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Phased whole-genome genetic risk in a family quartet using a major allele reference sequence.


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.

SUBMITTER: Dewey FE 

PROVIDER: S-EPMC3174201 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Phased whole-genome genetic risk in a family quartet using a major allele reference sequence.

Dewey Frederick E FE   Chen Rong R   Cordero Sergio P SP   Ormond Kelly E KE   Caleshu Colleen C   Karczewski Konrad J KJ   Whirl-Carrillo Michelle M   Wheeler Matthew T MT   Dudley Joel T JT   Byrnes Jake K JK   Cornejo Omar E OE   Knowles Joshua W JW   Woon Mark M   Sangkuhl Katrin K   Gong Li L   Thorn Caroline F CF   Hebert Joan M JM   Capriotti Emidio E   David Sean P SP   Pavlovic Aleksandra A   West Anne A   Thakuria Joseph V JV   Ball Madeleine P MP   Zaranek Alexander W AW   Rehm Heidi L HL   Church George M GM   West John S JS   Bustamante Carlos D CD   Snyder Michael M   Altman Russ B RB   Klein Teri E TE   Butte Atul J AJ   Ashley Euan A EA  

PLoS genetics 20110915 9


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 med  ...[more]

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