530;77819940-77820570;78149290-781 50130;78264810-

78265360;78340240-78340890;78507100-78507770;78620310-786 21470;78810230-

78811480;78811570-78812160;78872750-78873340;79089940-790 90880;79431680-

79433070;80695790-80696400;80779050-80779610;81000770-810 01360;81001850-

81003470;82043130-82044830;82045220-82046030;82047250-820 47810;82539650-

82540450;82647780-82648340;82680090-82681160;82709590-827 10160;83107070-

83108360;83206640-83207410;83283190-83283860;83447170-834 47970;84633240-

84634380;84657730-84658320;84715980-84716540;84980770-849 81780;84982120-

84982730;85794200-85795070;88255240-88256070;88256950-882 57640;88894950-

88895510;89088480-89089040;89333010-89333760;89334260-893 35050;89367440-

89369010;89370970-89371520;89378670-89379290;89400060-894 00690;89411330-

89412110;89486580-89487140;89496080-89496910;89575520-895 76180;89648650-

89649610;89776180-89777140;89814250-89815550;90184600-901 85280;90233430-

90234370;90664970-90666100;90717010-90717710;91854010-918 54750;91915910-

91916660;92393330-92394600;94231040-94232090;96333760-963 34700;96354180-

96354840;96409310-96409950;98547870-98548930;98650200-986 51100; 100373180-

100373870; 100880330-100880880; 100973160-100973950; 101276960-101277750; 101294770-

101295660; 101723890-101724580

Chromosome 16 60820-62170;78220-78850; 166030-166720;424870-425470;426390-427080;588550-

589940;635640-636590;641520-642090;649240-650250;667780-6 68890;677470-678030;683670-

685770;690090-690680;694680-695260;695400-696130;715400-7 16020;721060-722120;727550-

728450;740560-741490;807280-808120;970220-971020;980190-9 81110; 1308630-1309410; 1333730-

1334280; 1351190-1351900; 1351930-1352490; 1379220-1379770; 1475140-1475700; 1493230-

1494220; 1610190-1611320; 1705790-1706750; 1770610-1771880; 1772550-1773610; 1781600-

1782540; 1782720-1783340; 1826790-1827410; 1942670-1943320; 1971240-1972080; 1983370-

1984930; 1991520-1992280;2019820-2021020;2027130-2027730;2047350-2048 020;2179510- 2180310;2213740-2214510;2223350-2224210;2236470-2237140;2237 250-2238040;2250940-

2251830;2339640-2340380;2340780-2341500;2429390-2430170;2 467440-2468620;2470910-

2472090;2474100-2475020;2475520-2476120;2513600-2514170;2 715440-2716040;2752240-

2752850;2765920-2766470;2785250-2786020;2904280-2904840;2 963540-2964090;2966530-

2967850;2968990-2969540;2969550-2970120;2980290-2980950;2 983680-2984370;3019760-

3020610;3029320-3030210;3058260-3058990;3088940-3090590;3 106580-3107200;3119120-

3120350;3140550-3141490;3149680-3150280;3283270-3284010;3 295140-3295980;3304780-

3305330;3611080-3611830;3716900-3717810;3879380-3879950;3 880960-3881590;4114630-

4115810;4183310-4183870;4261520-4262080;4273360-4273960;4 416120-4416990;4476370-

4477050;4613830-4614550;4614570-4615130;4615930-4616870;4 624610-4625270;4693220-

4694520;4847490-4848330;4936410-4936970;4958210-4958790;4 987620-4988170;5032980-

5034040;5071640-5072330;9090080-9090940;9091740-9092310; 10179730-10180680; 10180860-

10182190; 10182560-10183640; 10941520-10942710; 10944200-10945060; 11254650-

11255710; 11742210-11743290; 12902060-12902780; 15642730-15643470; 19067510-

19068060; 19114430-19115520; 19168190-19169220; 19521450-19522220; 19523720-

19524300; 19555050-19555720; 19718180-19719040;20073440-20074080;20348170-

20349280;20806220-20806880;21599370-21600460;21663710-216 64290;22190020-

22190600;22205850-22206750;22373940-22375200;22813830-228 15200;22914810-

22915620;23301990-23302870;23452560-23453310;23557270-235 58010;23595850-

23596530;23641040-23641590;23678720-23679580;23712770-237 13320;23754460-

23755390;24361300-24361880;24539340-24540520;25257290-252 58060;25692850-

25693460;27313920-27314660;27549420-27550160;28062390-280 63140;28319740-

28320410;28823200-28824260;28863320-28864460;28880250-288 80800;28925020-

28925980;28950520-28951740;28974840-28975420;29790070-297 91080;29811900-

29812510;29816170-29816760;29862510-29863490;29876440-298 77530;29901100-

29902010;29925380-29926330;29961550-29962700;29995200-299 95770;30064830-

30065890;30076190-30076840;30377600-30378880;30394970-303 95590;30400120-

30400880;30406950-30408020;30417110-30418690;30429760-304 30790;30445080-

30445840;30524360-30525360;30526970-30527580;30555180-305 55960;30557890-

30558650;30569640-30570520;30571200-30571840;30571980-305 72660;30585030-

30585730;30604260-30605240;30609420-30610570;30650340-306 52100;30657460-

30658530;30761350-30762300;30782230-30784150;30786800-307 87490;30805420-

30806040;30874440-30875460;30894210-30894780;30930020-309 30710;30946600-

30947290;30957430-30957990;31032700-31034340;31042090-310 42740;31061210-

31062500;31063560-31064530;31073010-31073650;31094110-310 95020;31108020-

31109770;31117560-31118260;31142460-31143120;31148110-311 48880;31202220-

31203040;31214370-31215590;31216450-31217180;31224080-312 24890;31331080-

31331880;31441860-31443410;31459210-31460210;31472130-314 72890;31475740- 31476320;31476610■31477760;31487100■31489060;31569200-31 569780;31700630- 31701260;31713140■31713840;31819280■31819960;31873650-31 874340;46830410- 46831180;46843930■46844730;46883880■46885450;46973430-46 974060;47037250- 47038310;47142590■47143640;47460780■47461500;48244070-48 244780;48810810- 48811690;49280820■49281520;49838310■49839040;49857510-49 858130;49858440- 49859540;50065950■50066940;50673300■50674220;50693170-50 693780;51134660- 51135210;51150210■51151000;51152570■51153210;51155890-51 156560;53054750- 53055370;53434160■53434710;54281880■54282440;54284480-54 285880;54286610- 54287160;54931250■54931810;54932010■54933140;54933370-54 933950;54936360- 54937280;54937330·■54937990;54938520■54939090;55324460- 55325180;55656540- 55657250;56190500■56191060;56191730■56192350;56588910-56 590010;56625040- 56625760;56662920■56663550;56729860■56730560;56989200-56 989960;57092960- 57093530;57245000·■57245850;57283730·■57285220;5753619 0-57536810;57996730- 57997950;58000750·■58001330;58025230·■58027410;5812883 0-58129550;58249640- 58250420;58392370·■58392970;58463970■58464870;58500540- 58501090;58515460- 58516020;66270450■66271060;66402630■66403210;66549310-66 550330;66604090- 66605740;66695800■66696370;66696970■66697540;66844180-66 845390;66880140- 66881360;66921800■66922590;66924810■66925830;66933880-66 934780;67000220- 67001110;67013570■67014370;67029460■67030220;67109380-67 110460;67149190- 67151020;67154660■67156060;67159200■67160450;67162640-67 164210;67165070- 67166260;67173960■67174830;67183460■67184350;67184410-67 185200;67236840- 67237560;67247040■67247800;67248350■67249410;67278850-67 280110;67326420- 67327380;67393240·■67393800;67394590■67395330;67415930- 67416830;67430270- 67430990;67480880■67481460;67528990■67529550;67561860-67 562640;67563060- 67563610;67644540■67645480;67648620■67649200;67659390-67 660810;67661100- 67661770;67665960■67667530;67718750■67719670;67841860-67 842440;67847100- 67847750;67872710·■67873780;67892990■67893840;67935240- 67936800;67967840- 67969070;67980030■67980800;68022960■68023550;68084510-68 085220;68085390- 68086150;68234940■68236570;68236880■68238490;68244820-68 245720;68264650- 68265320;68446750■68447640;68447900■68448940;68737710-68 738640;69105630- 69106240;69106570■69108150;69132440■69133100;69311140-69 312220;69329520- 69330570;69338810■69339930;69385740■69386580;69565850-69 567010;70381380- 70381960;71358330■71359100;71625980■71626790;71883480-71 884580;73047620- 73048200;74296900■74297560;74700130■74700790;74774200-74 774990;74984590- 74985160;74999610■75000200;75478490·■75479690;75516680- 75517290;75529090- 75530270;75647650·■75648810;77434560■77435220;79599510- 79600200;83807810- 83808500;85612860■85613690;85799050■85800070;85898560-85 899380;86508030- 86508910:86509230■86510190:86510460■86511680;86515540-86 516090;86567190- 86567850;86578450-86579640;87602960-87604120;88436880-884377 90;88454490-

88455050;88455540-88456130;88569770-88570330;88785260-887 85990;88811360-

88812280;88940170-88941050;89278970-89279690;89507500-895 08250;89508280-

89508900;89560740-89561490;89576210-89577050;89700610-897 01730;89711580-

89712490;89720360-89722500;89850070-89850820;89971790-899 72360;90018710-90019260; 180160-

181030

Chromosome 17 491230-491880;731710-732270;732800-733490;751540-752160;7522 60-

752930;781710-782410; 1108790-1109840; 1179290-1179860; 1229410-1230130; 1267970-

1268640; 1271130-1271720; 1399900-1400760; 1455500-1456390; 1487160-1487720; 1561700-

1562330; 1628810-1629940; 1643400-1644360; 1649170-1649800; 1709740-1710760; 1715910-

1716520; 1724070-1725270; 1998190-1999130;2023670-2026110;2029810-2030420;2051020-

2051570;2053480-2054300;2054860-2055430;2056410-2057250;2 057730-2059080;2303370-

2304190;2336730-2337460;2393480-2394180;2399640-2400850;2 697990-2698540;2852790-

2853350;3386310-3386870;3636680-3637230;3667810-3669500;3 695680-3696540;3723610-

3724660;3845660-3846610;3892090-3892850;4142420-4143410;4 263210-4263920;4365110-

4366760;4499380-4500400;4584100-4585410;4710340-4711130;4 739440-4740390;4789540-

4790570;4833070-4834040;4939460-4940350;4947790-4948550;4 949350-4949920;4986860-

4988070;5078140-5078710;5191470-5192050;5419040-5419780;6 443830-6444830;6454860-

6455620;6555560-6556240;6995720-6996490;7012250-7012950;7 014540-7015360;7021830-

7022650;7043240-7043980;7173670-7174260;7214160-7214990;7 238700-7239510;7260920-

7262890;7281750-7282510;7294640-7295270;7295530-7296270;7 307160-7307780;7314770-

7315800;7328710-7329780;7351240-7352530;7380790-7381440;7 383470-7384810;7392870-

7393570;7394160-7395310;7404640-7405880;7436300-7437750;7 439610-7440160;7478890-

7479480;7548660-7549500;7561730-7562630;7573420-7574020;7 583530-7584110;7588920-

7589900;7651340-7652030;7688260-7688820;7717210-7717800;7 841310-7841950;7843380-

7843930;7851830-7852400;7853010-7853570;7887570-7888220;8 002520-8003270;8003370-

8004150;8072740-8073350;8078940-8080360;8109780-8110580;8 121400-8122260;8122330-

8123700;8188920-8190490;8383450-8384150;8435720-8436450;8 629420-8630150;8631150-

8631800;8965100-8966120;9003700-9004480;9020700-9021400;9 021740-9023790;9645710-

