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Efficient chromosome-scale haplotype-resolved assembly of human genomes

Garg, S.; Arkarachai Fungtammasan, A.; Carroll, A.; Chou, M.; Schmitt, A.; Zhou, X.; Mac, S.; Peluso, P.; Hatas, E.; Ghurye, J.; Maguire, J.; Mahmoud, M.; Cheng, H.; Heller, D.; Zook, J. M.; Moemke, T.; Marschall, T.; Sedlazeck, F. J.; Aach, J.; Chin, C.-S.; Church, G. M.; Li, H. M.

2019-10-18 bioinformatics
10.1101/810341 bioRxiv
Show abstract

Haplotype-resolved or phased sequence assembly provides a complete picture of genomes and complex genetic variations. However, current phased assembly algorithms either fail to generate chromosome-scale phasing or require pedigree information, which limits their application. We present a method that leverages long accurate reads and long-range conformation data for single individuals to generate chromosome-scale phased assembly within a day. Applied to three public human genomes, PGP1, HG002 and NA12878, our method produced haplotype-resolved assemblies with contig NG50 up to 25 Mb and phased [~]99.5% of heterozygous sites to 98-99% accuracy, outperforming other approaches in terms of both contiguity and phasing completeness. We demonstrate the importance of chromosome-scale phased assemblies to discover structural variants (SVs), including thousands of new transposon insertions, and of highly polymorphic and medically important regions such as HLA and KIR. Our improved method will enable high-quality precision medicine and facilitate new studies of individual haplotype variation and population diversity.

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