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

Area of Science:

• Genomics
• Epigenetics
• Human Genetics

Background:

• Hundreds of human genome loci exhibit differential DNA methylation based on parent of origin.
• These imprinted loci are generally conserved across tissues, individuals, and populations.
• Distinguishing parental origins of alleles is crucial for understanding genetic inheritance and disease.

Purpose of the Study:

• To develop a method for distinguishing maternal and paternal homologs for all human autosomes without parental DNA.
• To leverage DNA methylation patterns and long-range phase information for parent-of-origin determination.
• To assess the accuracy of this method in diverse human trios.

Main Methods:

• Integration of methylation-detecting nanopore sequencing with Strand-seq data.
• Utilizing long-range phase information from Strand-seq to infer chromosome-length haplotypes.
• Analysis of DNA sequence and DNA methylation in five diverse human trios.

Main Results:

• Successful parent-of-origin inference for all autosomes across five diverse trios.
• Achieved an average mismatch error rate of 0.31% for single nucleotide variations (SNVs).
• Achieved an average mismatch error rate of 1.89% for insertions or deletions (indels).

Conclusions:

• The developed method accurately determines the parent of origin for human autosomes using DNA methylation and haplotype data.
• This approach eliminates the need for parental DNA samples for parent-of-origin determination.
• The method holds significant potential for improving the diagnosis and management of genetic diseases by identifying the source of inherited disease alleles.