Phased Whole-Genome Genetic Risk in a Family Quartet Using a Major Allele Reference Sequence

• DOI: 10.1371/journal.pgen.1002280
• Publication Date: 2011-09-16T00:23:26Z
• Authors: Frederick E. Dewey; Rong Chen; Sergio P. Cordero; Kelly E. Ormond; Colleen Caleshu; Konrad J. Karczewski; Michelle Whirl-Ca...; Matthew T. Wheeler; Joel T. Dudley; Jake K. Byrnes; Omar E. Cornejo; Joshua W. Knowles; Mark Woon; Katrin Sangkuhl; Li Gong; Caroline F. Thorn; Joan M. Hebert; Emidio Capriotti; Sean P. David; Aleksandra Pavlovic; Anne West; Joseph V. Thakuria; Madeleine P. Ball; Alexander W. Zaranek; Heidi L. Rehm; George M. Church; John S. West; Carlos D. Bustamante; Michael Snyder; Russ B. Altman; Teri E. Klein; Atul J. Butte; Euan A. Ashley
• Keywords: 1000 Genomes Project

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 use it the analysis genomes from nuclear with history familial thrombophilia. We demonstrate major allele results in improved genotype accuracy disease-associated variant loci. infer recombination sites to lowest median resolution demonstrated date (<1,000 base pairs). inheritance state control error inform family-wide haplotype phasing, allowing quantification genome-wide compound heterozygosity. sequence-based methodology Human Leukocyte Antigen typing contributes disease risk prediction. Finally, advance methods pharmacogenomic across coding non-coding genome incorporate phased data. show these are capable identifying multigenic inherited thrombophilia informing appropriate pharmacological therapy. These ethnicity-specific, family-based approaches interpretation variation emblematic next generation assessment using whole-genome sequencing.