9646460; 10197780-10198660; 11241690-11242260;11997030-11997610; 12665330-

12665950; 12789420-12790360; 13600240-13602050; 14301120-14302980; 14345050-

14345720; 15262450-15263030; 15944360-15946110; 16000080-16000640; 16217110-

16217710; 16352620-16353290; 16406850-16407440; 16568380-16569470; 17205540-

17206420; 17494970-17496500; 17591160-17591950; 17682160-17682750; 17724480-

17725250; 17781810-17782510; 17782740-17783610; 17809580-17810680; 17810750-

17811330; 17836090-17837410; 17839950-17840660; 18038530-18039620; 18039640-

18040330; 18118620-18120270; 18183370-18185150; 18257910-18259150; 18314320-

18314870; 19003370-19004290; 19362120-19363150; 19378440-19379500; 19648140- 19648690; 19867860 -19868410; 19977330 -19978190;20009310 -20010180;21126730- 21127580;21375740 -21376340;21376870 -21377430;27793250· -27794200;27892890- 27893700;2822717O -28228170;28251030· -28251820;28306800 -28307580;28318460- 28319010;28357090 -28357810;28371550 -28372730;2838099O -28381960;28405730- 28406640;28552000 -28552890;28570950· -28571820;28644850 -28645500;28661650- 28662210;28716990 -28718360;28725520· -28726270;28726370· -28727500;28728430- 28729190;28744280 -28744960;28897180 -28898030;28902140 -28903470;28949760- 28950320;2895127O -28951820;29176480 -29177130;29565910 -29567050;29567200- 29568500;29572460 -29573370;29612020· -29613970;29615770 -29616380;29617660- 29618500;29622270 -29622850;29760830· -29761380;30235310 -30235990;30378920- 30379970;30824050· -30824800;30831850 -30832440;30921680 -30922240;30922250- 30923080;31391040 -31391590;31549390 -31550060;31559430 -31560470;31916650- 31917400;32006800 -32007560;32007590· -32008200;32266280· -32267130;32341910- 32342530;32444210· -32445050;32487510 -32488560;32876330 -32876950;33291210- 33291870;34579390 -34580350;34580710 -34582260;34626010 -34627080;34637480- 34638320;35119590 -35120140;35141790 -35142400;35587250 -35587810;35740770- 35741730;35794870 -35795910;36482640 -36483500;36545290 -36546060;36591440- 36592360;36601300 -36602080;36808040 -36808810;36935000 -36935560;36940200- 36940890;36941920 -36943140;36948760 -36949570;37358540 -37359980;37488970- 37489640;37490130 -37490690;37744350 -37744950;38352120 -38353060;38418620- 38419210;38509610 -38510190;38561240 -38562630;38563160 -38563730;38578180- 38579140;38673170 -38675540;3870237O -38703050;38704480 -38705140;38747270- 38748230;3874872O -38750350;38752780· -38753480;38798900 -38799550;38869450- 38871010;39197020 -39197880;39209540 -39210450;39224590 -39225970;39401050- 39402370;39605070· -39607330;39626830 -39627800;39668220 -39668790;39687710- 39688320;39730090 -39730900;39753870· -39754790;39927170 -39927820;40092890- 40093450;40122590 -40123490;40177510 -40178530;40191130 -40192070;40341040- 40341920;40341990 -40342900;40361340 -40361920;40362360 -40362920;40363470- 40364060;40417440 -40418010;41527400 -41527970;41733770 -41734540;41785890- 41786950;41810890 -41812290;41835760 -41836500;41864390 -41865540;41966400- 41967480;42039710 -42040700;42072170 -42073090;42107410 -42108160;42122470- 42123140;42180320 -42181630;42183880 -42184530;42287990 -42289100;42387780- 42388780;42404790 -42405550;42422450· -42423610;42566570 -42567830;42670340- 42671580;42672010 -42672570;42675530· -42676770;42679430 -42680670;42683630- 42684290;42684880 -42685700;42687310 -42688070;42760720 -42761590;42780750- 42781320;42785030 -42785800;42798330 -42799050;42980420 -42981460;43021600- 43022620;43545880 -43546580;43645780 -43646510;43754980 -43756120;43778020- 43778930;43832530· -43833880;43937700 -43938320;43952830· -43953680;43983570- 43984260;43994530■43995180;44004290■44006710;44066140-44 066930;44123110- 44123720;44314680■44315350;44315370■44315970;44324160-44 325420;44326290- 44326940;44354760■44355390;44363130■44363730;44502890-44 503950;44557400- 44559660;44758320■44758880;44774910■44776310;44829310-44 829980;44830420- 44830980;44898930■44899690;44947230■44948020;44959780-44 960590;44966820- 44967830;44968440■44969010;44969940■44970880;45021560-45 022400;45120720- 45121470;45131780■45132550;45132800■45133410;45144460-45 145040;45147140- 45148050;45149420■45150390;45247400■45248530;45261790-45 262480;45316720- 45317510;45395280■45395900;45396030■45396850;45405670-45 406220;45783340- 45784180;45784770■45785670;45893990■45894900;45894980-45 896040;46192560- 46193470;46768300■46768850;46769490■46770360;46772020-46 772730;46818400- 46819460;46851580■46852350;46978390■46979710;47253470-47 254130;47423270- 47423930;47649350■47649930;47709210■47709780;47732830-47 734140;47840690- 47841410;47847070■47848630;47850390■47851560;47895950-47 896920;47941330- 47941900;47970650■47971490;48023520■48024540;48048000-48 048740;48100740- 48101670;48429770■48430690;48526790■48527590;48543350-48 544020;48550450- 48551000;48581890■48582450;48592870■48594070;48596180-48 596820;48597410- 48598320;48610160■48610730;48614100■48614990;48615370-48 615990;48625740- 48626390;48633130■48634030;48646090■48647060;48817090-48 817800;48995820- 48996470;48997440■48998260;49013580■49014220;49132700-49 133480;49230360- 49230910;49259960■49260960;49494940■49495740;49495850-49 497170;49497190- 49497870;49506070■49506930;49576030■49576760;49677870-49 678450;49909900- 49910880;49968240■49969720;49971370■49972390;49972680-49 973250;49996660- 49997260;50055700■50056970;50095170■50095770;50117020-50 117960;50129890- 50130520;50149130■50150240;50397160■50397710;50425650-50 426560;50478530- 50479240;50508180■50508760;50541820■50542740;50560350-50 560910;50560980- 50561790;50634450■50635380;50719410■50720230;50865320-50 867260;51119780- 51120720;51165930■51167320;51260620■51261330;52157680-52 158620;55265420- 55265970;55421500■55422240;56592330·■56592950;56593610- 56595190;56595860- 56596410;56834000■56835200;56913350■56914670;57045660-57 046700;57085330- 57086330;57255890·■57256450;57884970■57885870;57954320- 57954920;58006440- 58007400;58156890■58157440;58278890■58279630;58324340-58 325280;58487210- 58488190;58514120■58514940;58517610■58518270;58755510-58 757050;59106210- 59107030;59332010■59332640;59892690■59893240;60149780-60 150640;60392080- 60392860;60421180■60422110;60600050■60601120;61395950-61 397730;61398750- 61399720;61402900■61403640;61404220■61406000;61412660-61 413210;61451970- 61453000;61454250■61455170;61456200■61457470;62137990-62 139300;62627210- 62628610:62679680■62680460:63445630■63447110;63538010-63 538600;63550140- 63551 170;63600680 ^■ 63601540;63698500 ^■ 63699160;63773160-63773750;63848860- 63849770;64129270 ^■ 64130970;65055630 ^■ 65056260;66302920-66303670;67366190- 67366760;67377670 ^■ 67378610;68035640 ^■ 68036430;68291710-68292280;68512320- 68512970;68599900 ^■ 68600710;69326430 ^■ 69327020;70168920-70169560;721 17760- 721 18420;72121 130 ^■ 72122220;72122420· ^■ 72123240;72591470-72592070;73192290- 73192840;73193120 ^■ 73193720;73310780· ^■ 73312680;73644230-73644830;74213200- 74214240;74325540 ^■ 74326490;74351590 ^■ 74352520;74356430-74358030;74431450- 74432060;744321 10 ^■ 74432680;74453700 74454250;74670960-74671750;74736540- 74737460;74748900 ^■ 74749530;74843160 ^■ 74843720;74851840-74852670;74892980- 74894160;74919430 ^■ 74920500;74923150 ^■ 74923750;74923880-74924550;74935860- 74936410;74972270 ^■ 74973320;74987460 ^■ 74988830;750031 10-75004090;75076990- 75077950;75131 130 ^■ 75131700;75153890 ^■ 75154610;75261 170-75261940;75270240- 75270910;7540503O ^■ 75405960;75514790 ^■ 75516500;75525810-75526380;75588420- 75589320;75720930· ^■ 75721860;75753400· ^■ 75754450;75764400-75765400;75784480- 75785450;75877680· ^■ 75878320;75896640 ^■ 75897230;75978700-75979700;76015020- 76015570;76071850 ^■ 76072710;76073940 ^■ 76075090;76076380-76077630;76121700- 76122670;76139830 ^■ 76140780;76140990 ^■ 76141780;76353060-76353790;76382670- 76383700;7638374O ^■ 76384310;76384750 ^■ 76385670;76385780-76386330;76452270- 76453500;76500770· ^■ 76501640;76537960 ^■ 76538700;76585540-76586230;76725850- 76727330;76736040· ^■ 76737260;76868840 ^■ 76869400;76869580-76870590;77957630- 77958440;78131410 ^■ 78132260;78168120 ^■ 78169170;78253870-78254860;78313640- 78314350;78358340 ^■ 78360120;78839860 ^■ 78841420;79023990-79024820;79183500- 79184240;79609680 ^■ 79610340;79748000 ^■ 79748550;79789560-79791 180;79791 190- 79792050;79796450 ^■ 79797420;79797790· ^■ 79798650;79798700-79799490;79800450- 79801670;79803930 ^■ 79804820;7981 1080 ^■ 7981 1910;79814780-79816290;79833600- 79834630;79839620 ^■ 79840340;79841370 ^■ 79842060;79842900-79844760;79950210- 79950820;80036050 ^■ 80037090;80146410 ^■ 80147130;80220050-80221210;80476730- 80478690;81222510 ^■ 81223640;81238400 ^■ 81239700;81294750-81295700;81341460- 81342260;81342550 ^■ 81343200;81345250 ^■ 81345940;81386570-81387860;81483790- 81484860;81487530 ^■ 81488320;81498850 ^■ 81499670;81514290-81514870;81518990- 81520000;81536460 ^■ 81537090;81551600 ^■ 81553100;81647580-81648220;81665990- 81667050;81683470 ^■ 81684510;81702990 ^■ 81703590;81832460-81833010;81860720- 81861690;81890590 ^■ 81891 170;81891670 ^■ 81892330;81901950-81902780;81917310- 81918270;81926630 ^■ 81927200;81927740 ^■ 81928320;81936780-81937770;81959240- 81959790;81959830 ^■ 81960840;81977090 ^■ 81977760;82023330-82024000;82030070- 82030630;82030680 ^■ 82031420;82032010 ^■ 82032560;82097470-82098050;82098910- 82099540;82212580 ^■ 82213480;82228120· ^■ 82228800;82273080-82274050;82333370- 82333960:82374260 ^■ 82375020:82458660 ^■ 82459510;82496660-82497340;82697590- 82698330;82698720-82699450;82751800-82752480;83051280-830518 30;83078740-83079340; 158140- 158910;657460-658040

Chromosome 18 712190-713110;906490-907050;2655830-2656580;2846450-2847040; 2906010-

2907130;3261560-3262390;3449570-3450470;3499070-3499650;3 879130-3880120;5628440-

5629400;5629790-5630800;6729580-6730190;7116710-7117420;7 566380-7566940;7567520-

7568390;7568440-7569000;8609860-8610510;8706340-8706920;9 136380-9137060;9334820-

9335420;9475420-9476050;9708570-9709120; l 1148500-11149520; 11689050-11690060; 11751330-

11752150; 11752350-11752940; 11908500-11909250; 11981440-11982210; 12038310-

12039200; 12308460-12309030; 12376560-12377270; 12656910-12657620; 12883090-

12883640; 12911580-12912730; 12947930-12948740; 13136500-13137560; 13218070-

13218730; 13725980-13726530;21600580-21601180;21704070-21705100;217411 80-

21742010;22169350-22170400;22171000-22171620;22176660-221 77460;23134900-

23135490;23136270-23137170;23453150-23453780;23619280-236 20150;23689080-

23690600;24014000-24014690;24014800-24015520;24397180-243 98050;24426370-

24427270;26089930-26090630;26226500-26227420;26546750-265 48210;31042310-

31042860;31101780-31102540;31497480-31498150;31942460-319 43010;32092570-

32093500;34222350-34223570;35041450-35042000;36128690-361 29860;36295800-

36296500;36298060-36298770;36828540-36829210;37253250-372 53960;37274240-

37275380;37565050-37565860;37566700-37567730;45837300-458 38060;46071600-

46072650;46173740-46174810;46333310-46333860;46679930-466 80610;46756170-

46757140;47246390-47246940;47248470-47249370;47251170-472 52000;47931040-

47931640;48029250-48030030;48161770-48162430;48409770-484 10530;48539120-

48540380;48540550-48541400;48949630-48950310;48951340-489 51970;48952250-

48953210;49460190-49460750;49813180-49813800;50194250-501 94870;50281540-

50282170;50282400-50283070;50728830-50729520;50878790-508 79960;55780010-

55780740;57436030-57437100;57441050-57441910;57586190-575 87100;57802260-

57803070;57803420-57803990;58671490-58672240;59268670-592 69240;59272200-

59273480;61554040-61554890;62187310-62188140;62522220-625 22770;62523850-

62524610;62596130-62597020;63317890-63318790;65750560-657 51610;67516060-

67516620;75204350-75205280;75455350-75456300;76441700-764 43100;78972890-

78973570;78973720-78974820;78977000-78977560;78980720-789 81410;78993430-

78994430;78994870-78995720;79069220-79069770;79637730-796 38850;79679230-

79679910;79787600-79788580;79798220-79799000;79950630-799 51180;79951830-

79952520;79964170-79964840;79988010-79988660;80034310-800 34860;80159600-

80160740;80246760-80247330

Chromosome 19 266870-267870;290670-291270;489170-489920;497740-498530;5073 60-

507970;530880-531550;590690-591820;719590-720320;796610-7 97160;821200-821810;852620-

853680;860380-861140;917220-918180;919040-920860;983940-9 84490; 1008750-1009350; 1026240- 1027190; 1028310-1028950; 1066670-1067890; 1070730-1071300; 1103980-1104690; 1104780-

1105960; 1173000-1173830; 1206530-1207220; 1241400-1242790; 1260660-1261600; 1266370-

1267640; 1299670-1300230; 1315570-1316180; 1383640-1384410; 1400870-1401930; 1437810-

1439130; 1444630-1445180; 1446240-1447200; 1450040-1450680; 1454960-1455550; 1456740-

1457300; 1465010-1466130; 1466350-1468420; 1468450-1469020; 1469920-1470750; 1478790-

1479690; 1491130-1491800; 1513350-1513950; 1556460-1557110; 1584960-1585630; 1748140-

1748920; 1749160-1749960; 1755060-1755630; 1757420-1758230; 1774850-1775590; 1776000-

1776670; 1854350-1854910; 1856940-1857510; 1884680-1885240; 1905170-1905860; 1978510-

1979460;2096290-2097450;2226880-2227430;2235490-2236540;2 236640-2237260;2250560-

2251310;2252100-2252650;2289750-2291550;2307390-2308020;2 328490-2329470;2427160-

2427940;2462110-2462700;2474390-2475210;2476150-2476970;2 610970-2611550;2717110-

2718190;2739760-2740370;2782820-2783470;2785340-2786010;2 840790-2842300;3275460-

3276070;3358370-3359220;3367080-3367870;3381320-3382360;3 434840-3435590;3462830-

3463660;3491280-3492130;3572450-3573760;3574080-3574630;3 577680-3578440;3599880-

3600690;3606280-3607230;3611770-3612570;3613030-3613650;3 626340-3626900;3785370-

3786110;3868610-3869310;3959060-3959760;3970700-3971440;4 054550-4055470;4172880-

4173520;4182110-4182840;4278740-4279920;4326820-4327480;4 493950-4494560;4651890-

4652550;4723210-4724010;4909020-4909760;5243680-5244520;5 593500-5594420;5622150-

5623830;5661380-5661940;5680150-5681530;5686340-5687700;5 690410-5691050;5803710-

5804540;5977510-5978230;6110310-6110890;6361360-6362090;6 392700-6393600;6459110-

6460070;6463820-6464830;6475240-6476020;6530980-6531640;6 740550-6741250;7098760-

7099820;7293270-7293890;7395170-7395800;7466910-7467470;7 500670-7501750;7519370-

7520660;7549850-7550670;7550930-7551490;7554460-7555110;7 555200-7555850;7596440-

7596990;7611720-7612430;7612560-7613240;7680230-7681540;7 681900-7682930;7729870-

7730470;7861690-7862610;7862860-7863900;7868740-7870190;7 872200-7872780;7873360-

7873950;7903390-7904010;7915790-7917240;7917280-7918120;7 919960-7920660;7924450-

7925120;7943240-7944180;8149000-8149600;8208520-8209100;8 209380-8210040;8333670-

8334940;8335540-8336100;8342620-8343640;8364050-8364780;8 390100-8390830;8413130-

8413760;8485510-8486080;8513680-8514360;8526300-8526900;8 584740-8585760;8697800-

8698440;9160570-9161400;9435070-9435620;9818330-9819110;9 913000-9913640; 10085950-

10086500; 10086820-10087370; 10119390-10120430; 10194420-10195240; 10224240-

10224840; 10230070-10230960; 10230990-10231710; 10252090-10252820; 10269890-

10270930; 10287580-10288140; 10290740-10293540; 10293720-10294920; 10295030-

10295960; 10332890-10333730; 10352670-10353540; 10416150-10417000; 10419310-

10420460; 10420610-10421500; 10424050-10424960; 10431600-10432160; 10432180-

10432730; 10479090-10479740; 10491490-10492470; 10502210-10503700; 10513860-

10515230; 10543820-10544370; 10565670-10566220; 10568210-10569560; 10602540-

10603110; 10717730-10718770; 10928190-10929630; 11033470-11034020; 11197400- 11198050;1134592011346610;1138151011382240;11382380-11382940 ;11383060- 11383960;1142226011423130; 1147924011479790; 11479970-11481010; 11483330- 11484300;1150521011505760;1163977011640320; 11694490-11695170; 11738330- 11739010;1179833011799200;1181410011814900;11925190-11925740 ;11987690- 11988320;1206461012065230;1213939012140510;12550920-12551470 ;12596770- 12597480;1266961012670400; 1269595012696660; 12720720-12721690; 12733880- 12734870;1275445012755180;1275741012758330;12782070-12783120 ;12791290- 12793190;1279347012794330;1280090012802130;12833880-12834780 ;12847380- 12848230;1285827012858910;1287317012875010;12884950-12886200 ;12938610- 12939320;1294561012946500; 1295660012957360;12983490-12984070;12996300- 12997090;1301003013010740;1301171013012690;13024430-13025700 ;13098510- 13100010;1314942013150160;1315194013152510;13152770-13153950 ;13162800- 13163500;1320858013209140;1329867013299550;13505670-13506400 ;13808720- 13809440;1383017013831060;1390604013906790;13952060-13952720 ;13962660- 13964220; 1400650014007060;1407194014073430;14075070-14075750;14136250 - 14137530;1416261014163490;1441899014419760;14433630-14434180 ;14473070- 14473700;1510973015110420;1511328015114150;15125030-15126020 ;15177170- 15177770;1522336015224100;1523173015232870;15233030-15233650 ;15379130- 15380720;1543274015433360;1546937015470250;15508160-15508860 ;15555820- 15556370;1607609016077230;1611163016112180;16326590-16327470 ;16471100- 16472420;1652501016525950;1654171016542790;16571520-16572130 ;16627410- 16628050;1662818016629210;1666046016661040;16896080-16896810 ;16897330- 16898170;1707498017075530;17226260· 17226870;17235240-17236070;17281910- 17282480;1732719017327930;1732815017329720;17333300-17333930 ;17334090- 17335160;1739036017390990;1741972017420700;17511590-17512580 ;17539080- 17539840;1755580017556550;1760567017606590;17648300-17649030 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19405000■19405630; 19513900-19515690; 19537070- 19537700; 19538110■19538820; 19539770■19540570; 19540610-19541340; 19543920- 19545790; 19627660■19628570; 19637800■19638570; 19663030-19664100; 19732320- 19733310;21586260■21587020;29212650■29213250;29529440-29 530440;29664930- 29665690;29715140■29715820;29812460■29813140;29873290-29 873850;30227190- 30228580;30443510■30444960;31348650■31349400;31351300-31 352170;32674360- 32677170;33063760·■33064850;33064940■33065670;33225020- 33226220;33301020- 33301620;33521310■33521960;33622030·■33623350;33771890- 33773080;33797000- 33797900;33798170·■33798750;33810970■33811890;33905790- 33907220;34171900- 34172450;34172600■34173200;34254910■34255540;34404250-34 404880;34428600- 34429180;34905030■34905580;35142610■35143720;35267020-35 267840;35533320- 35533880;35544820·■35546270;35558110■35558880;35644210- 35644980;35716110- 35717000;35717150■35717840;35755340■35756440;35756620-35 757180;35775200- 35775850;35845640■35846260;35856490■35857260;35900160-35 900840;35944370- 35945030;35958800■35959820;35994900■35996020;36009220-36 009770;36026150- 36026700;36054370■36055390;36113360■36113960;36115090-36 115740;36245600- 36246300;36418130■36418890;36488890■36489480;36605240-36 605900;36666910- 36667550;37078140■37078690;37466560■37467380;37551110-37 551780;37594690- 37595350;37691810■37692480;37906970■37907870;38082510-38 083140;38222190- 38222860;38223700·■38224760;38228550·■38229440;3825595 0-38256930;38264370- 38265060;38315310■38316380;38319540■38320570;38362020-38 362910;38374530- 38375420;38386720·■38387400;38387580■38388440;38388490- 38389320;38395260- 38395940;38403150■38403910;38561010■38561640;38565530-38 566150;38647310- 38648120;38849490■38850250;38869910■38870790;38899180-38 900240;38975140- 38975800;39031670■39032630;39125590■39126180;39196820-39 197430;39203820- 39204410;39307230■39308800;39313920■39315560;39390580-39 391200;39402450- 39403170;39409600■39410440;39498870■39499540;39502560-39 503150;39507290- 39507840;39514810■39515860;39532180■39533130;39914930-39 915790;40190800- 40191400;40191870■40192730;40217020■40217770;40217930-40 218680;40226070- 40227020;40403590 40404450;40425230■40425800;40465490-40466170;40512280- 40513030;40513070■40513820;40519240■40520280;40548950-40 549760;40553760- 40554890;40567500■40568550;40570160■40570970;40599960-40 600610;40604820- 40606040;40609300■40610060;40613070■40613620;40614310-40 614860;40690150- 40690720;40750630■40751180;41192810■41193460;41226090-41 226790;41262110- 41262890;41264280■41265020;41353220■41353830;41882490-41 883790;41884060- 41884640;41927600■41928350;41928540■41929140;41993770-41 994560;42075670- 42076730:42095270·■42095820:42216590■42217680;42254680- 42255610;42268020- 42268860;42279890■42280900;42301870■42302850;42313130-42 313910;42323380- 42324630;42325400·■42326450;42422980■42423540;43475230- 43475780;43591880- 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55083880;55092210-55092970;55173400-55173950;55354160-553 54980;55408050-

