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.
authors.affiliation: Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Stanford, California, USA.
authors.forename: Frederick E
authors.initials: FE
authors.lastname: Dewey
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.forename: Sergio P
authors.initials: SP
authors.lastname: Cordero
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Ormond
authors.forename: Colleen
authors.initials: C
authors.lastname: Caleshu
authors.forename: Konrad J
authors.initials: KJ
authors.lastname: Karczewski
authors.forename: Michelle
authors.initials: M
authors.lastname: Whirl-Carrillo
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Wheeler
authors.forename: Joel T
authors.initials: JT
authors.lastname: Dudley
authors.forename: Jake K
authors.initials: JK
authors.lastname: Byrnes
authors.forename: Omar E
authors.initials: OE
authors.lastname: Cornejo
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Knowles
authors.forename: Mark
authors.initials: M
authors.lastname: Woon
authors.forename: Katrin
authors.initials: K
authors.lastname: Sangkuhl
authors.forename: Li
authors.initials: L
authors.lastname: Gong
authors.forename: Caroline F
authors.initials: CF
authors.lastname: Thorn
authors.forename: Joan M
authors.initials: JM
authors.lastname: Hebert
authors.forename: Emidio
authors.initials: E
authors.lastname: Capriotti
authors.forename: Sean P
authors.initials: SP
authors.lastname: David
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Pavlovic
authors.forename: Anne
authors.initials: A
authors.lastname: West
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Thakuria
authors.forename: Madeleine P
authors.initials: MP
authors.lastname: Ball
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Zaranek
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Rehm
authors.forename: George M
authors.initials: GM
authors.lastname: Church
authors.forename: John S
authors.initials: JS
authors.lastname: West
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Bustamante
authors.forename: Michael
authors.initials: M
authors.lastname: Snyder
authors.forename: Russ B
authors.initials: RB
authors.lastname: Altman
authors.forename: Teri E
authors.initials: TE
authors.lastname: Klein
authors.forename: Atul J
authors.initials: AJ
authors.lastname: Butte
authors.forename: Euan A
authors.initials: EA
authors.lastname: Ashley
mesh_terms: D000483:Alleles; D001483:Base Sequence; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D005813:Genes, Synthetic; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D010375:Pedigree; D012015:Reference Standards; D018570:Risk Assessment; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D019851:Thrombophilia / Q000235:genetics*