METHODS AND SYSTEMS FOR GENOME ANALYSIS
The present disclosure provides methods and systems for prioritizing phenotype-causing genomic variants. The methods include using variant prioritization analyses and in combination with biomedical ontologies using a sophisticated re-ranking methodology to re-rank these variants based on phenotype information. The methods can be useful in any genomics study and diagnostics; for example, rare and common disease gene discovery, tumor growth mutation detection, drug responder studies, metabolic studies, personalized medicine, agricultural analysis, and centennial analysis.
1 .- 78 . (canceled)
79 . A computer-implemented method for identifying candidate disease-causing genetic variants of an individual, the method comprising:
(a) providing in a computer memory:
(i) variant prioritization information for a set of genetic variants obtained by polynucleotide sequencing of the individual and by scoring impacts of variant proteins on gene function,
(ii) a description of disease phenotypes of the individual, and
(iii) a set of gene ontologies that comprise human phenotype ontology (HPO) terms,
(b) prioritizing, with respect to their relevance to a genetic disorder of the individual, the set of genetic variants, wherein the prioritizing comprises combining the variant prioritization information with a likelihood of association of the gene with the genetic disorder of the individual, as inferred from a linkage of a set of disease phenotypes exhibited by the individual to the genes as represented in the set of gene ontologies; and
(c) automatically identifying and reporting on a user interface a list of genes harboring the set of genetic variants of the individual, prioritized by operation (b).
80 . The method of claim 79 , wherein the set of gene ontologies is represented as a directed acyclic graph.
81 . The method of claim 80 , wherein the disease phenotypes are represented as nodes in the directed acyclic graph.
82 . The method of claim 81 , further comprising assigning a value to any genes associated with the nodes in the directed acyclic graph.
83 . The method of claim 79 , wherein input variants are scored based at least in part on a sequence characteristic selected from the group consisting of an amino acid substitution (AAS), a splice site, a promoter, a protein binding site, an enhancer, and a repressor.
84 . The method of claim 83 , wherein the sequence characteristic is the AAS.
85 . The method of claim 83 , wherein the sequence characteristic is the splice site.
86 . The method of claim 83 , wherein the sequence characteristic is the promoter.
87 . The method of claim 83 , wherein the sequence characteristic is the protein binding site.
88 . The method of claim 83 , wherein the sequence characteristic is the enhancer.
89 . The method of claim 83 , wherein the sequence characteristic is the repressor.
90 . The method of claim 79 , wherein the set of genetic variants is ranked using at least one of VAAST, pVAAST, SIFT, ANNOVAR, a burden-test, and a sequence conservation scoring method.
91 . The method of claim 90 , wherein the set of genetic variants is ranked using VAAST.
92 . The method of claim 90 , wherein the set of genetic variants is ranked using pVAAST.
93 . The method of claim 90 , wherein the set of genetic variants is ranked using SIFT.
94 . The method of claim 90 , wherein the set of genetic variants is ranked using ANNOVAR.
95 . The method of claim 90 , wherein the set of genetic variants is ranked using the burden-test.
96 . The method of claim 90 , wherein the set of genetic variants is ranked using the sequence conservation scoring method.
97 . The method of claim 79 , wherein the description of the disease phenotypes is derived from at least one of a clinical examination of the individual, an electronic medical health record of the individual, and family phenotype information on affected and non-affected individuals.
98 . The method of claim 79 , further comprising assessing at least one of a phenotype ontology containing knowledge concerning mutation phenotypes in non-human organisms, and information pertaining to paralogous and homologues genes and their mutant phenotypes in humans and other organisms.