55408610;55451330-55452380;55480950-55481740;55482510-554 83350;55486330-

55486880;55516920-55517550;55529870-55530470;55578430-555 79280;55597370-

55597960;55600480-55601070;55602180-55602870;55605100-556 06140;55615310-

55616970;55621660-55622870;55640560-55641700;55642380-556 43190;55647780-

55648660;55654300-55655600;55675000-55675810;56088540-560 89210;56146800-

56147500;56217210-56218020;56507440-56508340;56538160-565 38730;56621560-

56622940;56643110-56643810;56663650-56665040;57559150-575 59940;57599910-

57600520;57663900-57664860;57726960-57727550;57934890-579 35440;57947620-

57948230;58059350-58060290;58183080-58183760;58216770-582 17470;58326910-

58327850;58347100-58348150;58350130-58351120;58355850-583 57250;58362600-

58363450;58367590-58368690;58408220-58409310;58455410-584 56580;58466750-

58467640;58513670-58514620;58519160-58520260;58554650-585 55360;58561970-

58563480;58572530-58573670;58575220-58576000;263540-26439 0;287540-288150;314420-

315090; 1476960-1477910;1649160-1649710; 1744170-1744930; 1891830-1892500;3518920-

3519860;3703260-3704220;5692610-5693230;5693350-5694270;5 695940-5696730;6865000-

6866230;8645290-8645910;8685130-8686230;9002800-9003500;9 004010-9004570;9207260-

9207890;9422680-9424360;9473620-9475320;9555820-9556490;9 630000-9630610; 10121920-

10122730; 10122810-10123740; 10302490-10303990; 10448740-10449340; 10720980-

10721600; 10912410-10913510; 11465610-11466180; 11481930-11482520; 11483030-

11483610; 11669260-11670220; 11746510-11747070; 12716910-12717980; 12718330-

12718890; 14632220-14633060; 14633770-14635300; 15940350-15941090; 15941810-

15942440; 16507940-16508650; 17878750-17879560; 18584260-18585040; 19989660-

19990620;20012140-20012710;20225160-20225740;20447210-204 48250;20650750-

20651490;20665750-20667040;23926130-23927630;23940610-239 41180;24009910-

24010600;24049480-24050710;24075900-24076670;24174710-241 75480;24359930-

24360480;25042000-25042880;25131250-25131980;25672630-256 73280;25673790-

25674340;25877840-25878840;25981450-25982240;25982270-259 82960;26034000-

26034990;26345760-26346570;26727350-26728810;26764280-267 64940;26785720-

26786810;26848180-26849110;26849440-26850010;26970140-269 70880;27032580-

27033530;27049880-27050680;27051320-27051870;27071140-270 72230;27085470-

27087120;27134120-27134740;27211300-27212290;27212300-272 13070;27261670-

27263010;27264250-27265420;27307170-27308510;27370150-273 70710;27380580-

27381230;27409210-27410150;27442230-27443140;27735320-277 35870;27771500-

27772150;27890170-27891200;28390310-28391000;28392400-283 94030;28810650-

28811410;28894580-28895180;29920070-29920630;30230860-302 31910;31137180-

31138990;32063840-32064390;32357070-32357880;32946990-329 47540;36356320- 36357060;36966170 ^■ 36966810;37324960 ^■ 37325560;37344620-37345320;37671010- 37671610;38074310 ^■ 38075550;38376300· ^■ 38376860;38602060-38602970;38959740- 38960430;42047280 ^■ 42047830;42101340 ^■ 42101890;42492360-42493810;42792590- 42793470;43224890 ^■ 43225460;44928450 ^■ 44929510;44942350-44943060;44944150- 44944840;45008230 ^■ 45009140;45010230 ^■ 45010840;45013400-45014420;45169100- 45170090;45651890 ^■ 45652650;46298730 ^■ 46299280;46698740-46699370;47520510- 47522020;47569580· ^■ 47570180;47570520· ^■ 47571 100;47571250-47571810;51027340- 51028460;53786760 ^■ 53787440;53970230· ^■ 53970820;54557690-54558440;54629110- 54629670;54725010 ^■ 54725570;55049450· ^■ 55050380;58240780-58241330;60460270- 60462260;60554080 ^■ 60555140;60581590 ^■ 60582220;61065770-61066450;61 176680- 61 177380;61470980 ^■ 61471540;61853790 ^■ 61854340;62196050-62196910;63047260- 63049010;63050490 ^■ 63051 100;63052750 ^■ 63053450;63055290-63056250;63058620- 63059440;63841020 ^■ 63841880;64454690 ^■ 64455240;64524250-64525070;64652880- 64653480;64654190 ^■ 64654760;64767900 ^■ 64768470;64988350-64989190;64989280- 64990380;65056300 ^■ 65057130;65129670 ^■ 65130230;65227420-65228370;65313580- 65314240;66433740 ^■ 66434600;66575810 ^■ 66576360;66581340-66582030;68319020- 68319980;68643170 ^■ 68644000;68654900 ^■ 68655450;69306470-69307430;69386630- 69387780;69643100 ^■ 69643940;69741750 ^■ 69742480;69829410-69830530;69914900- 69915990;70553420 ^■ 70554640;70790380 ^■ 70790950;70888760-70889400;70901 160- 70902080;70994870 ^■ 70995540;71129620 ^■ 71 130360;71226330-71227280;71276560- 71277170;71331640 ^■ 71332420;71453400 ^■ 71454180;71465920-71466520;72143590- 72144450;72144490 ^■ 72145130;72147000 ^■ 72147980;72149140-72149690;72825380- 72826170;7288705O ^■ 72888100;72915930 ^■ 72916640;72917140-72918890;72919770- 72921000;72923990· ^■ 72924950;73070590· ^■ 73071240;73071420-73072320;731 1 1970- 731 12660;73175550 ^■ 73176440;73177100 ^■ 73177780;73202470-73203100;73233510- 73234150;73268560 ^■ 73269280;73284130 ^■ 73284690;73291220-73292260;73385930- 73386560;73984040 ^■ 73984630;74002130 ^■ 74003340;74147460-74148260;74178100- 74178920;74198680 ^■ 74199510;74414530 ^■ 744161 10;74421290-74422250;74441070- 74442480;74457030 ^■ 74458200;74464500 ^■ 74465230;74482020-744831 10;74497860- 74498670;74507120 ^■ 74507850;74514030 ^■ 74516720;74529340-74530580;74548980- 74549880;74553930 ^■ 74555200;74647620 74648340;74654410-74654960;74833940- 74835310;75199200 ^■ 75199830;75560540 ^■ 75561210;75710420-7571 1290;80302240- 80303740;84879780 ^■ 84880540;84880570 ^■ 84881400;84904790-84906160;84971740- 84972310;85132790 ^■ 85133370;85133850 ^■ 85135630;855841 10-85584840;85602070- 85603220;85611340 ^■ 85612450;85754080 ^■ 85755290;85888280-85888870;86336730- 86337370;86441860 ^■ 86442420;86622680 ^■ 86623250;88055010-88055940;88451560- 88452120;88626490 ^■ 88627460;961 15520 ^■ 961 17520;96144550-96145100;96145230- 96145800:96207850 ^■ 96208670:96264970 ^■ 962661 10;96321 1 10-96322320;96324940- 96325530;96335660-96336270;96500320-96501000;96536770-965382 30;96637590-

96638140;96638150-96638720;96817120-96817750;96839700-968 40340;96857490-

96858490;96868250-96870610;97663920-97664660;97723720-977 24820;97995080-

97995670;98086510-98087550;98821790-98822410;98822730-988 23690;99140950-

99141500;100322040-100322780;100818370-100819130;10082050 0-100821220;101252820-

101253740;101307830-101308900;101473900-101474670;1023555 50-102356220;104842560-

104843690;104844300-104845360;104853930-104854500;1048564 10-104857000;104862040-

104862760;105337440-105338060;105398670-105399830;1058810 00-105882120;106065330-

106065880;106193480-106194030;106886000-106886630;1068869 10-106887720;107986360-

107986910;109128000-109129890;109614900-109615770;1106775 40-110678240;111117600-

111118170; 111118990-111119690; 111120300-111120910; 111120970-111121780; 111122810-

111123360;112055410-112056200;112137930-112138480; 112275390-112276070;112541790-

112542980;112645090-112645900; 113198580-113199620; 113275740-113276360;113277340-

113277990;113756210-113756930;115161810-115162760; 117859650-117860200; 118835390-

118836410;118841960-118842510;118842870-118843440;1188555 40-118856230;118857430-

118858000; 119157510-119158280;119158400-119159200; 119366600-119367470; 119431500-

119432330;119523750-119524620;119544070-119545220;1200132 80-120013840;120313740-

120314350;120344080-120344720;120346370-120347240;1203494 10-120350070;120576640-

120577310;120586740-120587340;120867200-120867790;1212844 20-121285440;121648800-

121649380;121649890-121650540;121736460-121737170;1217554 00-121756130;127106460-

127107420;127218650-127219420;127408100-127408820;1274226 90-127423480;127664010-

127664630;127674490-127675070;128026750-128027320;1280276 80-128028730;128233120-

128233780;128317510-128318370;128492870-128493750;1303559 60-130357070;130372080-

130372890;130797510-130798550;130836540-130837550;1310395 20-131040800;131093370-

131093930;132669050-132669990;134718010-134718670;1349187 00-134919270;135531310-

135532040;135741760-135742810;135876210-135876760;1361172 90-136118730;138779900-

138780910;143936650-143937630;144515540-144516260;1445242 90-144524850;148643940-

148645820;148875200-148876500;148887840-148888400;1504860 50-150487020;152097910-

152098910;152175350-152175960;152334970-152335730;1534778 40-153479110;154697420-

154698290;154698430-154699600;156319720-156320920;1563290 20-156330050;156333720-

156334270;156342490-156343240;156435460-156436330;1584572 10-158457780;158968160-

158969400;159797670-159798290;159904070-159904860;1604926 90-160493510;161244570-

161245480;161414300-161415000;161416380-161417340;1614184 20-161419350;161423930-

161424540;161427590-161428560;162073500-162074460;1646208 70-164621450;164840820-

164841630;165793640-165794430;167292530-167293080;1672931 60-167293840;168246320-

168246870;168456480-168457210;169362120-169363070;1693640 90-169364650;169768000-

169768980;169824400-169824960;170713150-170714360;1707158 00-170716840;170716870-

170717700;170771020-170771590;170818110-170818750;1709288 80-170929720;170973360- 170974070; 171434170■171434960; 171522260■171523260; 171894170-171894740; 172084350- 172085510; 172086320■172087180; 172088010■172088630; 172094830-172095570; 172099950- 172101060; 172101150■172101730; 172101850■172102640; 172172370-172173140; 172427530- 172428170; 172555870■172556800; 172735950■172736510; 174012660-174013210; 174248120- 174248970; 174335670■174337450; 174340040■174340900; 174342150-174342870; 174682120- 174682680; 175005030■175005720; 176081920■176082770; 176082970-176084030; 176085880- 176086520; 176093060■176093790; 176106590■176107530; 176122680-176123620; 176128680- 176129230; 176157430■176157980; 176164580■176165530; 176171270-176172590; 176188560- 176189720; 177212690■177213450; 177263740■177265200; 177392490-177393100; 178193850- 178195460; 178450460■178451020; 178480190■178481130; 181457230-181457830; 181678150- 181678890; 181891900■181892790; 182865930■182866790; 183037480-183038680; 184598510- 184599170; 185738640■185739190; 186485740■186486300; 186589550-186590710; 189580630- 189581370; 190180280■190181270; 190343510■190344300; 190534350-190535310; 191244990- 191246170; 192194220■192195540; 195656640■195657590; 196170860-196171450; 196593410- 196593970; 197453140■197453960; 197515770■197516580; 197705240-197706160; 197785780- 197787160; 197804320■197805650; 199455530■199456630; 199456810-199457520; 199459040- 199460000; 199464090■199465030; 199470560■199471150; 199471190-199471760; 199911270- 199912120;200307220■200307840;200509610■200510250;200585 700-200586330;200963180- 200963820;201116220■201116970;201450980■201452450;202032 640-202033690;202033760- 202036540;202237770·■202238610;202871180■202872160;2030 14480-203015080;203238450- 203239000;203327990·■203329060;203534600■203535160;2045 45210-204546310;205682310- 205682900;206159490■206160440;206443970■206444570;207529 550-207530290;207625010- 207626230;207766740·■207769140;207769260■207770240;2084 06320-208407040;209423720- 209424280;209771630■209772180;210224910■210225640;212538 210-212539070;212832030- 212833440;213284130■213284820;214809220■214809910;216633 770-216634360;216694040- 216694950;218009640■218011030;218217020■218217600;218387 720-218388320;218567900- 218568630;218710630■218711460;218781580■218782570;218859 840-218860500;218870990- 218872120;218873020■218874220;218880230■218881170;218892 470-218893520;218897130- 218897740;218908800■218909350;218960360■218961330;218981 910-218982600;218984180- 218984750;218993400■218994100;219002840■219003450;219057 220-219058000;219059850- 219060540;219060980■219061640;219176370■219176960;219206 590-219207390;219218200- 219219030;219229350■219229980;219253440■219254690;219387 250-219387860;219418210- 219419260;219434720■219435660;219447710■219449380;219483 260-219484150;219484280- 219485280;219496740■219497480;219541430■219542410;219542 920-219544500;219552060- 219553500;219569720■219570700;221570660■221572070;221573 230-221574140;222298150- 222299180;222319920·■222320760;222424620·■222425250;22 2860800-222861800;223944820- 223945550;224038490·■224039040;224039450■224040040;2255 82060-225582680;226797330- 226799260:227163880■227164700:229713680■229714260;230067 560-230068540;230827880- 230828850;230864410-230865540;231052650-231053260;231395050- 231395660;231395980- 231396620;231411850-231412610;231463730-231465300;231529870- 231530950;231614610- 231615170;231706450-231707530;231707600-231708500;231780660- 231781210;231786010- 231786990;231925030-231926500;232350900-232351520;232352170- 232352720;232386580- 232387730;232419080-232419900;232420360-232421190;232458510- 232459250;232485550- 232486980;232522290-232522910;232523800-232524560;232550140- 232551260;232634450- 232635010;232927240-232927810;233251730-233252330;234495690- 234496520;234952550- 234953120;235493170-235493730;235494920-235495600;236163830- 236164870;236166860- 236167760;236172560-236173650;236567670-236568660;237085760- 237086350;237626800- 237627350;237691130-237691910;238163320-238163900;238238750- 238239360;238239990- 238240590;238240750-238241330;238319910-238320550;238426180- 238426740;238426800- 238427570;238846240-238846970;238848230-238849950;240135820- 240136610;240435960- 240436940;240453740-240454320;240520340-240520930;240557540- 240558090;240560080- 240560710;240569090-240569640;240586190-240587030;240818560- 240819190;240820520- 240821560;240983050-240983910;240997980-240998620;241102000- 241102750;241356080- 241356790;241507820-241508970;241541220-241542220;241559280- 241559960;241637390- 241637990;241686380-241687470;241701300-241701900;241735140- 241735880;241803100- 241804110;241947090-241947640;297860-298780;326380-327020

