Dataset Information

Integrating read-based and population-based phasing for dense and accurate haplotyping of individual genomes.

ABSTRACT: MOTIVATION:Reconstruction of haplotypes for human genomes is an important problem in medical and population genetics. Hi-C sequencing generates read pairs with long-range haplotype information that can be computationally assembled to generate chromosome-spanning haplotypes. However, the haplotypes have limited completeness and low accuracy. Haplotype information from population reference panels can potentially be used to improve the completeness and accuracy of Hi-C haplotyping. RESULTS:In this paper, we describe a likelihood based method to integrate short-range haplotype information from a population reference panel of haplotypes with the long-range haplotype information present in sequence reads from methods such as Hi-C to assemble dense and highly accurate haplotypes for individual genomes. Our method leverages a statistical phasing method and a maximum spanning tree algorithm to determine the optimal second-order approximation of the population-based haplotype likelihood for an individual genome. The population-based likelihood is encoded using pseudo-reads which are then used as input along with sequence reads for haplotype assembly using an existing tool, HapCUT2. Using whole-genome Hi-C data for two human genomes (NA19240 and NA12878), we demonstrate that this integrated phasing method enables the phasing of 97-98% of variants, reduces the switch error rates by 3-6-fold, and outperforms an existing method for combining phase information from sequence reads with population-based phasing. On Strand-seq data for NA12878, our method improves the haplotype completeness from 71.4 to 94.6% and reduces the switch error rate 2-fold, demonstrating its utility for phasing using multiple sequencing technologies. AVAILABILITY AND IMPLEMENTATION:Code and datasets are available at https://github.com/vibansal/IntegratedPhasing.

SUBMITTER: Bansal V

PROVIDER: S-EPMC6612846 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Integrating read-based and population-based phasing for dense and accurate haplotyping of individual genomes.

Bansal Vikas V

Bioinformatics (Oxford, England) 20190701 14

<h4>Motivation</h4>Reconstruction of haplotypes for human genomes is an important problem in medical and population genetics. Hi-C sequencing generates read pairs with long-range haplotype information that can be computationally assembled to generate chromosome-spanning haplotypes. However, the haplotypes have limited completeness and low accuracy. Haplotype information from population reference panels can potentially be used to improve the completeness and accuracy of Hi-C haplotyping.<h4>Resul ...[more]

PMID: 31510646

Similar Datasets

Project description:BackgroundHaplotype information is useful for many genetic analyses and haplotypes are usually inferred using computational approaches. Among such approaches, the importance of single individual haplotyping (SIH), which infers individual haplotypes from sequence fragments, has been increasing with the advent of novel sequencing techniques, such as dilution-based sequencing. These techniques could produce virtual long read fragments by separating DNA fragments into multiple low-concentration aliquots, sequencing and mapping each aliquot, and merging clustered short reads. Although these experimental techniques are sophisticated, they have the problem of producing chimeric fragments whose left and right parts match different chromosomes. In our previous research, we found that chimeric fragments significantly decrease the accuracy of SIH. Although chimeric fragments can be removed by using haplotypes which are determined from pedigree genotypes, pedigree genotypes are generally not available. The length of reads cluster and heterozygous calls were also used to detect chimeric fragments. Although some chimeric fragments will be removed with these features, considerable number of chimeric fragments will be undetected because of the dispersion of the length and the absence of SNPs in the overlapped regions. For these reasons, a general method to detect and remove chimeric fragments is needed.ResultsIn this paper, we propose a general method to detect chimeric fragments. The basis of our method is that a chimeric fragment would correspond to an artificial recombinant haplotype and would differ from biological haplotypes. To detect differences from biological haplotypes, we integrated statistical phasing, which is a haplotype inference approach from population genotypes, into our method. We applied our method to two datasets and detected chimeric fragments with high AUC. AUC values of our method are higher than those of just using cluster length and heterozygous calls. We then used multiple SIH algorithm to compare the accuracy of SIH before and after removing the chimeric fragment candidates. The accuracy of assembled haplotypes increased significantly after removing chimeric fragment candidates.ConclusionsOur method is useful for detecting chimeric fragments and improving SIH accuracy. The Ruby script is available at https://sites.google.com/site/hmatsu1226/software/csp.

Dataset Information

Integrating read-based and population-based phasing for dense and accurate haplotyping of individual genomes.

Publications

Integrating read-based and population-based phasing for dense and accurate haplotyping of individual genomes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets