{"doi":"10.1371/journal.pgen.1002280","title":"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.","journal":"PLoS Genetics","year":2011,"id":11148,"datarank":0.7324202883879557,"base_score":4.882801922586371,"endowment":4.882801922586371,"self_citation_contribution":0.7324202883879557,"citation_network_contribution":0.0,"self_endowment_contribution":0.7324202883879557,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":131,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0622,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2011-09-15","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":50,"name":"Rong Chen","orcid":"0000-0001-6322-0340","position":1,"is_corresponding":false},{"id":89970,"name":"Sergio P. 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