Chromosome 20 380890-381520;408170-408730;663220-663930;675600-676150;8451 20-

845710; 1184650-1185410;1266260-1266990; 1466240-1467280; 1802770-1803900;2101550-

2102100;2102410-2103540;2524710-2525600;2693410-2694160;2 749260-2750040;2820920-

2821640;2840150-2841110;2872180-2873230;3045550-3046960;3 071310-3072690;3082250-

3083500;3092590-3093160;3164290-3165240;3172960-3173520;3 173800-3174640;3238440-

3240520;3470920-3471580;3660380-3661640;3673300-3674300;3 681630-3682580;3749390-

3750250;3751270-3751910;3768170-3768970;3777630-3778760;3 785250-3785960;3795560-

3796310;3820060-3820680;3889110-3889960;4221410-4222300;4 247830-4248680;4686020-

4686830;4686860-4687410;5119350-5120130;5126360-5127520;6 006000-6006680;6767960-

6769140;6769800-6770690;8132200-8133140;9068950-9069500;9 838300-9839240; 10218680-

10219270; 10672580-10673140; 10674280-10674850; 13221810-13222400; 13995440-

13996370; 17530670-17531800; 17570130-17570750; 18056730-18057370; 18288380-

18288950; 18587750-18588310; 19758160-19758830; 19975090-19975650;20016990-

20017930;20364280-20364830;20369250-20369980;20712540-207 13320;21101000-

21101900;21125630-21126280;21391230-21392120;21505840-215 07000;21511820-

21512730;21520710-21522570;21702910-21703490;21706420-217 07050;22582070-

22583630;22584670-22585330;23035470-23036120;23047720-230 49670;23361840-

23362850;23365220-23365950;23637250-23637970;24469860-244 70410;25057000-

25057840;25081370-25082160;25148110-25149000;25247370-252 47920;25389860-

25390460;25584800-25585810;25623150-25624120;31475180-314 75830;31483840- 31484710;31514140 ^■ 31515100;31723010 ^■ 31724170;31861240-31861800;31870490- 31871040;32030780 ^■ 32031560;32051810 ^■ 32052620;32189720-32190740;32207150- 32207730;3235892O ^■ 32359490;32457060 ^■ 32457660;32743240-32744020;33663310- 33663970;33666780 ^■ 33668230;3381 1 130 ^■ 33812020;33993700-33994250;341 1 1420- 341 12480;34268840 ^■ 34269550;34363590 ^■ 34364190;34558240-34559750;34676670- 34677660;34704060 ^■ 34704970;35147050 ^■ 35147600;35542100-35542650;35600620- 35602140;35615660 ^■ 35616330;35664380 ^■ 35665050;35698730-35699890;35953430- 35955280;36064510 ^■ 36065280;36091850 ^■ 36093950;36435800-36436400;36574450- 36575350;36605450 ^■ 36606410;36773330 ^■ 36774070;36815230-36816260;36863890- 36864510;37178960 ^■ 37179570;37345440 ^■ 37346000;37384690-37385550;37902410- 37902960;37903070· ^■ 37903640;38472530 ^■ 38473470;38724410-38725150;38725910- 38726790;38727070· ^■ 38728950;38748350· ^■ 38749030;38805560-38806620;38926160- 38927350;3904973O ^■ 39050620;40682940 ^■ 40684000;40687700-40689750;40689950- 40690970;41028400 ^■ 41029980;41137670 ^■ 41 138230;41316870-41317420;41618580- 41619150;43188800 ^■ 43189390;43190120 ^■ 43190690;43507290-43507950;43915040- 43916630;441 15670 ^■ 441 16580;44247050 ^■ 44247750;44310680-4431 1490;44651200- 44652200;44745520 44746450;44749930 ^■ 44750810;44909960-44910540;44966030- 44966950;45097450 ^■ 45098440;45293020 ^■ 45293910;45297940-45298600;45304100- 45304960;45306520 ^■ 45307180;45347930 ^■ 45348490;45405450-45406870;45470290- 45470980;45823800 ^■ 45824480;45833910 ^■ 45834680;45890150-45891890;4591 1600- 45912520;45932650 ^■ 45933220;46013880 ^■ 46014700;46021560-460221 10;46029060- 46029810;46057160 ^■ 46057730;46057810 ^■ 46058530;46088940-46090310;46174190- 46174790;46210010 ^■ 46210830;46250810 ^■ 46251680;46307170-46307970;46651050- 46651840;46688800 ^■ 46689800;46894970 ^■ 46895680;49318160-49319080;49481830- 49483020;49484270 ^■ 49484870;49610820 ^■ 4961 1650;49982120-49982940;501 12440- 501 13170;50190060 ^■ 50191020;50191530 ^■ 50192640;50730770-50732200;51004220- 51004940;51009460 ^■ 51010670;51022540 ^■ 51023800;51523120-51524210;51542080- 51542650;51562170 ^■ 51563040;51801680 ^■ 51802240;52104970-52105560;52191280- 52192460;54207720 ^■ 54208590;56003790 ^■ 56004450;560051 10-56005860;56467990- 56468930;56625020 ^■ 56625680;56626240 ^■ 56626940;56628860-56629630;56630620- 56631200;56925060 ^■ 56925870;57265570· ^■ 572671 10;57389090-57389890;58388720- 58389850;58514320 ^■ 58515010;58649480 ^■ 58650400;58839980-58840980;58854490- 58855530;59006590 ^■ 59007560;59042410 ^■ 59043040;59191670-59192590;59933770- 59934360;59938730 ^■ 59939640;61253380 ^■ 61253940;62302410-62303790;62366400- 623671 10;62386830 ^■ 62387420;62474840 ^■ 62475810;62476050-62476930;62551250- 62551800;62642390 ^■ 62643590;62708940 ^■ 62709490;62794010-62794940;62795000- 62795820;62804800 ^■ 62805830;62878980 ^■ 62880170;63005910-63006520;63006680- 63007290:63072120 ^■ 63072810:63101910 ^■ 63103280;63174740-63175680;63176650- 63178640;63216240-63216890;63253670-63254540;63471750-634724 20;63499380-

63499950;63520040-63520720;63553610-63554550;63651900-636 52960;63657960-

63658610;63707380-63708810;63737620-63738170;63740360-637 40930;63790120-

63790760;63831780-63832390;63861860-63862660;63865310-638 65860;63940350-

63941240;63955340-63956620;64038140-64039600;64042140-640 42790;64063180-

64063960;64083350-64084560;64102020-64102980;64255290-642 55850

Chromosome 21 15063990-15064570; 17512470-17513640; 17612240-17613340; 17818680-

17819330;20997610-20998230;25561660-25562730;25735300-257 35900;26170020-

26171290;26572570-26573460;26844060-26845360;26965470-269 66200;29298180-

29299100;31251550-31252240;31557850-31559110;31731030-317 31920;31872730-

31873300;31873890-31874450;32411360-32412850;32771090-327 71890;33025700-

33026390;33026740-33027500;33069760-33070490;33070960-330 72040;33109520-

33110190;33230040-33230670;33324380-33324940;33479160-334 80690;33587990-

33589070;33642320-33642900;34669320-34669880;34670140-346 70690;34792220-

34792800;34886610-34887460;34888800-34889990;36134860-361 35800;36295340-

36295940;36385120-36386160;36698340-36699050;36699370-367 00100;36707680-

36708610;36965880-36966440;36980380-36981130;37005450-370 06300;37073170-

37073900;37266890-37267470;38383330-38383880;38660170-386 60820;38661310-

38661870;38805770-38806750;41168480-41169390;41426100-414 27110;41506980-

41507640;41766320-41767330;41953190-41953780;42009550-420 10430;42219210-

42220290;42234460-42235380;42514170-42514910;42893190-428 93750;42973940-

42974530;43657800-43658420;43659120-43660210;43694030-436 94580;43718200-

43718990;43719140-43720300;43789230-43790030;44011580-440 12250;44012600-

44013350;44285630-44286190;44339030-44339750;44801320-448 02170;44818300-

44819250;44872900-44874620;44931500-44932120;44932360-449 32920;44939560-

44940140;45018050-45018710;45405740-45406370;45531260-455 32270;46097870-

46099250;46228160-46229040;46285540-46286360

Chromosome 22 17638270-17638820; 18000730-18001750; 19122390-19123210; 19177540-

19178440; 19431720-19432630; 19447270-19447840; 19523300-19524660; 19717710-

19719420; 19721370-19722800; 19756300-19756920; 19766760-19767330; 19854360-

19855000; 19855110-19855660;20015980-20016630;20020650-20021320;200858 40-

20086390;20116630-20117530;20298740-20299290;20393970-203 94550;20405540-

20406730;20425850-20426590;20428820-20430140;20430310-204 31730;20436090-

20437240;20437940-20438670;20494930-20495480;20507370-205 08040;20858400-

20859000;20917100-20918280;20957250-20957810;20982060-209 82810;21446190-

21446750;21567680-21568290;21628850-21630250;21651720-216 52790;21665830-

21666810;21735160-21735730;21982310-21983120;23181590-231 82190;23750700-

23751600;23767830-23768820;23786810-23787590;23838160-238 39440;23894040- 23895050;24155810■24157050;24423550■24424870;24805770-24 806860;24952470- 24953200;26169450■26170160;26433620■26434270;26589380-26 590210;26657380- 26657930;2779670O■27800380;27800720·■27802660;28742050- 28742680;29308000- 29308630;29313000■29313990;29314530■29315320;29315530-29 316090;29479770- 29480660;29603360■29604220;30079500■30080580;30246070-30 246790;30289000- 30290140;30356390■30357470;30425620· .30426440;30554790-30556020;30635400- 30636080;30667700■30668430;30694950■30695530;30802460-30 803270;30822080- 30823040;30905620■30906340;30968960■30969580;31084520-31 085490;31104710- 31105270;31106970■31107940;31211930■31212630;31344790-31 345930;31495970- 31496940;31630250■31630890;31753530■31754320;32474520-32 475440;32801390- 32802510;35400050■35400610;35540940■35541520;35551400-35 552240;36065780- 36066380;36386930■36387620;36387700·■36388290;36505820- 36506610;36564280- 36565010;36816690■36817430;37018350■37018980;37024030-37 025050;37334730- 37335500;37374960·■37375730;37419390·■37420480;3742703 0-37427620;37518560- 37519390;37560840■37561890;37608830■37609410;37746430-37 747010;37804440- 37805280;37818390■37819270;37843510 .37844640;37953410-37954200;38080610- 38081410;38088500■38089190;38097630■38098250;38201800-38 203150;38214040- 38214890;38335880■38336620;38427180■38428450;38467620-38 468450;38505590- 38506630;38569480■38570290;38656380■38657190;38681730-38 682430;38700890- 38701770;38705620·■38706790;38866710■38867440;38871490- 38872050;39144840- 39145480;39242670■39243230;39243280·■39244220;39350220- 39350870;39456320- 39456920;39487300■39488600;40044410■40044970;40045410-40 045960;40370380- 40371470;40636230■40636780;40950630■40951700;41021840-41 022470;41196940- 41197930;41237280■41238030;41238100■41238990;41285450-41 286870;41301610- 41302300;41413000■41414280;41446290■41446860;41446950-41 447540;41447640- 41448300;41543850 41544740;41832370■41834230;41909440-41910230;41910510- 41911220;41957370■41958320;41977070■41977730;41998610-41 999390;42070250- 42071160;42090080■42090900;42368490■42369380;42720080-42 720710;42857090- 42857690;43110480■43111820;43142770■43143720;43343460-43 344290;43891400- 43892450;43923620■43924680;43954570■43955370;44330610-44 331280;44496810- 44497460;45008950■45009620;45309430■45310230;45645260-45 646100;45671910- 45672690;45978560■45979280;46027190■46028000;46035720-46 036340;46070320- 46070870;46150850■46151820;46249770■46250550;46262210-46 262770;46267590- 46268390;46535340■46536460;48489800■48490390;49771180-49 771880;49823340- 49823890;49848260■49849050;49849100■49849760;49852850-49 853640;49918080- 49918730;49961140■49962210;49982960■49983600;49999770-50 000360;50014610- 50015390;50029760■50030470;50176580■50178000;50184670-50 185730;50200240- 50200910:50250650■50251860:50267180■50268340;50271260-50 272210;50299440- 50300500;50306810-50307410;50327230-50327900;50480900-504821 20;50526230- 50526920;50529350-50532170;50548370-50549360;50582380-505833 30;50603630- 50604300;50628200-50628750;50673330-50674090;50675000-506755 70

Chromosome 3 4303000-4303570;6861250-6862290;8767530-8768630;8985310-8986 010;9600700-

9601350;9703580-9704430;9731570-9732460;9769680-9770340;9 809870-9810790;9915060-

9916100;9932690-9933600;9946260-9948020; 10141560-10142390; 10164650-10165350; 10248130-

10249030; 10992900-10993460; 11719590-11720930; 11846520-11847070; 12288140-

12288910; 12663610-12664330; 12967010-12967880; 12993310-12993890; 12994350-

12995430; 13281870-13282540; 13479360-13479910; 13480360-13480930; 13654970-

13655780; 13818840-13819520; 13895020-13895600; 14124100-14125630; 14401990-

14403380; 15064690-15065400; 15205890-15206860; 15331730-15332680; 15859790-

15860530; 16884090-16884710; 18443600-18444890;22372230-22373000;23810330-

23811350;24494370-24495390;24521310-24522280;25782800-257 83400;27484200-

27484790;27720820-27721850;27721950-27722550;28575630-285 76650;30606460-

30607600;31980690-31981250;32106270-32107340;32391540-323 92670;32401450-

32402030;32502430-32503220;32570100-32571080;32684980-326 85570;32816530-

32817150;32818660-32819220;33096270-33097360;33113890-331 14620;33218280-

33218890;33717690-33718240;35638950-35639980;36944390-369 45420;36992630-

36993410;37175580-37176480;37242940-37243650;37860490-378 61440;38029080-

38030230;38039060-38040100;38138060-38139100;38165380-381 66320;38346580-

38347230;38454820-38455380;38648900-38649560;39106920-391 07670;39152570-

39153430;39180570-39181350;39502210-39502940;39809630-398 10710;40524450-

40525410;42263260-42264060;42265120-42266080;42581770-425 82350;42600520-

42601120;42685390-42686680;43286030-43286580;43995070-439 96100;43997700-

43998390;43998820-43999810;44477220-44477950;44584750-445 85390;44761350-

44762220;44975710-44976640;45035370-45036280;45145570-451 46580;45594090-

45594720;45689170-45689720;45795780-45796850;46464380-464 65090;46565630-

46566690;46693710-46694270;46833480-46834030;46845650-468 46480;46881220-

46882350;46898200-46899250;47009790-47010410;47163050-471 63870;47164020-

47164930;47282300-47283140;47380810-47381860;47475240-474 76170;47513230-

47514010;47577440-47578240;47579050-47579690;47781230-477 82390;47802350-

47803730;47824680-47825560;47846080-47847010;47849630-478 50190;48088530-

48089300;48187430-48188620;48428910-48430220;48446390-484 47460;48503860-

48504610;48556310-48557230;48634760-48635880;48656070-486 57590;48660680-

48662350;48662750-48663360;48685230-48686440;48846950-488 48340;48898630-

48899180;48918270-48919710;48989620-48990170;48990380-489 91240;49007170-

49007910;49017540-49018790;49020580-49022650;49093230-490 93790;49093880-

49094500;49120290-49121240;49165680-49166590;49171150-491 71700;49199060- 49200060;49339810-49340650;49357610-49358470;49411390-494122 00;49469910-

