Dataset Information

Integrating dilution-based sequencing and population genotypes for single individual haplotyping.

ABSTRACT:

Background

Haplotype 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.

Results

In 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.

Conclusions

Our 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.

SUBMITTER: Matsumoto H

PROVIDER: S-EPMC4162929 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHaplotype information is useful for various genetic analyses, including genome-wide association studies. Determining haplotypes experimentally is difficult and there are several computational approaches that infer haplotypes from genomic data. Among such approaches, single individual haplotyping or haplotype assembly, which infers two haplotypes of an individual from aligned sequence fragments, has been attracting considerable attention. To avoid incorrect results in downstream analyses, it is important not only to assemble haplotypes as long as possible but also to provide means to extract highly reliable haplotype regions. Although there are several efficient algorithms for solving haplotype assembly, there are no efficient method that allow for extracting the regions assembled with high confidence.ResultsWe develop a probabilistic model, called MixSIH, for solving the haplotype assembly problem. The model has two mixture components representing two haplotypes. Based on the optimized model, a quality score is defined, which we call the 'minimum connectivity' (MC) score, for each segment in the haplotype assembly. Because existing accuracy measures for haplotype assembly are designed to compare the efficiency between the algorithms and are not suitable for evaluating the quality of the set of partially assembled haplotype segments, we develop an accuracy measure based on the pairwise consistency and evaluate the accuracy on the simulation and real data. By using the MC scores, our algorithm can extract highly accurate haplotype segments. We also show evidence that an existing experimental dataset contains chimeric read fragments derived from different haplotypes, which significantly degrade the quality of assembled haplotypes.ConclusionsWe develop a novel method for solving the haplotype assembly problem. We also define the quality score which is based on our model and indicates the accuracy of the haplotypes segments. In our evaluation, MixSIH has successfully extracted reliable haplotype segments. The C++ source code of MixSIH is available at https://sites.google.com/site/hmatsu1226/software/mixsih.