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. © 2011 Dewey et al.
Phased whole-genome genetic risk in a family quartet using a major allele reference sequence / Dewey, Frederick E.; Chen, Rong; Cordero, Sergio P.; Ormond, Kelly E.; Caleshu, Colleen; Karczewski, Konrad J.; Whirl-Carrillo, Michelle; Wheeler, Matthew T.; Dudley, Joel T.; Byrnes, Jake K.; Cornejo, Omar E.; Knowles, Joshua W.; Woon, Mark; Sangkuhl, Katrin; Gong, Li; Thorn, Caroline F.; Hebert, Joan M.; Capriotti, Emidio; David, Sean P.; Pavlovic, Aleksandra; West, Anne; Thakuria, Joseph V.; Ball, Madeleine P.; Zaranek, Alexander W.; Rehm, Heidi L.; Church, George M.; West, John S.; Bustamante, Carlos D.; Snyder, Michael; Altman, Russ B.; Klein, Teri E.; Butte, Atul J.; Ashley, Euan A. - In: PLOS GENETICS. - ISSN 1553-7390. - ELETTRONICO. - 7:9(2011), pp. e1002280.1-e1002280.15. [10.1371/journal.pgen.1002280]
Phased whole-genome genetic risk in a family quartet using a major allele reference sequence
CAPRIOTTI, EMIDIO;
2011
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. © 2011 Dewey et al.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
