Parent-of-origin detection and chromosome-scale haplotyping using long-read DNA methylation sequencing and Strand-seq

Summary

Hundreds of loci in human genomes have alleles that are methylated differentially according to their parent of origin. These imprinted loci generally show little variation across tissues, individuals, and populations. We show that such loci can be used to distinguish the maternal and paternal homologs for all human autosomes without the need for the parental DNA. We integrate methylation-detecting nanopore sequencing with the long-range phase information in Strand-seq data to determine the parent of origin of chromosome-length haplotypes for both DNA sequence and DNA methylation in five trios with diverse genetic backgrounds. The parent of origin was correctly inferred for all autosomes with an average mismatch error rate of 0.31% for SNVs and 1.89% for insertions or deletions (indels). Because our method can determine whether an inherited disease allele originated from the mother or the father, we predict that it will improve the diagnosis and management of many genetic diseases.

Graphical abstract

Highlights

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  Genomic imprinting can help infer the parent of origin of homologs

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  Imprinted DNA methylation must be combined with chromosome-length haplotypes

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  The method was validated for five trios with diverse genetic backgrounds

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  In future, parent-of-origin phasing will improve cascade genetic testing

Abstract

Akbari et al. present a method for identifying homologous chromosomes inherited from the mother or the father without using data from the parents. The method relies on phased DNA methylation at maternally and paternally imprinted loci, as well as chromosome-length phasing of DNA sequence. Testing on five trios showed that the method can correctly infer the parent of origin of all autosomes with a mismatch error rate of 0.31% for SNVs.