49470990;49652210-49653020;49674150-49674930;49717960-497 19650;49723330-

49724500;49786210-49787290;49802610-49803170;49803190-498 04110;49869220-

49870440;49903360-49903960;49910030-49911100;49939860-499 40600;50089300-

50089920;50193400-50195070;50204940-50205850;50226920-502 27960;50236050-

50236750;50259900-50260680;50273060-50274150;50274890-502 77140;50292390-

50292960;50319830-50320420;50320830-50321720;50327830-503 28510;50336790-

50338360;50345330-50346250;50350360-50351160;50358690-503 59760;50364710-

50365760;50611200-50612200;50617260-50617820;51384750-513 85540;51391770-

51392800;51538280-51539360;51707000-51707570;51956140-519 56750;51973660-

51974250;51982890-51983720;52055440-52056180;52154100-521 54900;52238800-

52239770;52245110-52245660;52409640-52410190;52410500-524 11140;52455110-

52456010;52534000-52534690;52536140-52537230;52705530-527 06470;52770370-

52771170;52897040-52898040;53046360-53047050;53255300-532 56120;53493800-

53494390;53823200-53823880;53845500-53847010;54087570-540 88220;54121410-

54121960;55469990-55470670;55474080-55474630;55487000-554 88260;56682910-

56683460;57078560-57079220;57164370-57165460;57227630-572 28710;57555930-

57557550;57692630-57693400;57756420-57757400;58008470-580 09020;58237550-

58238270;58433280-58434110;59049650-59050400;61561430-615 62480;62370110-

62370700;62370780-62371350;62371910-62372490;62373640-623 74360;63863230-

63863790;63911590-63912290;64023040-64023690;64099010-640 99890;64444760-

64445340;64685380-64686800;64687210-64688290;65356340-653 57270;65549000-

65549720;66038070-66038670;66039300-66039930;68931960-689 32520;69012890-

69013940;69084890-69085610;69385650-69386590;69542080-695 42650;69739450-

69740130;71581270-71581990;71582000-71583230;73383410-733 83970;79018680-

79019260;84959000-84959550;86990810-86991390;98522450-985 23260;98732090-

98733030; 100260640-100261290;100334610-100335260; 101676380-101677270;101778890-

101779450; 101848940-101850300; 105368860-105369520; 107523240-107523930; 108090710-

108091430; 111071290-111071930; 111859440-111860040; 112561510-112562080; 112990850-

112991400; 113211440-113212080; 113696380-113697020; 114350610-114352120; 119034220-

119035270; 119240410-119241230; 119293960-119294510; 119579350-119580110; 120348510-

120349500; 120908140-120908830; 122183820-122184440; 122564290-122564880; 122680700-

122681710; 122795100-122795830; 122912750-122914080; 122921930-122922500; 123027550-

123028140; 123066860-123067950; 123447370-123447920; 123448400-123449170; 124032570-

124033230; 124033430-124034220; 125375030-125375600; 126084040-126084600; 126180160-

126180800; 126343410-126343960; 126356070-126356970; 126474650-126475350; 126523850-

126524570; 126541370-126542090; 126654760-126655360; 127589690-127590730; 127590770-

127591630; 127597950-127598770; 127629560-127630120; 127672180-127672790; 127672960- 127673680; 128076470128077370;128123510128124090;128153280-128153900;12 8432570- 128433570;128486630128488720;128489150128490330;128492030-12 8492580;128492730- 128493280;128555000128555870;128607830128608700;128680780-12 8681490;128726460- 128727020;129001090129002510; 129045620129046380;129121090-129121690;129278940- 129279680; 129314960129315910;129439440129440500; 129605310-129606440; 129974420- 129976080;130894180130894770;131381620131382500;132417220-13 2417860;132660100- 132661030;132721800132722510;133037890133038560;133805760-13 3806380;133894810- 133895760;133895790133896410;134029300134030110;134250850-13 4251440;134312820- 134313390;134374040134375090;134650630134651180;134795350-13 4796030;136195220- 136195910;136752130136752760; 137764640137765700;138009820-138010390;138329250- 138330100;138347920138348850;138434780138435760;138608750-13 8609360;138834120- 138834770;138935870138936680;138944690138945670;138946180-13 8947100;138949740- 138950630;139539060139539950;139934750139935560;141051160-14 1052080;141065910- 141066910;141231040141231590;141232030141232670;141401830-14 1402380;142149090- 142149710;142224930142225710;142888660142889590;142962390-14 2963160;143119130- 143122300;143971930143973200; 147390660147391650;147395890-147396650;147409820- 147411230;148697840148698500;149129520149130090;149656760-14 9657520;149970370- 149970960;149971010149971590;150408570150410990;150545850-15 0546550;150763170- 150763720;151085070151086490;152268300152269690;153161850-15 3162540;153162550- 153163560;154428290154429240; 155079690155080300;155805790-155806690;155870190- 155871630;156674010156675230;156816800156817530;156826040-15 6826670;157120180- 157120730;157159510157160500;157437230157438040;158094300-15 8094880;158097760- 158098550;158105490158106110;159763130159764190;159764470-15 9765300;160225040- 160225970; 160226070160226730;160565180160566370;160755270-160756810;16 1104790- 161105340;168094920168095700;168249660168250490; 169764280-169765400; 169812200- 169812840;170037680170038500;170357730· 170358340;170418340-170419430;170419480- 170420210;170585220170585800;171459790171460690;171810100-17 1810830;172040040- 172041160;174440880174441650;179148610179149200;179347640-17 9348220;179450840- 179451390;179562940179563650;180601980180602610;181694980-18 1695860;181711970- 181712780;181726500181727190;182682260182683060;182793800-18 2794360;183253670- 183255110;183427680183428840;183635930183636900;183698020-18 3698580;183824580- 183825300;184017210184017810;184135290184135910;184169920-18 4170630;184174590- 184175400;184229990184231290; 184249490184250360; 184260730-184261320; 184262510- 184263060;184299080184299660;184335630184336610;184338350-18 4339070;184361080- 184361680;184361730184362320;184362760184363670;185253760-18 5254480;185498430- 185499380;185586010185586720;185823190185823810;185825640-18 5826540;186108170- 186109290;186806290186806860;188153440188154080;190120020-19 0120990;190862580- 190863130;191329060191329970;192409540192410440;192514410-19 2515350;194140660- 194141210; 194203940-194204490; 194333190-194333950; 194396830-194397400; 194686490- 194687880; 195260330-195260880; 195270300-195270850; 195442150-195443420; 195542680- 195543290; 195543310-195543900; 196081290-196082070; 196431740-196432960; 196502940- 196503540; 196639390-196640090; 196660100-196660670; 196712470-196713030; 196867470- 196868550; 196969120-196969850; 197029080-197030150; 197297710-197298600; 197736250- 197737290; 197749340-197750720; 197791100-197792070;

Chromosome 4 107110-108150;336330-337150;499030-499620;577270-577910;6635 80-

664290;688590-689430;785890-786880;826690-827250;931650-9 33010;973740-974350;986790-

987500; 1001770-1002350;1003220-1003770; 1170770-1171790; 1172260-1172830; 1346170-

1346930; 1402380-1402940; 1404640-1405190; 1406830-1408120; 1471410-1472410; 1579270-

1579980; 1593240-1593820; 1684540-1685200; 1711560-1712270; 1712320-1712870; 1720320-

1720990; 1793960-1794530; 1794550-1795110; 1855920-1857040; 1870140-1870830;2008640-

2009820;2040340-2040990;2041270-2042220;2042250-2042990;2 046680-2047560;2058110-

2058740;2416550-2417310;2462240-2463040;2535550-2536520;2 537270-2537860;2962670-

2964180;3291850-3292660;3766730-3767420;3871180-3871910;4 386400-4388200;4859930-

4860590;5051200-5052270;5887790-5888570;6105270-6106150;6 199040-6199680;6221960-

6222710;6470380-6471410;6640760-6641670;6715900-6716910;6 987010-6987700;7043590-

7044280;7054180-7055100;7067310-7068080;7939040-7939830;8 157990-8158650;8158850-

8159570;8440720-8441270;8861390-8862080; 10018790-10019420; 11399100-11399690; 13483600-

13484180; 13541750-13542840; 15001810-15002390; 15654490-15655060; 15778460-

15779080; 17577190-17577770; 17780910-17782200; 17810290-17810900; 18021740-

18022340;20003930-20004480;20252910-20253540;24470300-244 71020;24472340-

24473140;24583860-24584780;24799450-24800470;25233910-252 34750;25505160-

25506130;25655150-25656140;26319440-26320040;30720290-307 21170;30721270-

30721990;30722240-30723240;37243600-37244490;37244730-372 45510;37453450-

37454000;37685730-37686350;37826560-37827140;38664220-386 64810;39446560-

39447560;39527630-39528180;39638290-39639400;39697680-396 98780;40056650-

40057410;40437580-40439120;41214150-41214730;41256880-412 57910;41360230-

41361630;42151210-42151820;42152300-42152860;42397800-423 98770;44447180-

44448810;46993260-46993940;47032390-47032970;47837490-478 38150;48016460-

48017510;52051090-52052030;52659460-52660170;52712340-527 13120;52750820-

52751570;52862230-52862780;54100010-54101090;54101360-541 01990;54230590-

54231200;54233130-54234410;54657950-54658760;55346140-553 46810;55395820-

55396690;55853510-55854300;55948510-55949410;56049350-560 49970;56315470-

56316040;56434890-56435510;56435910-56436530;56655590-566 56250;56908770-

56909440;56976350-56977120;57109530-57110490;61200620-612 01210;61202010-

61202560;68349630-68350250;70705040-70705700;70838850-708 39610;72569060-

72569680;73258100-73259380;73998060-73998640;74444900-744 45610;75630280- 75631130;75673040-75673740;75940170-75941260;76213400-762142 00;76306150-

76306720;76741330-76741990;76896750-76898200;80202990-802 03710;80335690-

80336400;81214390-81215470;82373360-82374060;82428750-824 29510;82429780-

82430450;82430680-82431330;82900430-82901120;83012160-830 13270;83284160-

83284710;83484480-83485050;84482670-84483420;84493180-844 93820;84497210-

84497770;84498070-84498660;84582390-84582940;84582950-845 83660;86594030-

86594940;86934640-86935610;87006980-87007540;87219730-872 20800;88158490-

88159300;88283810-88284370;88456880-88457820;88591930-885 93430;89110640-

89111250;90127730-90128730;92305190-92305750;93829370-938 30000;94207530-

94208150;98261660-98262210;98657790-98658530;98928070-989 29250;98995760-

98996420;99946100-99946780;99949210-99949800;99950400-999 50970;101346300-

101347740;102344340-102345410;102500740-102501370;1028274 20-102828110;103075890-

103076970;103719070-103719760;105146260-105147130;1058952 00-105896910;107931560-

107932290;108168400-108169190;108172440-108173100;1093018 90-109302850;109560180-

109560730;109729290-109729890;110631930-110633010;1121458 70-112146440;112231570-

112232120;112411650-112412320; 112514560-112516270; 112516470-112517130; 112705550-

112706560;116925900-116926460;119627420-119628020;1200662 30-120066960;121071750-

121072580;121696540-121697270;121764400-121765350;1218231 80-121824010;121932040-

121933260;121951470-121952140;123397120-123397750;1247119 90-124712720;125315390-

125315950;125316360-125317930;127622740-127623350;1277816 70-127782220;127782520-

127783070;127880820-127881400;127964760-127965390;1280606 20-128061310;128061720-

128062590;128287630-128288200;128288340-128288890;1288108 70-128811500;129093080-

129093810;133150070-133152750;139083290-139084380;1391760 50-139177210;139177560-

139178360;139295260-139296050;139555200-139557270;1401525 40-140153690;140252560-

140253180;140497510-140498360;140756180-140757070;1411328 40-141133730;142845730-

142847230;143185070-143186080;143336680-143337390;1436998 80-143700770;145481190-

145482210;145732990-145733550;145936260-145937050;1459386 50-145939210;146638160-

146638710;146640030-146640600;146655030-146655610;1474810 20-147481570;147731490-

147732090;147732120-147732830;148444540-148445370;1500788 70-150079520;150579570-

150580250;150582670-150584190;151015200-151015820;1513248 80-151325680;152535430-

152536180;152935750-152938150;153152960-153153960;1533444 00-153345160;153759250-

153760220;153792330-153792990;154489790-154490780;1547430 20-154743620;154781300-

154781940;155666950-155667630;155759670-155760260;1586718 90-158672540;163343630-

163344290;165112190-165112990;165378810-165379740;1692708 10-169271640;170089360-

170090010;171813320-171814000;173509170-173509740;1735295 40-173530210;174522220-

174522800;176319570-176320820;176791960-176792550;1824480 70-182448870;182799380-

182800100;182917480-182918110;183097740-183098740;1834445 60-183445410;183503980-

183505600;183659200-183659790;183722750-183723320;1837972 90-183797920;183905520- 183907310; 184474360-184475260; 185017970-185019010; 185019150-185019820; 185020050-

185020940; 185203430-185204000; 185209030-185209670; 185395900-185396660; 185471390-

185472000; 185534810-185535610; 187995100-187995890;320470-322900;343630-344350

Chromosome 5 464740-465570;523520-524070;612040-612950;892140-892700; 1003610-

1004260; 1004480-1005040; 1009140-1009970; 1111540-1112290; 1245890-1246440; 1293320-

1295320; 1386020-1386830; 1444770-1445730; 1874760-1875510; 1875740-1876830; 1881550-

1882370; 1882980-1883960; 1887140-1887730;2739180-2739980;2748860-2750100;2752530-

2753080;2755040-2755600;2756440-2756990;3591170-3591800;3 594450-3595030;3598950-

3600160;3602140-3602970;5140220-5140830;6448900-6449720;6 583010-6583930;6633180-

6634240;6712290-6712860;7850790-7851420;7868760-7869420; 10333340-10333920; 10353770-

10354470; 10441650-10442580; 10563500-10564150; 10564540-10565150; 14011430-

14011980; 14142460-14143280; 14143990-14145120; 14460770-14461340; 14581590-

14582140; 15927860-15928410; 15936330-15937270; 16465050-16466000; 17216290-

17217070;28809280-28809830;32173360-32174500;32312090-323 13090;32711430-

32712740;33936790-33938240;34656210-34657090;34915380-349 16060;35617560-

35618320;36151350-36152150;36875760-36876870;37248900-372 49620;37834310-

37835030;37836930-37837500;37839230-37840090;38258230-382 59190;40680850-

40682260;40755110-40755880;41869600-41870670;42424360-424 25000;43121340-

43121950;43192360-43192950;43556420-43557650;44808920-448 09670;45261820-

45262600;52787770-52788320;54517990-54519030;55220490-552 21370;55223090-

55223850;55226530-55227860;55232670-55233770;56815920-568 16760;56908840-

56909400;58459480-58460040;58460160-58461130;60843630-608 44240;61161810-

61162840;62306160-62306880;62412530-62413230;64165730-641 66280;64506220-

64506850;65722090-65722930;65925780-65926590;66144150-661 44850;66596540-

66597140;67163130-67163700;69093740-69094630;69217660-692 18460;69414890-

69415830;69492300-69493200;69493270-69494080;71587100-715 87690;72107490-

72108040;72319820-72320380;72816070-72817320;72955540-729 56310;73233310-

73233940;73298940-73299540;73381350-73382090;73419770-734 20380;73436260-

73437340;73437360-73438120;73444180-73445010;73450880-734 51720;73498350-

73498900;74639700-74640880;74684850-74685760;74866510-748 67060;75052410-

75052970;75053100-75053780;75336830-75337480;76402900-764 03870;76715440-

76716000;76953870-76954500;77030210-77031210;77087000-770 87570;77630060-

77631170;77636490-77637050;77775660-77776530;77851190-778 52080;77972520-

77973100;78294230-78294840;78509840-78510610;78647880-786 48680;78985000-

78985600;79069320-79070020;79236380-79237740;79513150-795 13710;79689410-

79690270;80487620-80488650;80569030-80570890;80654100-806 54910;81393700-

81394500;81750670-81751420;83471500-83472050;84383840-843 84390;88674230-

88675050;88675540-88676390;88884010-88884610;93571990-935 72540;93579140- 93580610;93580830-93581610;93587600-93588460;93621260-936218 50;93740720-

93741380;94618100-94618670;95283580-95284600;95284660-952 85630;95621020-

95621730;95731000-95732130;95960980-95962260;96661980-966 62800;96662850-

96663490;96807150-96808140;98768440-98769580;98927990-989 29920;100535400-

100536030;103258750-103259960;107670060-107670760;1076708 00-107671850;108381260-

