Journal
GENOME RESEARCH
Volume 27, Issue 5, Pages 801-812Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gr.213462.116
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Funding
- National Institutes of Health [HG007430, HG007836, GM114362]
- National Science Foundation [DBI-1458557, IIS-1318386]
- Direct For Biological Sciences
- Div Of Biological Infrastructure [1458557] Funding Source: National Science Foundation
- Div Of Information & Intelligent Systems
- Direct For Computer & Info Scie & Enginr [1318386] Funding Source: National Science Foundation
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Many tools have been developed for haplotype assembly-the reconstruction of individual haplotypes using reads mapped to a reference genome sequence. Due to increasing interest in obtaining haplotype-resolved human genomes, a range of new sequencing protocols and technologies have been developed to enable the reconstruction of whole-genome haplotypes. However, existing computational methods designed to handle specific technologies do not scale well on data from different protocols. We describe a new algorithm, HapCUT2, that extends our previous method (HapCUT) to handle multiple sequencing technologies. Using simulations and whole-genome sequencing (WGS) data from multiple different data types-dilution pool sequencing, linked-read sequencing, single molecule real-time (SMRT) sequencing, and proximity ligation (Hi-C) sequencing-we show that HapCUT2 rapidly assembles haplotypes with best-in-class accuracy for all data types. In particular, HapCUT2 scales well for high sequencing coverage and rapidly assembled haplotypes for two long-read WGS data sets on which other methods struggled. Further, HapCUT2 directly models Hi-C specific error modalities, resulting in significant improvements in error rates compared to HapCUT, the only other method that could assemble haplotypes from Hi-C data. Using HapCUT2, haplotype assembly from a 90x coverage whole-genome Hi-C data set yielded high-resolution haplotypes (78.6% of variants phased in a single block) with high pairwise phasing accuracy (similar to 98% across chromosomes). Our results demonstrate that HapCUT2 is a robust tool for haplotype assembly applicable to data from diverse sequencing technologies.
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