MethPhaser: Methylation-Based Long-Read Haplotype Phasing of Human Genomes

Authors

Yilei Fu
Sergey Aganezov
Medhat Mahmoud
John Beaulaurier
Sissel Juul
Todd J Treangen
Fritz J Sedlazeck

Publication Date

6-22-2024

Journal

Nature Communications

DOI

10.1038/s41467-024-49588-0

PMID

38909018

PMCID

PMC11193733

PubMedCentral® Posted Date

6-22-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Genome, Human, Haplotypes, DNA Methylation, Polymorphism, Single Nucleotide, Cell Line, Mutation, Computational biology and bioinformatics, Software, Genome informatics

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, a method that utilizes methylation signals from Oxford Nanopore Technologies to extend Single Nucleotide Variation (SNV)-based phasing. We demonstrate that haplotype-specific methylations extensively exist in Human genomes and the advent of long-read technologies enabled direct report of methylation signals. For ONT R9 and R10 cell line data, we increase the phase length N50 by 78%-151% at a phasing accuracy of 83.4-98.7% To assess the impact of tissue purity and random methylation signals due to inactivation, 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. The concept of MethPhaser can also be extended to non-human diploid genomes. MethPhaser is available at https://github.com/treangenlab/methphaser.

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