期刊
PLOS GENETICS
卷 7, 期 9, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1002280
关键词
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资金
- NIH/NHLBI [T32 HL094274-01A2, KO8 HL083914]
- Stanford University School of Medicine
- NIH National Research Service [F32 HL097462]
- NHGRI [U01HG005715]
- NIH/NIGMS [U01 GM61374, R01 GM079719]
- NIH/NHGRI [5 P50 HG003389-05]
- Lucile Packard Foundation for Children's Health
- Hewlett Packard Foundation
- NIH/NLM [T15 LM007033]
- NIH [OD004613]
- Breetwor Family Foundation
- Novartis
- 23andMe
- Lilly
- NuMedii
- Johnson and Johnson
- Genstruct
- Tercica
- Prevendia
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.
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