108381950;108382060-108382620;109690040-109690740;1112240 70-111224950;114362620-

114363700; 115169120-115169880;115169960-115170570; 115296020-115296720; 115841870-

115842460;116573320-116574140;120463910-120464710;1220768 30-122078400;123036240-

123037280;123095190-123095750;123098370-123098940;1234230 50-123423610;126600760-

126601560;126776920-126778040;127029850-127031720;1280842 50-128084870;128537780-

128538340;129094440-129095590;129460770-129461820;1299042 70-129905900;131263450-

131264680;131796640-131797410;132011200-132012150;1322273 20-132228380;132294190-

132295200;132410260-132411410;132496540-132497380;1326562 50-132656930;132736800-

132737550;132747200-132748070;132777330-132778150;1328145 00-132815360;132822510-

132823620;132825190-132825770;132829650-132830450;1328305 10-132831090;132962970-

132963880;133051680-133052740;133611480-133612910;1340040 20-134004570;134004870-

134005470;134225440-134225990;134226070-134227060;1344115 40-134412120;134524650-

134525210;134526130-134527000;134632330-134633080;1348457 40-134846820;134904330-

134905590;135028800-135029690;135031190-135031790;1350330 20-135033860;135038940-

135040060;135399150-135399790;135534740-135535990;1355783 10-135578980;135930370-

135931100;136028700-136029520;136132510-136133690;1361917 80-136192920;136356500-

136357360;137752990-137754260;137754270-137754820;1380324 10-138033360;138274190-

138274900;138331790-138332390;138337680-138338260;1384647 10-138466280;138467230-

138468110;138491540-138492590;138542440-138543190;1387536 30-138754410;139293430-

139294200;139392080-139393480;139393640-139395370;1394386 60-139439590;139648370-

139650100;139696940-139697650;139709020-139710250;1397103 80-139710930;139746270-

139747020;139747150-139747950;139795180-139795750;1399037 20-139904730;140042280-

140043770;140107330-140108110;140114370-140115250;1401457 20-140146710;140175020-

140176050;140346010-140346590;140400680-140402600;1405474 40-140548200;140563950-

140565130;140632060-140633220;140639370-140639960;1406469 50-140647810;140787370-

140788520;140795780-140797040;140802210-140803460;1408228 50-140824080;140857410-

140857960;140862900-140863660;140870390-140871380;1408771 20-140877780;140883340-

140884670;140926450-140927470;140966490-140967300;1413038 20-141304750;141320300-

141320930;141361470-141362230;141371950-141372560;1413893 80-141390000;141409370-

141410460;141419050-141419920;141427530-141428380;1414308 70-141431940;141441570-

141442180;141477340-141477990;141484880-141486090;1414913 80-141492820;141618660-

141619210;141636980-141638020;141849340-141849940;1418776 30-141878240;142108550-

142109540;142324160-142324890;142769990-142770580;1427707 90-142771480;143402450- 143403020;146339500-146340640;147509200-147510280;148383550- 148384310;148826470-

148827070;149141310-149142000;149271910-149272620;1495510 40-149551600;149730270-

149731240;149731610-149732440;150000660-150001250;1501663 10-150166890;150190010-

150190560;150302040-150302990;150357340-150358390;1506715 00-150672590;151020370-

151020920;151080490-151081450;151157270-151157980;1512236 00-151224160;154038390-

154039180;154189610-154190510;154446230-154447050;1544759 70-154476520;154477410-

154478200;154478770-154479570;154755580-154756240;1548579 20-154858990;154937750-

154938390;157671320-157671870;159096710-159097440;1592628 80-159263700;159916150-

159916980;159917040-159917590;160118340-160119630;1603701 40-160371010;163459710-

163460530;166978530-166979120;168529820-168530490;1685788 30-168579710;169300100-

169300740;170503740-170504730;170744340-170745000;1713081 00-171308820;171308900-

171310690;171310800-171312400;171316300-171316990;1720060 30-172006730;172187400-

172189180;172641210-172642390;172669890-172670550;1727483 80-172749250;172770370-

172771240;172833890-172834520;173056060-173056920;1732323 50-173233520;173243760-

173244830;173327030-173327710;173329370-173330170;1743117 10-174312350;174724440-

174725420;174731750-174732530;174735260-174736130;1754444 00-175445170;175478150-

175478810;175657890-175658730;175796430-175797300;1758717 90-175872740;176365050-

176366530;176387910-176388640;176415890-176416500;1764479 50-176448580;176536920-

176537690;176542470-176543090;176543460-176544020;1766091 60-176609810;176619590-

176620280;176629810-176630810;176743250-176743820;1768174 10-176818480;177005810-

177006730;177022640-177023360;177131610-177132170;1771340 80-177134690;177302930-

177303670;177311850-177312610;177362720-177363320;1773669 40-177368010;177399830-

177400930;177402440-177403080;177403450-177404080;1774041 20-177404930;177446210-

177446770;177446990-177447700;177454100-177456350;1774978 10-177498360;177516950-

177517500;177553720-177554300;177591840-177592690;1779842 90-177984940;178130390-

178131470;178590240-178590830;178730150-178730700;1793436 20-179344570;179530270-

179531090;179678860-179679410;179795400-179796620;1798166 00-179817630;179820700-

179821700;180071980-180072540;180494620-180495280;1805909 30-180591840;180648740-

180649360;180791870-180792830;181059060-181059650;1812047 70-181205540;391080-

394010;1383690-1384500

Chromosome 61390200-1391380;1393150-1394100;1608420-1609020;1613700-161 5420;1619450- 1620090;2244870-2245950;2970690-2971650;3068150-3068920;3162 530-3163160;3227120- 3227910;3457180-3457900;3750920-3752310;3849510-3850970;5084 350-5085690;5086050- 5086650;6002120-6002920;6002930-6003530;7051210-7051790;7107 690-7108560;7541250- 7542600;10384610-10385460;10389750-10390510;10404100-1040501 0;10409600- 10410570;10412520-10413620;11093570-11094150;12749570-127502 70;13364560- 13365700;13486490-13487500;13614500-13615150;13615370-136159 20;13813600- 13814600;15244450-15245420;15662220-15663190;16761510-167622 50;17280490- 17281170; 17281570■17282120; 17600220■17601200; 17706080-17707140; 18122110- 18122680; 18154730■18155720;20212060■20212940;20401750-20402510;20 403220- 20404050;21587090■21587820;21588020■21588720;21594180-21 595220;21664200- 21664990;24910440■24911180;25279010■25279640;26171740-26 172530;26250040- 26250650;26595720·■26596280;26613660■26614340;27020000- 27020550;27250600- 27252270;27472660·■27473640;27838530·■27839080;2789021 0-27890920;28136980- 28137560;28616070■28616760;28838570■28839280;28863840-28 864440;28922830- 28923930;2962735O■29628080;29632980■29633560;29723320-29 724270;30071120- 30071700;30074990■30075900;30212840■30213730;30326470-30 327630;30345240- 30345790;30489280■30490490;30555550■30556830;30647340-30 647910;30742460- 30743180;31580480■31581640;31652000■31653120;31681030-31 681960;31682700- 31683640;31728400■31729310;31795180■31796370;31862010-31 863040;31958530- 31959500;31971000■31971550;31971890■31972550;32087020-32 087630;32095720- 32097330;32148640■32149800;32150080■32151120;32152950-32 153530;32195490- 32196560;33161300■33162030;33192740■33193410;33199820-33 200790;33207810- 33209080;33277040·■33277870;33298410·■33299930;3331332 0-33313930;33314960- 33315660;33391200■33392260;33409930■33410620;33410950-33 411610;33621380- 33622200;33788200·■33789320;34144050■34146050;34196080- 34196950;34248550- 34249610;34392090■34393240;34465450■34466470;35213710-35 214950;35317940- 35318680;35342370■35342920;35468500■35469050;35496040-35 496910;35497470- 35498610;35687800■35688560;35727590·■35728570;35776270- 35776960;35920820- 35921480;36027730■36028470;36442560■36443520;36678410-36 679310;36679890- 36680700;36839870■36840450;36874570■36875130;37170080-37 171660;37648680- 37649620;37658060■37658830;37696460■37697410;37698510-37 699100;37819250- 37819860;38639390■38640450;38714960■38715610;40587370-40 588000;41028050- 41028630;41072710■41073280;41373450■41374590;41427480-41 428470;41638400- 41639100;41733910■41734530;41806000■41806870;41940330-41 942260;42104180- 42105080;42452280■42453470;42727120·■42727710;42746840- 42747530;42782990- 42783760;42960190■42961350;42978470■42979210;43013750-43 014470;43171970- 43172600;43181850■43182540;43228820■43229740;43247130-43 247920;43274830- 43275680;43275970·■43276970;43368590■43369150;43454330- 43455300;43509150- 43510670;43628700■43629510;43644760■43645470;43770400-43 772150;44127720- 44128520;44223510■44224250;44275230·■44276840;44297160- 44298100;45422510- 45423910;45663180■45663930;46015390■46016090;46652830-46 653730;46687850- 46688920;47309390■47310150;47477320 47478640;50714950-50715520;50823240- 50824000;52361780■52362860;53061360■53062290;53065180-53 066100;53348060- 53348920;53544000■53545450;53651410■53652400;53794880-53 795670;53795800- 53796380:54846320■54846950:57172070■57172900;57221520-57 222310;63572240- 63573840;63635860-63636580;69867190-69867800;70413280-704141 50;70955590-

70956500;72182150-72183370;72621590-72622800;73451420-734 51990;73461530-

73462410;73523150-73523890;73653530-73654140;75085000-750 85560;75284120-

75284850;75601470-75602820;75749230-75749780;77462350-774 63660;79631180-

79632030;79946810-79947510;81753040-81753590;82364930-823 65780;83708460-

83709630;85449570-85450630;85593370-85594430;85643620-856 44200;85678750-

85679480;87151850-87152800;87154920-87156080;87701160-877 02040;88047560-

88048330;88165650-88167390;88963010-88963580;89145780-891 46950;89352170-

89352840;89352900-89353450;89411520-89412070;89433310-894 34130;90294820-

90295680;90610820-90611530;97282780-97283350;98835370-988 36240;98847610-

98848590;99514910-99516030;99588560-99589130;99606590-996 07140;99612690-

99614860;100449170-100449770;104859360-104860130;10651192 0-106512990;106975130-

106976060;107068700-107069750;107459620-107460170;1076336 00-107634260;107957540-

107958640;108074520-108075280;108118740-108119640; 108157550-108158360; 108165590-

108166190;108260490-108261400;108558160-108558950;1085597 90-108560600;108560610-

108561920;109440030-109440580;109440770-109441390;1094557 70-109456580;109482750-

109483360;109978890-109980160;110476630-110477180;1108143 00-110815180;110874880-

110876130; 111087750-111088400; 111259540-111260120; 111483470-111484080; 112087090-

112087710;112366650-112367630; 113858510-113859220;113970900-113971730;114342360-

114343690;116370510-116371630;116461750-116462560; 116680740-116681610;116764920-

116765840;117675640-117676290; 117907670-117908540;118650890-118651730;118894750-

118895360;119348550-119349500;122399690-122400330;1226099 50-122610950;122789070-

122789880;125749400-125750390;125956740-125957510;1271186 60-127120180;127266780-

127267530;127475030-127476420;127515490-127516160;1285201 50-128521090;130365380-

130365990;131062750-131063570;131627790-131628610;1324007 00-132401690;132512660-

132513210;133241520-133242420;133889540-133890180;1339532 30-133953850;134174940-

134175970;135182320-135182900;135497280-135498040;1362890 40-136289900;136550320-

136551170;136791290-136792150;136822600-136823210;1369211 90-136923220;136923510-

136924410;137044360-137045230;137493320-137494180;1374953 10-137496090;137867160-

137868050;138106850-138107860;138424190-138424770;1386920 60-138692640;138795740-

138796380;138987260-138987830;138987920-138988550;1390290 00-139029790;139373350-

139373930;142945260-142946320;143677870-143678720;1440637 30-144064810;144095820-

144096370;144150000-144150700;144186600-144187570;1442846 70-144285510;145814190-

145814880;146029150-146029780;147507560-147508690;1487473 40-148748260;149450520-

149451160;149456380-149457270;149566300-149567340;1497491 90-149750160;149863080-

149864510;150143040-150143770;150600260-150600830;1508660 70-150866820;151452230-

151453080;151807720-151808310;152982420-152983000;1531298 50-153130430;154510010-

154510900;154994520-154995260;154995580-154996210;1572361 00-157237140;157274240- 157275490; 157380010-157381170; 157382120-157382670; 157823540-157824200; 157980850- 157982690; 158559990-158560750; 158643980-158644730; 158818920-158819840; 159969460- 159970030; 160348500-160349140; 160520310-160520880; 160991130-160992380; 162727280- 162727960; 163415660-163416230; 165660430-165661320; 165661490-165662040; 165662990- 165663590; 165805090-165805690; 165988410-165989210; 166166460-166167020; 166167240- 166168020; 166168350-166168960; 166383390-166384040; 166900280-166901260; 166955790- 166956560; 166997880-166998740; 168441030-168441580; 169231550-169232210; 169723010- 169723730; 169751730-169752300; 170022980-170023620; 170288980-170291140; 170291210- 170291780; 170295260-170296670; 191990-192570;493540-494410

Chromosome 7 517830-519250;520060-521430; 1223910-1224930; 1233430-1234180; 1241330-

1241880; 1247330-1247920; 1539710-1540660; 1569730-1570630; 1664670-1665460; 1666130-

1667760; 1670210-1671090;2403780-2404390;2559130-2559680;2647030-2647 610;4883000-

4883670;5190100-5190720;5332620-5333260;5500530-5502110;5 556240-5556950;6348250-

6348890;6483320-6484170;6503110-6503940;6652230-6652950;6 706270-6706900;7182750-

7183380;7566930-7567510;8261400-8262010; 16420870-16421850; 17298630-17299510; 19116400-

19117000;20777670-20778250;20784070-20785290;20798410-207 99050;23013270-

23014120;23105810-23106510;23468780-23470240;23473610-234 74890;24284370-

24284930;24756920-24757860;25179950-25180500;25852270-258 53040;26152470-

26153310;26376440-26377000;26397830-26398610;27107840-271 08830;27110290-

27110880;27113450-27114030;27142800-27144200;27147210-271 48120;27150880-

27151510;27155810-27156710;27164930-27165680;27173370-271 74640;27184240-

27185050;27192250-27193170;27235380-27235930;28409580-284 10350;28955260-

28959000;29194220-29195400;29988460-29990030;30028200-300 29010;30681560-

30682860;31052630-31053480;32298240-32299120;32495320-324 95980;32957130-

32958060;33062130-33062930;33904630-33905290;36366500-363 67580;37915830-

37916650;38631160-38631800;39623500-39624060;39950120-399 51790;40133940-

40135570;41965920-41966720;43112190-43112770;43112900-431 13670;43444730-

43445650;43582440-43583030;43583340-43583910;43758100-437 59090;43868800-

43869940;43925930-43926970;44081870-44082540;44113500-441 14120;44145030-

44146200;44309300-44310100;44606410-44607450;44761430-447 62170;44795920-

44796710;44796720-44797310;44847500-44848390;44884250-448 85130;44962240-

44963420;44999520-45000090;45088710-45089390;45111670-451 12250;45157640-

45158260;45574850-45575550;45888340-45889190;45920300-459 21570;47536480-

47537050;48035800-48036520;48089260-48089910;49773510-497 74400;49775400-

49776310;50399680-50400820;51315810-51316570;55019420-550 20240;55254610-

55255180;55571380-55572240;56115630-56116560;56174690-561 75780;63054060-

63054620;64307060-64307710;64882090-64882700;65981630-659 82610;66044070-

66044700;66204910-66206100;66505220-66506440;66628790-666 29350;70694860- 70695790;70790190-70791020;71132430-71133140;71752190-717527 40;72336700-

