MethPhaser: methylation-based haplotype phasing of human genomes

Abstract

The assignment of variants across haplotypes, phasing, is crucial for predicting the consequences, interaction, and inheritance of mutations and is a key step in improving our understanding of phenotype and disease. However, phasing is limited by read length and stretches of homozygosity along the genome. To overcome this limitation, we designed MethPhaser, the first method that utilizes methylation signals from Oxford Nanopore Technologies to extend SNV-based phasing. Across control samples, we extend the phase length N50 by almost 3-fold while minimally increasing the phasing error by [~]0.02%. Nevertheless, methylation signals have limitations, such as random signals on sex chromosomes or tissue purity. To assess the latter, we also applied MethPhaser on blood samples from 4 patients, still showing improvements over SNV-only phasing. MethPhaser further improves phasing across HLA and multiple other medically relevant genes, improving our understanding of how mutations interact across multiple phenotypes. MethPhaser is available at https://github.com/treangenlab/methphaser.