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- Title
Phased whole-genome genetic risk in a family quartet using a major allele reference sequence.
- Authors
Dewey, Frederick E; Chen, Rong; Cordero, Sergio P; Ormond, Kelly E; Caleshu, Colleen; Karczewski, Konrad J; Whirl-Carrillo, Michelle; Wheeler, Matthew T; Dudley, Joel T; Byrnes, Jake K; Cornejo, Omar E; Knowles, Joshua W; Woon, Mark; Sangkuhl, Katrin; Gong, Li; Thorn, Caroline F; Hebert, Joan M; Capriotti, Emidio; David, Sean P; Pavlovic, Aleksandra; West, Anne; Thakuria, Joseph V; Ball, Madeleine P; Zaranek, Alexander W; Rehm, Heidi L; Church, George M; West, John S; Bustamante, Carlos D; Snyder, Michael; Altman, Russ B; Klein, Teri E; Butte, Atul J; Ashley, Euan A
- Abstract
Whole-genome sequencing harbors unprecedented potential for characterization of individual and family genetic variation. Here, we develop a novel synthetic human reference sequence that is ethnically concordant and use it for the analysis of genomes from a nuclear family with history of familial thrombophilia. We demonstrate that the use of the major allele reference sequence results in improved genotype accuracy for disease-associated variant loci. We infer recombination sites to the lowest median resolution demonstrated to date (< 1,000 base pairs). We use family inheritance state analysis to control sequencing error and inform family-wide haplotype phasing, allowing quantification of genome-wide compound heterozygosity. We develop a sequence-based methodology for Human Leukocyte Antigen typing that contributes to disease risk prediction. Finally, we advance methods for analysis of disease and pharmacogenomic risk across the coding and non-coding genome that incorporate phased variant data. We show these methods are capable of identifying multigenic risk for inherited thrombophilia and informing the appropriate pharmacological therapy. These ethnicity-specific, family-based approaches to interpretation of genetic variation are emblematic of the next generation of genetic risk assessment using whole-genome sequencing.
- Publication
PLoS genetics, 2011, Vol 7, Issue 9, pe1002280
- ISSN
1553-7404
- Publication type
Journal Article
- DOI
10.1371/journal.pgen.1002280