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Genome Res. 2017 May;27(5):801-812. doi: 10.1101/gr.213462.116. Epub 2016 Dec 9.

HapCUT2: robust and accurate haplotype assembly for diverse sequencing technologies.

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Department of Computer Science & Engineering, University of California, San Diego, La Jolla, California 92053, USA.
Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California 92053, USA.


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 90× 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 (∼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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