Constructing hepitypes: phasing local genotype and DNA methylation

Whole-genome DNA methylation sequencing provides both methylation patterns and genetic information. We utilized base resolution methylomes to directly identify allelic linkage of DNA methylation and genomic variants. The paired association was further extended to construct hepitypes by the simultaneous phasing of genotype and methylation. Using such approach, the sequencing reads provide direct statistics of the interdependence between methylcytosines and nucleotide variations; consequently, the detailed patterns of genetic and epigenetic variations can be readily inferred by data. Moreover, the analysis is not limited by known single nucleotide variants. We demonstrate the utility of our method by identifying methylation sites that were strongly associated with genetic variations in the human genome using H1 and IMR90 methylomes. In addition to imprinted regions and SNV-in-CpG sites, we show numerous cis-regulatory sequence-associated DNA methylation sites. We next extended this strategy to incorporate multiple nucleotide and methylation sites and ranked hepitypes according to the observed frequency. The top-ranked hepitypes indicate that methylated sites are often observed from the same allele. Moreover, we used the informative nucleotide variants in both methylation and expression data of the same cell lines to investigate the extent of allele-specific gene regulation. We identified a set of genes for which the exonic allele-specific methylation patterns are correlated with their allele-specific expression levels. Allele-specific methylation plays an essential role in allelic regulation. Our finding may shed light on the function of non-coding nucleotide variations, DNA methylation polymorphism and inter-individual differences. This approach is applicable to any largescale differential methylation studies and can integrate various types of high-throughput sequencing data.