Extensive sequence-influenced DNA methylation polymorphism in the human genome

Asaf Hellman,Andrew Chess

doi:10.1186/1756-8935-3-11

Abstract

BackgroundEpigenetic polymorphisms are a potential source of human diversity, but their frequency and relationship to genetic polymorphisms are unclear. DNA methylation, an epigenetic mark that is a covalent modification of the DNA itself, plays an important role in the regulation of gene expression. Most studies of DNA methylation in mammalian cells have focused on CpG methylation present in CpG islands (areas of concentrated CpGs often found near promoters), but there are also interesting patterns of CpG methylation found outside of CpG islands.ResultsWe compared DNA methylation patterns on both alleles between many pairs (and larger groups) of related and unrelated individuals. Direct observation and simulation experiments revealed that around 10% of common single nucleotide polymorphisms (SNPs) reside in regions with differences in the propensity for local DNA methylation between the two alleles. We further showed that for the most common form of SNP, a polymorphism at a CpG dinucleotide, the presence of the CpG at the SNP positively affected local DNA methylation in cis.ConclusionsTaken together with the known effect of DNA methylation on mutation rate, our results suggest an interesting interdependence between genetics and epigenetics underlying diversity in the human genome.

Highlights

Epigenetic polymorphisms are a potential source of human diversity, but their frequency and relationship to genetic polymorphisms are unclear
The presence of the single nucleotide polymorphisms (SNPs) was essential to our ability to observe monoallelic methylation, this method could not determine whether the observed monoallelic methylation was influenced by the SNPs or by other sequence differences in linkage disequilibrium (LD) with the SNPs
We suggest the term 'sequence-influenced methylation polymorphism' (SIMP) to reflect this effect of sequence on local methylation propensity and to account for the fact that the two alleles may have different propensities for methylation, it is not an all or nothing situation

Summary

Introduction

Epigenetic polymorphisms are a potential source of human diversity, but their frequency and relationship to genetic polymorphisms are unclear. Most studies of DNA methylation in mammalian cells have focused on CpG methylation present in CpG islands (areas of concentrated CpGs often found near promoters), but there are interesting patterns of CpG methylation found outside of CpG islands. DNA methylation patterns can be transmitted directly between human generations if the methylation (or other epigenetic mark that can be a placeholder) is maintained during gametogenesis and embryonic development. Another possible mode of transmission is through DNA sequence polymorphisms that affect methylation prevalence at linked sites. Mendelian inheritance of methylation patterns near variable number tandem repeats (VNTRs) has been reported [1]. In the case of these VNTR-associated methylation differences, it was not determined whether the methylation

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