NCM 2022: Simultaneous haplotyping and parent-of-origin assignment of homologous chromosomes without parental sequence data

While phasing algorithms are able to distinguish homologous chromosomes, parent-of-origin (PofO) assignment of phased homologs requires access to parental sequence data. Here, we demonstrate chromosome-scale phasing and PofO detection without the need for parental sequencing information. We demonstrate that single-cell DNA template strand sequencing (Strand-seq) in combination with long-read Oxford Nanopore sequencing allows the construction of chromosome-scale haplotypes. Subsequently, we inferred DNA methylation at CpG dinucleotides from nanopore raw signals and used the known origin (paternal or maternal) of methylation at human imprinted intervals to assign PofO to haplotyped homologs. We were able to assign PofO for autosomal chromosomes with an average mismatch error rate of 0.31% for SNVs and 1.89% for indels. Because our method can determine whether an inherited allele originated from the mother or the father, we predict that it will improve genealogy and diagnosis and management of many genetic diseases where the phenotype is affected by the parental origin of the allele.