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bioRxiv · 10.1101/126136

Dense And Accurate Whole-Chromosome Haplotyping Of Individual Genomes

Porubsky, D.·Garg, S.·Sanders, A. D.·Korbel, J. O.·Guryev, V.·Lansdorp, P. M.·Marschall, T.
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Abstract

The diploid nature of the genome is neglected in many analyses done today, where a genome is perceived as a set of unphased variants with respect to a reference genome. Many important biological phenomena such as compound heterozygosity and epistatic effects between enhancers and target genes, however, can only be studied when haplotype-resolved genomes are available. This lack of haplotype-level analyses can be explained by a dearth of methods to produce dense and accurate chromosome-length haplotypes at reasonable costs. Here we introduce an integrative phasing strategy that combines global, but sparse haplotypes obtained from strand-specific single cell sequencing (Strand-seq) with dense, yet local, haplotype information available through long-read or linked-read sequencing. Our experiments provide comprehensive guidance on favorable combinations of Strand-seq libraries and sequencing coverages to obtain complete and genome-wide haplotypes of a single individual genome (NA12878) at manageable costs. We were able to reliably assign > 95% of alleles to their parental haplotypes using as few as 10 Strand-seq libraries in combination with 10-fold coverage PacBio data or, alternatively, 10X Genomics linked-read sequencing data. We conclude that the combination of Strand-seq with different sequencing technologies represents an attractive solution to chart the unique genetic variation of diploid genomes.

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Porubsky, D., Garg, S., Sanders, A. D., Korbel, J. O., Guryev, V., Lansdorp, P. M., Marschall, T.. 2017-04-10. Dense And Accurate Whole-Chromosome Haplotyping Of Individual Genomes. https://doi.org/10.1101/126136

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