72337300;73434620-73435240;73577830-73578660;73623020-736 23940;73682630-

73684020;73738860-73739520;73769040-73770940;74084090-740 84680;74173680-

74174310;74174430-74175040;74254340-74254960;74289580-742 90330;75073080-

75073720;76201710-76202360;76266980-76267880;76282650-762 83350;76302750-

76303510;76393100-76394100;76397410-76398080;77415730-774 16690;77696560-

77697320;77797920-77798650;77798740-77799560;80134920-801 35680;82442740-

82443900;83162400-83163130;86786120-86787170;87934780-879 35420;91264860-

91266950;91940650-91941420;92133620-92134600;92178880-921 79440;92246040-

92246620;92447440-92448130;92527990-92528780;92832630-928 33750;92834770-

92835320;94655710-94656270;94664170-94664720;97020930-970 21800;97024120-

97024780;97732620-97733650;98106540-98107410;98251740-982 52660;98400730-

98401380;98616480-98617310;98617630-98618320;99325430-993 26150;99374030-

99374980;99375010-99375670;99392590-99393240;99407970-994 08980;99438420-

99439430;99558030-99558730;99918890-99919790;100015560-10 0016330;100081130-

100081680;100088530-100089430;100100770-100101630;1001276 40-100128190;100157880-

100158980;100170950-100172300;100176840-100178020;1004311 70-100431720;100483630-

100484250;100493330-100494250;100539030-100539630;1005696 30-100570740;100585660-

100586580;100603730-100604300;100604330-100605070;1006051 30-100606030;100612210-

100613030;100626350-100627170;100632940-100633730;1006557 90-100656630;100675230-

100675800;100720280-100721210;100827720-100828340;1008521 20-100852990;100874920-

100875910;100889090-100889770;100892200-100892890;1008950 40-100895930;100895940-

100896540;101163350-101166050;101169790-101170360;1011719 40-101172880;101179710-

101180740;101201640-101202470;101251780-101252650;1012832 20-101283780;101362460-

101363190;101814870-101815630;102286060-102286610;1022871 30-102287830;102300270-

102300930;102464330-102465340;103149090-103149700;1043286 00-104329300;105244260-

105244820;106111530-106112250;106285030-106285590;1068676 80-106868230;107890860-

107891610;108455650-108456380;108525690-108526290;1085696 90-108570240;111728290-

111728840; 112205840-112206960; 112790200-112790800; 114084420-114085420; 114086300-

114086910;116525980-116526810;116862200-116863020;1173226 00-117323670; 117872770-

117873450;120274690-120275270;122143820-122144550;1223038 00-122304650;122310110-

122310820;122885660-122886870;124032000-124032890;1272514 40-127252390;127252710-

127254160;127391460-127392570;127584940-127585720;1275879 90-127589130;127651590-

127652780;128030030-128030680;128103820-128104770;1281664 10-128168160;128240810-

128241390;128350930-128351880;128361220-128362190;1284093 20-128410340;128738760-

128739720;128790470-128791120;128791150-128791980;1288304 20-128831330;128869350-

128870280;128890910-128891550;128937500-128938980;1291692 00-129169790;129188210-

129189820;129502610-129503200;129779070-129780810;1299525 00-129953050;130486110- 130486760;130732990-130733780;131107310-131108330; 131327380-131328320; 131555730-

131556530;134316300-134317260;135170150-135171060;1355097 60-135510320;138459960-

138461340;139035230-139036420;139108600-139109740;1393410 10-139341750;139359380-

139360680;139482560-139483950;139776870-139777430;1401773 10-140177920;140230190-

140231150;140397970-140398710;140673220-140673870;1406965 80-140697290;141073000-

141075060;142796880-142797530;142854790-142855450;1433616 60-143362520;143380780-

143382540;148698290-148699880;149071140-149072050;1490901 10-149091710;149147500-

149148660; 149261560-149262840; 149281630-149282260; 149431870-149432980; 149460590-

149461150;149474230-149474790;149764620-149766140;1498382 40-149839270;149873150-

149874320;150368030-150368650;150371590-150373220;1503791 10-150379660;150407450-

150408010;150720320-150720870;150800060-150800780;1509746 20-150975460;151018230-

151018810;151018900-151019600;151050820-151051600;1510801 80-151080990;151081050-

151081930;151083080-151084010;151086990-151088100;1511225 80-151123480;151125670-

151126420;151167890-151168610;151232180-151233150;1512450 70-151246090;151341490-

151342090;151381270-151382090;151409030-151410850;1514398 70-151440450;151519490-

151520300;151875640-151876760;151876990-151877900;1550709 20-155071680;155297880-

155298730;155448870-155449430;155458780-155459380;1556439 00-155644700;155786980-

155787770;155803300-155804090;155804510-155805410;1558062 80-155806880;155808300-

155808950;155811680-155812590;156948630-156949360;1569500 60-156950740;157000070-

157000640;157005320-157006070;157009230-157009810;1570106 30-157011300;157279530-

157280100;157409660-157410430;157684610-157685460;1576887 90-157689850;157692570-

157694210;158489990-158490600;158704400-158705320;1591440 30-159144890

Chromosome 8736690-737480;1548610-1549680;4993760-4994470;8723080-87236 70;9150440-

9151240;9906480-9907140;10054270-10054820;10729840-107306 60;11563850-11564430;11708020-

11708620;12754600-12755150;12951180-12951790;17497250-174 97810;21788540-

21789180;21789330-21790420;22047840-22048620;22066190-220 66850;22108670-

22109790;22129810-22131630;22165170-22165890;22245080-222 45630;22367200-

22367860;22440730-22441820;22551160-22552130;22564970-225 66350;22578710-

22579830;22689600-22693040;22865250-22866100;23068420-230 68980;23246510-

23247240;23403380-23404450;23528880-23529770;23681970-236 83130;23702310-

23703140;24913560-24915290;24955290-24957010;25457580-254 58130;26513680-

26514980;26864370-26865260;27310560-27311280;28494040-284 94900;28622750-

28623410;28701090-28702040;28890550-28891100;29349440-293 50660;29351730-

29352490;30082610-30083420;30095470-30096140;30384820-303 85530;30657500-

30658480;30812550-30813120;32547830-32549240;33514270-335 14850;33599410-

33600040;35235280-35236040;37694510-37695120;37695870-376 96670;37696840-

37698720;37736130-37737280;37762540-37763290;37797280-377 97850;37841070-

37841950;37842040-37842660;37898960-37899510;37965190-379 66620;38030440- 38031420;38176520-38177330;38231250-38232450;38268900-382696 20;38381560-

38383500;38386470-38387390;38467940-38468880;38756830-387 57640;38787190-

38788420;38974270-38974950;38996520-38997620;39107360-391 08120;41308260-

41309240;41489900-41490720;41725290-41725880;41766730-417 68160;41896070-

41896640;42139860-42140640;42152080-42152740;42153120-421 53700;42391620-

42392410;42897120-42897840;43092940-43093950;47737030-477 37610;47738440-

47739130;47959740-47960610;47960700-47961540;48260000-482 60860;52564930-

52565890;52713540-52714580;52939560-52940940;52941220-529 41810;53250640-

53251380;53880010-53882650;54021520-54022640;54453510-544 54920;54457770-

54458720;54459020-54460170;55101110-55102040;55880160-558 80910;56113090-

56114100;56117600-56118290;56156740-56157600;56445700-564 46910;56992850-

56993450;57994420-57995320;58146010-58146860;58658970-586 59950;60516920-

60517640;60651690-60652300;60909720-60910560;63038460-630 39600;63085490-

63086400;63168690-63169300;64373350-64374230;64581330-645 82090;64587020-

64587610;66176750-66177620;66428900-66429820;66612480-666 14060;66666190-

66667270;66712750-66713330;66924920-66925550;66961800-669 62690;67064750-

67065330;67343120-67343750;68330750-68331300;69832580-698 33600;70069370-

70069990;70403610-70404240;71843320-71844640;73008700-730 09510;73295270-

73295830;73976160-73976790;74314900-74315870;74320290-743 21510;76682060-

76682900;79765090-79765800;79767330-79767930;79783550-797 84250;79891370-

79892060;80485430-80486020;80486940-80487660;80578620-805 79220;81111530-

81112160;81280170-81281050;85177630-85178250;85463260-854 63880;89901960-

89902520;89984120-89984670;90644910-90645610;90646030-906 46580;92101590-

92102400;92102490-92103220;92965570-92966150;93700090-937 01020;94261790-

94262730;94894940-94895840;95024930-95025510;96145140-961 45810;96160240-

96160830;96261910-96262790;96493930-96494580;97277460-972 78100;97644100-

97645000;97775750-97776460;98064630-98065290;98293630-982 94670;98427750-

98428720;98940210-98940760;98973480-98974980;99013110-990 13670; 100106030-

100106580; 100157680-100158690; 100309090-100310310; 100721430-100722030; 100722260-

100722970; 100951410-100952140; 101080450-101081020; 101126230-101127060; 101205580-

101206450; 101493440-101494250; 102123930-102124480; 102411860-102413050; 102806830-

102807490; 102810150-102810790; 102862880-102863430; 103140380-103141130; 103414460-

103415310; 103500180-103501140; 104466340-104467080; 108082170-108082830; 109644400-

109645110; 109691150-109691900; 109973650-109974690; 118110330-118110920; 119855620-

119856190; 120811150-120811790; 122782270-122782900; 123041740-123042610; 123072620-

123073260; 123160770-123161320; 123273960-123275640; 123540520-123541080; 123767920-

123769110; 124474820-124475440; 124727370-124728010; 125429840-125431400; 126556190-

126557640; 127738210-127739080; 131904020-131905030; 132774980-132775820; 133569660- 133571790;133571820-133572550;138496450-138497040;139618390- 139619050;139702150- 139702990;139705430-139706340;140457100-140457790;140511090- 140511990;141417500- 141418200;142403250-142403820;142450170-142450720;142450750- 142452770;142463830- 142464970;142613420-142614710;142727050-142727950;142738910- 142739790;142777560- 142778120;143159380-143160140;143266740-143267740;143275740- 143276840;143290640- 143291590;143295680-143297070;143368590-143369560;143407550- 143408130;143428880- 143429780;143430890-143431660;143540570-143541610;143569370- 143569950;143596990- 143597590;143598660-143599530;143608940-143609550;143635970- 143636660;143707600- 143708360;143716260-143716850;143726860-143727680;143728390- 143729090;143770710- 143771410;143839260-143840080;143840280-143840860;143953240- 143953880;143975920- 143978350;143990530-143991440;144048570-144050230;144051740- 144053050;144060260- 144061140; 144078100-144079060; 144082320-144083650; 144094320-144095740; 144103450- 144104170;144104380-144104980;144109020-144109630;144147030- 144147900;144147920- 144148490;144326700-144327470;144332070-144332820;144333030- 144333650;144337260- 144337890;144358350-144359120;144373800-144374960;144391570- 144392180;144408910- 144409980; 144427850-144428670; 144443500-144444350; 144472550-144473470; 144477870- 144478530;144500050-144501050;144505750-144506490;144508430- 144509150;144509410- 144510070;144517170-144517790;144517940-144518570;144522220- 144523410;144528690- 144529360;144530360-144530930;144580750-144581530;144684380- 144685240;144699790- 144700480;144713560-144714410;144786960-144787510;144791730- 144792360;144798450- 144799350;144807260-144808470;144826380-144827440;144852450- 144853150;144900800- 144901350

Chromosome 9841550-842260;1051430-1052420;2017290-2018270;2622420-26229 80;4490110-

4491050;4662350-4663120;4792830-4793670;4984830-4985470;5 628960-5629760;6006920-

6007940;6412990-6414130;6645060-6645690;14313230-14313840 ;14322100-14323140;14693160-

14693740;15306540-15307210;15510410-15511340;19049410-190 50090;20620540-

20621590;21993780-21994480;21994740-21995300;22008440-220 09520;22446780-

22447750;26946800-26947400;29212120-29212960;32384090-323 85040;32550460-

32551330;33166530-33167970;33263800-33264830;34126200-341 26930;34370870-

34372830;34380540-34381410;34457190-34457850;34458060-344 58820;34577990-

34578580;34589950-34590660;34590970-34591550;34623420-346 24170;34628530-

34629080;34637010-34637990;34646350-34647300;34664930-346 65550;34701320-

34702110;35071750-35073030;35079600-35080240;35096070-350 96800;35115730-

35116360;35161870-35162460;35489570-35490330;35616590-356 17590;35689550-

35690310;35690530-35691200;35748580-35749360;35790740-357 91340;35792510-

35793140;35814610-35815340;36190690-36191630;36257980-362 58980;36400200-

36400860;36572460-36573370;37002380-37003040;37592220-375 92810;37787020-

37787810;37800660-37801710;38067650-38068490;68704810-687 05390;68779850- 68780790;69013410-69014010;69173890-69174630;69220850-692215 30;69516400-

69517430;69671490-69672310;70412300-70413500;70413610-704 14320;71446460-

71447330;71910230-71911270;72149150-72150010;72364210-723 65590;74497830-

74498930;74952190-74953300;75027460-75028680;75087890-750 88890;75890550-

75891460;76905740-76906620;77016030-77016890;77019500-770 20110;77177090-

77178080;77647570-77648340;78235970-78236750;78296610-782 97500;83062350-

83063390;83538040-83539020;83623170-83623770;83707140-837 08030;83920860-

83921490;83980930-83981490;84140440-84141200;84670090-846 70970;85741370-

85742400;85940940-85941710;86281820-86283180;87497150-874 97740;87498010-

87498800;88535180-88536020;88991370-88991930;89311270-893 11890;89318310-

89319230;89605360-89606350;91361330-91362210;91421100-914 21840;91424120-

91424900;91949480-91950070;92114780-92115620;92669800-926 70400;92764990-

92765600;93058360-93059550;93096250-93096960;93451990-934 52800;93825910-

93826680;93945750-93946420;94030260-94031320;94638860-946 39750;95004110-

95004670;95349930-95350490;95506260-95507100;95515420-955 16130;96020930-

96022590;96218890-96219870;96417930-96418610;96418650-964 19490;96450550-

96451490;96854080-96854660;97411740-97412830;97501890-975 02490;97633460-

97634100;97696660-97697600;97852850-97854200;97854730-978 55290;97982920-

97983680;98056150-98057140;98087210-98087800;98087820-980 88480;98118660-

98119450;98192800-98193430;98255280-98255980;98943750-989 44300;99819280-

99819970;99821150-99821880;99821910-99822940;99823670-998 24360;99906590-

99907480; 100098650-100099280;100473550-100474130; 101028800-101029560;101737630-

101738340; 105448170-105448720; 105655980-105656800; 105694550-105695260; 107282870-

107284080; 107487410-107488310; 107488320-107489320; 107489960-107490610; 109012690-

109013570; 109119170-109119880; 109499340-109500300; 109640360-109641350; 110255900-

110256450; 110578810-110579890; 111037480-111038050; 111631150-111632070; 112332770-

112333630; 112717760-112718670; 112751010-112751590; 113220980-113221670; 113463280-

113464040; 114153740-114154940; 114398090-114398640; 114503930-114505190; 119368930-

119369940; 120792940-120793670; 120876050-120877160; 120928350-120929450; 121074690-

121075330; 121299470-121300360; 121369630-121370540; 121499350-121500140; 121597960-

121598660; 121599180-121600150; 121736070-121736620; 122092560-122093680; 122126570-

122127320; 122213460-122214640; 122218940-122219540; 122225910-122228550; 122346440-

122347040; 124008070-124008990; 124012310-124013010; 124014950-124015830; 124017280-

124017980; 124477790-124478370; 124502720-124503470; 124503500-124504540; 124776720-

124777820; 124809750-124810420; 124868800-124869890; 124940610-124941690; 125240450-

125241300; 125261740-125262390; 125407790-125408880; 125748020-125748720; 126612070-

126613210; 126625500-126627010; 127396920-127397760; 127397770-127398340; 127451420-

127452260; 127568190-127568860; 127612960-127613570; 127714650-127715560; 127734280- 127734830;127734870-127735690;127742320-127742930;127771310- 127771900;127877260-

127878110;127916550-127917620;127921500-127922310;1279268 70-127927540;127930520-

127931350;127979830-127980540;128067960-128069030;1281601 80-128160760;128191040-

128192050;128203770-128204340;128249790-128251140;1282755 60-128276110;128322620-

128323270;128391990-128393020;128419930-128420820;1284560 10-128457150;128552710-

128553320;128702260-128703660;128771180-128772340;1288189 40-128819590;128946780-

128947560;129027580-129028150;129036400-129037260;1290806 40-129081640;129110010-

129110600;129111190-129111810;129258170-129258840;1293832 70-129384170;129460390-

129460960;129482090-129482640;129487980-129489080;1295971 20-129597810;129610340-

129611040;129619980-129620850;129641530-129642490;1297189 10-129719800;129802950-

129804020;130042010-130042850;130043060-130043820;1302656 90-130266660;130433090-

130434180;130444810-130445650;130659210-130660040;1306642 10-130665390;130666280-

