Improved haplotyping of rare variants using next-generation sequence data

TL;DR

This paper introduces a novel statistical method that integrates paired-end sequencing read data with population genotype data to significantly improve haplotype phasing accuracy, especially for rare variants, in human genomes.

Contribution

The method extends shapeIT by incorporating sequencing read information, enhancing haplotype reconstruction accuracy in unrelated individuals using next-generation sequencing data.

Findings

Significant reduction in switch error rates (4-15%) across different panels.

Greater improvements observed with longer reads and higher throughput.

Enhanced accuracy in phasing rare variants using the new approach.

Abstract

Accurate identification of haplotypes in sequenced human genomes can provide invaluable information about population demography and fine-scale correlations along the genome, thus empowering both population genomic and medical association studies. Yet phasing unrelated individuals remains a challenging problem. Incorporating available data from high throughput sequencing into traditional statistical phasing approaches is a promising avenue to alleviate these issues. We present a novel statistical method that expands on an existing graphical haplotype reconstruction method (shapeIT) to incorporate phasing information from paired-end read data. The algorithm harnesses the haplotype graph information estimated by shapeIT from genotypes across the population and refines haplotype likelihoods for a given individual to be compatible with the sequencing data. Applying the method to HapMap individuals genotyped on the Affymetrix Axiom chip at 7,745,081 SNPs and on a trio sequenced by Complete Genomics, we found that the inclusion of paired end read data significantly improved phasing, with reductions in switch error on the order of 4-15% against shapeIT across all panels. As expected, the improvements were found to be most significant at sites harboring rare variants; furthermore, we found that longer read sizes and higher throughput translated to greater decreases in switching error, as did higher variance in the size of the insert separating the two reads--suggesting that multi-platform next generation sequencing may be exploited to yield particularly accurate haplotypes. Overall, the phasing improvements afforded by this new method highlight the power of integrating sequencing read information and population genotype data for reconstructing haplotypes in unrelated individuals.