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

PLoS Genet 2011 Sep 15;7(9):e1002280. Epub 2011 Sep 15.

Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Stanford, California, USA.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1002280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174201PMC
September 2011
26 Reads

Publication Analysis

Top Keywords

reference sequence
12
genetic risk
8
genetic variation
8
whole-genome sequencing
8
major allele
8
allele reference
8
risk
5
compound heterozygosity
4
allowing quantification
4
haplotype phasing
4
phasing allowing
4
heterozygosity develop
4
quantification genome-wide
4
genome-wide compound
4
sequence-based methodology
4
typing contributes
4
contributes disease
4
disease risk
4
antigen typing
4
leukocyte antigen
4

Similar Publications