130667250;130680770-130681390;130939090-130940400;1310964 30-131097260;131373150-

131374090;131502140-131502710;131502730-131503650;1320793 70-132080120;132161040-

132161750;132162750-132163680;132197810-132198690;1322405 30-132241190;132586870-

132587720;132589180-132590290;132669660-132671050;1328778 80-132878510;133144190-

133144830;133274680-133276250;133335740-133336590;1333754 00-133376480;133417700-

133418430;133429550-133430160;133478740-133479530;1339910 80-133991670;133992990-

133993610;134025330-134025960;134135200-134135980;1341634 50-134164250;134325250-

134326000;135075030-135076050;135500260-135501420;1360511 50-136051870;136118590-

136119430;136132440-136133090;136193050-136194390;1361983 30-136199190;136201340-

136202330;136363390-136364320;136399740-136400370;1364105 40-136411100;136438830-

136439640;136482370-136483130;136483470-136484040;1365449 00-136545590;136546160-

136547140;136686820-136687540;136687610-136688180;1367117 00-136712250;136728300-

136729030;136799540-136800160;136821710-136822430;1368475 70-136848890;136977600-

136978450;136994500-136995620;137053290-137054080;1370778 80-137078550;137085940-

137087260;137129230-137129850;137138450-137139230;1371480 20-137148590;137156530-

137157130;137161760-137163570;137167160-137170040;1371883 10-137189470;137204830-

137206010;137280500-137281720;137294780-137295490;1373026 60-137303270;137316120-

137316700;137417000-137418070;137422510-137423110;1374413 10-137441890;137458300-

137459030;137551950-137552580;137578410-137579250;1376056 80-137606240;137834080-

137835500;137878250-137879210;138022670-138023330;346120- 346990

Chromosome X 358090-358790;386860-387550;630760-631570;631820-632370;6439 90-

645010;1248610-1249370;1391530-1392380;1465310-1466940;15 91330-1591890;1593410-

1594260;2488690-2490020;2500030-2500630;2583300-2583910;2 608890-2609960;2691040-

2691830;5893090-5893650;7148040-7148770;7926830-7927770;8 730700-8732820;9342670-

9343230;9464400-9464970;9465570-9466540;9785160-9785790;9 992610-9993450;10014220-

10014950;10016040-10016610;10157940-10159090;10208040-102 08610;10566800- 10567420; 10619830■10620780; 11111010■11111980; 11138880-11139640; 11664190- 11666120; 11758470■11759200; 12138010■12139390; 12771560-12772140; 12790760- 12791610; 12791910■12792660; 12975300■12976220; 13569500-13570510; 13652740- 13653710; 13688500■13689490; 13734070■13734630; 13937800-13939290; 14029640- 14030430; 14528920■14529540; 14872860 .14874070; 15335080-15336060; 15737750- 15738750; 15822750·■15823370; 15853840■15854600; 15854830-15855820; 16711490- 16712970; 16719180■16719980; 16720340■16720890; 16785620-16786370; 16786810- 16787530; 16945970■16946610; 17374800■17375910; 17376110-17376910; 17376940- 17378090; 17654930■17656660; 17737410■17738000; 17859950-17860670; 17861500- 17862050; 18353580■18354410; 18424590■18425210; 18425260-18426570; 18983660- 18985000; 19121380■19121980; 19122760■19123310; 19343690-19344800; 19886440- 19886990; 19887950■19888920; 19990070■19990820;20115900-20116750;20116970- 20118170;20141170■20142880;20265970■20266550;20266910-20 267740;20268060- 20268610;21373460■21374120;21374430■21375580;21655580-21 659170;21839440- 21840160;21856790■21857810;21940130■21940730;23331870-23 332630;23332900- 23334190;23334970·■23335590;23667100■23668190;23742650- 23744020;23782640- 23783190;23907310■23908500;23988560■23989140;24024440-24 025190;24025800- 24026370;24210550■24211340;24465280■24466150;24646580-24 647460;24693260- 24694390;25001960■25002520;25002720·■25004040;25004210- 25006130;25006790- 25007920;25012400·■25013310;25015210■25016780;25017450- 25018180;25020470- 25021370;25022510·■25023560;29955200·■29955850;3024696 0-30247600;30307940- 30309910;30653120■30654240;30685140■30685700;30720510-30 721120;30888440- 30889170;30889190■30889810;31071570■31072170;31266240-31 267040;33726260- 33727080;34130410■34131360;34131790■34132480;34146790-34 147580;37348820- 37350060;37685170■37685750;37685800·■37686620;37846790- 37847870;38220090- 38221370;38327020·■38327880;38561620■38562200;38804030- 38805610;38805840- 38806400;39040630■39041440;39688230■39688920;39689060-39 690130;39730810- 39731360;39821830■39822560;39900170■39900890;40004800-40 010100;40011250- 40014650;40014880■40015920;40061830■40062850;40073370-40 074010;40083180- 40084420;40089720■40090870;40091110■40092380;40094280-40 095810;40098110- 40099670;40102440■40103060;40104280■40104940;40105330-40 105930;40106430- 40109250;40144760■40148610;40151340■40152800;40152960-40 154450;40154470- 40156680;40157790■40158340;40167130■40169210;40169680-40 170280;40171320- 40173030;40173810■40174760;40174790■40176670;40266670-40 267910;40580220- 40581690;40622750■40624300;40646950■40647870;40734680-40 736110;40834130- 40834840;41084520■41085430;41085560■41086810;41253170-41 254150;41274850- 41275470;41275640■41277410;41332630■41333390;41334010-41 334660;41441980- 41442910:41474110■41475000:41922420■41923060;41923740-41 924410;42777470- 42778550;4365472O■43656590;43881790■43882810;44029020-44 029650;44343940- 44344890;44505060■44505680;44542610■44543170;44844000-44 844980;44872020- 44872980;44873060■44874380;45157420■45157970;45381530-45 382260;45850100- 45851460;46446650■46447680;46544930■46546170;46573240-46 574960;46575110- 46575780;46758200■46758950;46759300■46759980;46837110-46 837700;46913030- 46913850;47128460■47129190;47143840■47145620;47174600-47 175200;47176060- 47176810;47179720■47180590;47185880■47186630;47190040-47 191940;47193450- 47194510;47205920■47206470;47217500■47219840;47224220-47 225020;47232610- 47234150;47241900■47242540;47366080■47366900;47367090-47 367640;47482310- 47483490;47523290■47524630;47556380■47557020;47560810-47 561980;47572560- 47573110;47573600■47575090;47582150■47582780;47618960-47 619940;47619950- 47620550;47626010■47626600;47649870■47650680;47658480-47 659330;48475400- 48477060;48507740■48508320;48508530■48509920;48521480-48 522670;48538680- 48540250;48558830■48560430;48574110■48575140;48597310-48 598370;48598440- 48599880;48604780■48605360;48675950■48677230;48685410-48 686050;48688250- 48688860;48699790■48700960;48706100■48706810;48736890-48 738040;48801210- 48802740;48817860■48818430;48826060■48827960;48830990-48 832030;48832190- 48832790;48834510■48835510;48890720■48892360;48897060-48 898260;48901870- 48902880;48904790■48905610;48911150■48911970;48918270-48 919830;48923530- 48924160;48957820■48958500;48968950■48970540;48971830-48 972420;48982800- 48983710;49001660■49002700;49042700■49043410;49043430-49 044130;49053190- 49054300;49072010■49073110;49073440 49074470;49075290-49075990;49079330- 49080840;49100750■49101950;49123780■49124390;49124590-49 125200;49146100- 49146670;49165820■49166930;49171440■49173090;49175710-49 176260;49185570- 49187060;49190870■49191950;49199650■49200680;49209510-49 210210;49230010- 49231380;49233730■49234590;49235190■49235990;49251280-49 251830;49269260- 49269820;49270190■49270990;49285830■49286410;49878900-49 879810;49879960- 49881330;49922370■49923660;50204260■50204910;50468600-50 469850;50813190- 50814600;51334820■51335490;51395790■51396670;51407510-51 408270;51743100- 51744350;51893800■51894650;52994950■52995720;53000220-53 001220;53048560- 53049620;53076390■53077860;53081890■53083110;53088830-53 089710;53093860- 53094890;53193020■53193800;53194220■53194780;53198750-53 199300;53224200- 53225370;53234820·■53235380;53236040·■53236730;5325015 0-53251220;53254310- 53255260;53319960■53321110;53321550■53322120;53356260-53 356810;53382200- 53382750;53405460·■53406050;53412860■53413650;53422000- 53423180;53433710- 53434780;53440630■53441240;53441560■53442160;53543450-53 544010;53548930- 53549590;53550660■53551210;53583560■53584120;53683490-53 684610;53685920- 53686850:54042170■54043050:54043420 .54044700;54182130-54183300;54183870- 54184700;54357160-54359150;54440340-54440890;54494860-544954 10;54495830-

54496410;54999890-55000600;55160950-55161990;55451860-554 53160;55487980-

55488550;55488600-55489370;56231720-56233470;56563370-565 65190;56994820-

56995890;64204360-64206440;65034240-65035720;65501620-655 02410;65534240-

65535170;65667620-65668190;67543830-67544390;67545020-675 46500;68432800-

68434360;68498370-68499540;68686030-68686910;68693430-686 94530;68827750-

68828540;68828710-68830860;68840150-68840710;68894310-688 95150;69136500-

69137470;69162070-69162640;69164960-69165540;69503680-695 04290;69615610-

69617300;70062310-70063600;70289420-70290840;70433500-704 35210;70445140-

70445820;70452140-70453190;70454570-70455650;70908170-709 08890;70930400-

70930950;71067760-71068920;71095430-71096010;71096100-710 97300;71118320-

71119440;71129080-71129640;71136160-71136850;71144410-711 45070;71147520-

71148290;71153090-71153880;71166960-71167940;71169180-711 70190;71223710-

71224800;71240760-71241520;71253820-71254640;71283300-712 84410;71365550-

71366140;71491890-71493070;71532180-71532750;71532800-715 34150;71546270-

71547310;71577420-71578850;71612200-71612800;71616180-716 17530;71911100-

71912060;72018080-72019170;72130680-72131690;72181380-721 82020;72238560-

72239180;72239210-72239800;72255040-72256000;72276840-722 77460;72304840-

72306280;72306980-72308280;72572180-72573120;72713350-727 14810;72715370-

72715920;73214120-73214740;73447120-73448050;73562780-735 63770;74292260-

74293160;74304140-74304950;74420580-74423240;74535630-745 37100;74613990-

74614790;74923880-74925480;75273970-75274710;75522570-755 23520;75781650-

75782230;76172640-76173320;76427810-76428490;76428720-764 29600;77446670-

77447240;77447250-77448650;77785770-77786480;77910250-779 11150;78139120-

78139770;80334960-80335810;80574450-80575170;80807880-808 09070;81120350-

81120900;83508100-83509690;83510300-83511200;84187050-841 88000;84188060-

84188800;85244150-85245150;85326160-85326870;86147450-861 48170;86148290-

86149420;91434390-91435320;91435450-91436500;93672860-936 73830;93673910-

93674750;96684590-96685640;96884470-96885310; 100406300-100408610; 100408900-

100409530; 100409640-100410740; 100410750-100412450; 100636140-100637180; 100731370-

100732340; 100820290-100820840; 100928420-100929590; 101097660-101098490; 101290840-

101291830; 101348070-101349380; 101407940-101408600; 101418180-101418810; 101484980-

101486040; 101551480-101552410; 101623290-101624370; 101624940-101625770; 101656220-

101656890; 101931600-101932220; 102155180-102155810; 102516170-102516840; 102768630-

102769650; 103063610-103064440; 103214890-103215600; 103220750-103221520; 103254760-

103255330; 103310020-103311250; 103347890-103348760; 103376060-103377430; 103629450-

103630670; 103786340-103787090; 104253490-104255800; 104255890-104256960; 104564600-

104565150; 104565630-104566690; 104566840-104567430; 104568320-104569000; 105822280- 105823590;106611410106612680;106726330106727630; 106802770106803330;106998780- 106999670; 107000050107000600;107118190107118750;107205330107206230; 107272240- 107273680;107448540107449590; 107450200107450840;107506950107507890;107627990- 107629440; 107676390107677310;107715720107717390;107774850107776660;107 825500- 107826230; 107826720107827350;107935550· 107936900;108090830108092210;108734940- 108735670;108735780108736920; 109475740109476330;109536640109537190;109624340- 109625490; 109732460109733910;110003500110004360;110317230110318080;110 795470- 110796110;111096180111096800;111098610111099340;111409800111 410680;111680810- 111681830;112840240112840790;114581210114582250;114582470114 583450;114583740- 114585460;114906600114907440;115233310115234390;115968260115 969080;118116220- 118116810;118345850118347050;118496090118496940; 118727000118727580; 118727800- 118728580;118823640118824270;118839140118840090;118973340118 974200; 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129777060- 129777810; 129842990129844290; 129932830129933580;129952970129953590;129956230- 129958300;129979630129980690;129980930129983560;129984400129 985030;130013660- 130014810;130034540130035150;130059870130061020;130109350130 110200;130111220- 130111930;130120060130121280;130121320130121880;130165230130 166160;130171020- 130172650;130268160130268980;130401920130402520;131057910131 059040;131067790- 131068650;131068890131069510;131082010131083070;131626010131 626730;131741120- 131741760;131795430131796330;132022900132024140;132216400132 218050;132218120- 132218790;132955860132958860;133413450133415520;133415530133 416510;133984520- 133985590;134171190134173170;134173210134174260;134236570134 237930;134373180- 134374100;134459560134460120;134460370134461070;134544490134 546910;134549050- 134550430;134550550134551690;134796620134797510;134806060134 806810;134914310- 134915460;134990540134991630;135003800135004660;135343270135 344080;135344260- 135345540;135436430135437400;135520700135521600;135521790135 522390;135973160- 135974040;135984440135984990;135985110135986350;136097370136 098170;136098230- 136098880;136146570136147210;136208960136209510;136250400136 250990;136497560- 136498170;136766650136768350;136879860136880410;136881180136 882140;136909300- 136910290;136954170136954740;137030890137032410;137033310137 033870;137051900- 137053560;137425360137425930;137427730· 137428540;137429310137429990;137430120- 137430870;137545610137546180;137547270137547910;137548740137 549620;137549770- 137551430;137565370137568330;137568360137569760;137573840137 575310;138710500- 138711300;139194290139195330;139202980139203530;139203550139 204340; 139204420- 139205520;139691380139692650;139931450139932120;139932640139 933190;140090690- 140091260;140091630140092590;140439160140440030;140502210140 503120;140503300- 140503870;140504370140506700; 140507740140508740;140510560140511740;140712590- 140713340;140764160140765050;141176340141177140;143629770143 630780;143633550- 143634540;145817740145819010;145822030145822670;147911350147 911900;147912250- 147913080;148499830148500470;148500970148502040; 149504660149505210;149630990- 149631590;150361080150362280;150362300150365040;150365100150 365900;150547300- 150548370;150567800150569580;150693840150694450;150898790150 899770;150982410- 150983320;151174830151175960;151176960151178400;152637650152 638840;152830680- 152831710;152897290152898020;152941240152942080;153031930153 033010;153333550- 153334330;153334420· 153335080;153347040153348240;153410800153411820;153420390- 153421470;153469920153471390;153474940153475520;153579810153 580400;153598170- 153598900;153599390153599940;153610040153611050;153642000153 642660;153642840- 153644100;153644490153645040;153646610153647170;153647210153 648110;153649190- 153649740;153723310153724370;153724450153726360;153788060153 788620;153793510- 153795630;153803130153805300;153806790153807340;153818440153 819550;153828360- 153830240;153831070153831640;153831700153832270;153864700153 865640;153875550- 153876140;153884900153885850;153921050153921950;153927780153 928870;153934140- 153934790;153935300153936090;153943410153944180;153949950153 950610;153954860- 153955620;153959870153960420;153970520153972350;154018930154 019580;154096260- 154097050;154097850154098440;154125080154125940;154136520154 137250;154359040- 154360790;154370350154372530;154374790154375350;154377730154 378840;154379100- 154380160;154397350154398440;154410960154412530;154427930154 429390; 154437490- 154438080;154458450154459050;154478150154479740; 154490040154491490;154515380- 154516440;154517190154517740;154532180154533000;154546270154 546830;154546990- 154548120;154550480154551030;154750140154750840;154762480154 763510;154804830- 154806070;155026280155027650;155069940155071100;155215870155 216900;155263670- 155264750:155612450155613070:155880630155881880