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Phased whole-genome genetic risk in a family quartet using a major allele reference sequence
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نویسنده
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dewey f.e. ,chen r. ,cordero s.p. ,ormond k.e. ,caleshu c. ,karczewski k.j. ,whirl-carrillo m. ,wheeler m.t. ,dudley j.t. ,byrnes j.k. ,cornejo o.e. ,knowles j.w. ,woon m. ,sangkuhl k. ,gong l. ,thorn c.f. ,hebert j.m. ,capriotti e. ,david s.p. ,pavlovic a. ,west a. ,thakuria j.v. ,ball m.p. ,zaranek a.w. ,rehm h.l. ,church g.m. ,west j.s. ,bustamante c.d. ,snyder m. ,altman r.b. ,klein t.e. ,butte a.j. ,ashley e.a.
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منبع
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plos genetics - 2011 - دوره : 7 - شماره : 9
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چکیده
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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.
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آدرس
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center for inherited cardiovascular disease,division of cardiovascular medicine,stanford university,stanford,ca, United States, division of systems medicine,department of pediatrics,stanford university school of medicine,stanford,ca, United States, biomedical informatics graduate training program,stanford university school of medicine,stanford,ca, United States, department of genetics,stanford university school of medicine,stanford,ca,united states,center for biomedical ethics,stanford university,stanford,ca, United States, center for inherited cardiovascular disease,division of cardiovascular medicine,stanford university,stanford,ca, United States, biomedical informatics graduate training program,stanford university school of medicine,stanford,ca,united states,department of genetics,stanford university school of medicine,stanford,ca, United States, department of genetics,stanford university school of medicine,stanford,ca, United States, center for inherited cardiovascular disease,division of cardiovascular medicine,stanford university,stanford,ca, United States, division of systems medicine,department of pediatrics,stanford university school of medicine,stanford,ca,united states,biomedical informatics graduate training program,stanford university school of medicine,stanford,ca, United States, department of genetics,stanford university school of medicine,stanford,ca, United States, department of genetics,stanford university school of medicine,stanford,ca, United States, center for inherited cardiovascular disease,division of cardiovascular medicine,stanford university,stanford,ca, United States, department of genetics,stanford university school of medicine,stanford,ca, United States, department of genetics,stanford university school of medicine,stanford,ca, United States, department of genetics,stanford university school of medicine,stanford,ca, United States, department of genetics,stanford university school of medicine,stanford,ca, United States, department of genetics,stanford university school of medicine,stanford,ca, United States, department of genetics,stanford university school of medicine,stanford,ca, United States, department of genetics,stanford university school of medicine,stanford,ca, United States, center for inherited cardiovascular disease,division of cardiovascular medicine,stanford university,stanford,ca, United States, wellesley college,wellesley,ma, United States, division of genetics,massachusetts general hospital,boston,ma, United States, department of genetics,harvard medical school,boston,ma, United States, department of genetics,harvard medical school,boston,ma, United States, department of pathology,harvard medical school,boston,ma, United States, department of genetics,harvard medical school,boston,ma, United States, personalis,palo alto,ca, United States, department of genetics,stanford university school of medicine,stanford,ca, United States, department of genetics,stanford university school of medicine,stanford,ca, United States, department of genetics,stanford university school of medicine,stanford,ca,united states,department of bioengineering,stanford university,stanford,ca, United States, department of genetics,stanford university school of medicine,stanford,ca, United States, division of systems medicine,department of pediatrics,stanford university school of medicine,stanford,ca, United States, center for inherited cardiovascular disease,division of cardiovascular medicine,stanford university,stanford,ca, United States
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Authors
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