Whole-genome haplotype reconstruction using proximity-ligation and shotgun sequencing.

摘要: Rapid advances in high-throughput sequencing facilitate variant discovery and genotyping, but linking variants into a single haplotype remains challenging. Here we demonstrate HaploSeq, an approach for assembling chromosome-scale haplotypes by exploiting the existence of 'chromosome territories'. We use proximity ligation to show that alleles on homologous chromosomes occupy distinct territories, therefore this experimental protocol preferentially recovers physically linked DNA homolog. Computational analysis such data sets allows accurate (∼99.5%) reconstruction chromosome-spanning ∼95% hybrid mouse cells with 30× coverage. To resolve human genome, which has low density variants, coupled HaploSeq local conditional phasing obtain ∼81% ∼98% accuracy from just 17× sequencing. Whereas methods based were originally designed investigate spatial organization genomes, our results lend support their as general tool haplotyping.