Phased whole-genome genetic risk in a family quartet using a major allele reference sequence.

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.
Competing Interests: JVT and AWZ are founders, consultants, and equity holders in Clinical Future; GMC has advisory roles in and research sponsorships from several companies involved in genome sequencing technology and personal genomics (see http://arep.med.harvard.edu/gmc/tech.html); MS is on the scientific advisory board of DNA Nexus and holds stock in Personalis; RBA has received consultancy fees from Novartis and 23andMe and holds stock in Personalis; AJB is a scientific advisory board member and founder for NuMedii and Genstruct, a scientific advisory board member for Johnson and Johnson, has received consultancy fees from Lilly, NuMedii, Johnson and Johnson, Genstruct, Tercica, and Prevendia and honoraria from Lilly and Siemens, and holds stock in NuMedii, Genstruct, and Personalis. EAA holds stock in Personalis.