Parent-of-origin detection and chromosome-scale haplotyping using long-read DNA methylation sequencing and Strand-seq
Vahid Akbari,
Vincent C.T. Hanlon,
Kieran O’Neill,
Louis Lefebvre,
Kasmintan A. Schrader,
Peter M. Lansdorp,
Steven J.M. Jones
Affiliations
Vahid Akbari
Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada; Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
Vincent C.T. Hanlon
Terry Fox Laboratory, BC Cancer, Vancouver, BC, Canada
Kieran O’Neill
Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
Louis Lefebvre
Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
Kasmintan A. Schrader
Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; Department of Molecular Oncology, BC Cancer, Vancouver, BC, Canada
Peter M. Lansdorp
Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; Terry Fox Laboratory, BC Cancer, Vancouver, BC, Canada; Corresponding author
Steven J.M. Jones
Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada; Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; Corresponding author
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.
