Whole-genome haplotyping using long reads and statistical methods

Rapid growth of sequencing technologies has greatly contributed to increasing our understanding of human genetics. Yet, in spite of this growth, mainstream technologies have been largely unsuccessful in resolving the diploid nature of the human genome. Here we describe statistically aided long read haplotyping (SLRH), a rapid, accurate method based on a simple experimental protocol that requires potentially as little as 30 Gbp of sequencing in addition to a standard (50x coverage) whole-genome analysis for human samples. Using this technology, we phase 99% of single-nucleotide variants in three human genomes into long haplotype blocks of 200 kbp to 1 Mbp in length. As a demonstration of the potential applications of our method, we determine allele-specific methylation patterns in a human genome and identify hundreds of differentially methylated regions that were previously unknown. Such information may offer insight into the mechanisms behind differential gene expression.