Journal article
Phased whole-genome genetic risk in a family quartet using a major allele reference sequence
PLoS genetics, Vol.7(9), pp.e1002280-e1002280
09/2011
Handle:
https://hdl.handle.net/2376/105177
PMCID: PMC3174201
PMID: 21935354
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.
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Details
- Title
- Phased whole-genome genetic risk in a family quartet using a major allele reference sequence
- Creators
- Frederick E Dewey - Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Stanford, California, USARong ChenSergio P CorderoKelly E OrmondColleen CaleshuKonrad J KarczewskiMichelle Whirl-CarrilloMatthew T WheelerJoel T DudleyJake K ByrnesOmar E CornejoJoshua W KnowlesMark WoonKatrin SangkuhlLi GongCaroline F ThornJoan M HebertEmidio CapriottiSean P DavidAleksandra PavlovicAnne WestJoseph V ThakuriaMadeleine P BallAlexander W ZaranekHeidi L RehmGeorge M ChurchJohn S WestCarlos D BustamanteMichael SnyderRuss B AltmanTeri E KleinAtul J ButteEuan A Ashley
- Publication Details
- PLoS genetics, Vol.7(9), pp.e1002280-e1002280
- Academic Unit
- Biological Sciences, School of
- Publisher
- United States
- Grant note
- U01 GM061374 / NIGMS NIH HHS F32 HL097462 / NHLBI NIH HHS T32 HL094274 / NHLBI NIH HHS R01 GM079719 / NIGMS NIH HHS K08 HL083914 / NHLBI NIH HHS OD004613 / NIH HHS R01 HG003229 / NHGRI NIH HHS U01 HG005715 / NHGRI NIH HHS T15 LM007033 / NLM NIH HHS 5 P50 HG003389-05 / NHGRI NIH HHS U01 GM61374 / NIGMS NIH HHS P50 HG003389 / NHGRI NIH HHS T32 HL094274-01A2 / NHLBI NIH HHS U01HG005715 / NHGRI NIH HHS
- Identifiers
- 99900546794801842
- Language
- English
- Resource Type
- Journal article