Phased Whole-Genome Genetic Risk in a Family Quartet Using a Major Allele Reference Sequence

PLoS Genet. 2011 Sep;7(9):e1002280. doi: 10.1371/journal.pgen.1002280. Epub 2011 Sep 15.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Base Sequence
  • DNA Mutational Analysis / methods*
  • Female
  • Genes, Synthetic*
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Genome, Human
  • Genome-Wide Association Study / methods*
  • Genotype
  • Haplotypes
  • Humans
  • Male
  • Pedigree
  • Reference Standards
  • Risk Assessment
  • Sequence Alignment
  • Sequence Analysis, DNA
  • Thrombophilia / genetics*