METHODS OF ANALYZING GENETIC VARIANTS BASED ON GENETIC MATERIAL
Provided are methods for identifying gene variants associated with a phenotype, for example by inferring and scoring of structural variants from whole-genome or exome data or processing a set of genes against a known set of genes having known variants associated with a set of phenotypes, and optionally determining how likely each of the genes are to cause the phenotype.
1 .- 42 . (canceled)
43 . A computer-implemented method for inferring a structural variant, said method comprising:
(a) constructing a set of badges to span an exon, an upstream region, a downstream region, a gene regulatory element, or any combination thereof of one or more genes or transcripts thereof;
(b) identifying one or more genetic variants having one or more attributes to a human subject and overlapping said set of badges, and using said one or more attributes to determine a ploidy of said one or more genetic variants in said set of badges; and
(c) reporting a structural variant by using at least said ploidy determined in (b) to indicate a change in gene or regulatory element dosage caused by said structural variant that deviates from a normal human karyotype.
44 . The method of claim 43 , wherein said ploidy is determined based at least in part on an analysis of (i) discrepancy in distributing genetic variant alleles zygosities from expectation for a genomic segment overlapped by said badges or (ii) a distribution of reads harboring alternative alleles for said one or more genetic variants overlapped by said badges.
45 . The method of claim 43 , wherein said one or more genetic variants are from a whole-genome sequencing or whole-exome sequencing of a human subject.
46 . The method of claim 43 , wherein said badges are configured to span (i) an exon region of a transcript of a human genome or (ii) each exon of said transcripts.
47 . The method of claim 43 , wherein said badges further comprise (i) an upstream or a downstream buffer region associated with said exon region of said transcript or (ii) a gene regulatory region.
48 . The method of claim 43 , wherein said badges represent a DNA sequence coordinate of said exon region of said transcript.
49 . The method of claim 43 , wherein said ploidy is determined based at least in part on (i) a frequency of its alleles in human populations of said one or more genetic variants or (ii) defining an expectation of zygosity of overlapping genetic variants from a subject by comparing to a frequency of its alleles in human populations of said one or more genetic variants.
50 . The method of claim 43 , wherein said structural variant is associated with a disease phenotype or a gene associated with a disease phenotype.
51 . The method of claim 43 , further comprising determining a score inferring severity of an impact of a structural variant on a structure of overlapping genes that can be associated with a disease phenotype.
52 . The method of claim 43 , wherein said genetic variants or said genes or transcripts thereof have been ranked by VAAST, VVP, PHEVOR, pVAAST, SIFT, CAD, ANNOVAR, a burden-test, a sequence conservation scoring method, a machine learning method, or any combination thereof.
53 . The method of claim 43 , further comprising prioritizing a single nucleotide variant (SNV), an insertion or deletion (INDEL), or said structural variant.
54 . The method of claim 43 , further comprising automatically prioritizing compound heterozygous genotypes comprising a single nucleotide variant (SNV) or an insertion or deletion (INDEL) in trans to a larger structural variant.
55 . The method of claim 43 , further comprising merging said badges if adjacent in genome coordinates, discrepant to expectation of said human normal karyotype, or are of similar inferred ploidy.
56 . A method for inferring a structural variant, said method comprising:
(a) providing one or more genetic variants attributable to a subject;
(b) identifying said one or more genetic variants overlapping one or more badges, wherein said one or more badges represents a portion of a human genome;
(c) determining a ploidy of said one or more genetic variants based at least in part on an analysis of sequencing read depth of said one or more genetic variants; and
(d) reporting a structural variant by using at least said ploidy determined in (b) to indicate a change in gene or regulatory element dosage caused by said structural variant that deviates from a normal human karyotype.
57 . A method for analyzing a genome of a subject, comprising:
(a) providing a set of genes or gene regulatory elements suspected of having one or more single nucleotide variants (SNVs), insertions or deletions (INDELs), structural variants, or any combination thereof, which set of genes or gene regulatory elements is generated from a nucleic acid sample of said subject;
(b) processing said set of genes or gene regulatory elements against a known set of genes or gene regulatory elements to identify at least one gene or gene regulatory element of said set of genes or gene regulatory elements that is associated with a known set of phenotypes, wherein said known set of phenotypes is associated with one or more phenotypes of said subject;
(c) determining a likelihood that said at least one gene or gene regulatory element identified in (b) is causative of a phenotype; and
(d) outputting a report that is indicative of said at least one gene or gene regulatory element identified in (b) and said likelihood determined in (c).
58 . The method of claim 57 , wherein said set of genes or gene regulatory elements comprises genetic variants.
59 . The method of claim 57 , wherein (a) further comprises sequencing a DNA sample of said subject.
60 . The method of claim 57 , wherein (b) further comprises annotating variant impact on overlapping gene structure or regulatory element locations.
61 . The method of claim 57 , wherein (b) further comprises determining score variant deleteriousness on gene function.
62 . The method of claim 57 , wherein (b) further comprises gene burden scoring.
63 . The method of claim 57 , wherein (b) further comprises phenotype-based prioritizing.
64 . The method of claim 57 , wherein said one or more phenotypes of said subject is the same as one or more phenotypes in said known set of phenotypes.
65 . The method of claim 57 , wherein said at least one gene or gene regulatory element identified in (b) is causative of a disease, and wherein said disease is associated with said known set of phenotypes.
66 . The method of claim 57 , wherein (c) further comprises determining a Bayes factor.
67 . The method of claim 57 , wherein (c) further comprises using a machine learning algorithm.
68 . The method of claim 57 , wherein (c) further comprises integrating variant, pedigree, phenotype information, or any combination thereof about said subject.
69 . The method of claim 57 , wherein (c) further comprises using ExAC, gnomAD, OMIM, ClinVar, GARD, Orphanet, HGMD, or any combination thereof as an input source.
70 . The method of claim 57 , wherein said INDEL is less than 50 bp, or said structural variant is 50 bp or greater than 50 bp.