Epigenetic variation in monozygotic twins: a genome-wide analysis of DNA methylation in buccal cells.

Jenny Van Dongen,Erik Ehli,Roderick Slieker,Bastiaan Heijmans,Zachary Weber,Dorret Boomsma,P Slagboom,Gareth Davies,Meike Bartels

doi:10.3390/genes5020347

Abstract

DNA methylation is one of the most extensively studied epigenetic marks in humans. Yet, it is largely unknown what causes variation in DNA methylation between individuals. The comparison of DNA methylation profiles of monozygotic (MZ) twins offers a unique experimental design to examine the extent to which such variation is related to individual-specific environmental influences and stochastic events or to familial factors (DNA sequence and shared environment). We measured genome-wide DNA methylation in buccal samples from ten MZ pairs (age 8–19) using the Illumina 450k array and examined twin correlations for methylation level at 420,921 CpGs after QC. After selecting CpGs showing the most variation in the methylation level between subjects, the mean genome-wide correlation (rho) was 0.54. The correlation was higher, on average, for CpGs within CpG islands (CGIs), compared to CGI shores, shelves and non-CGI regions, particularly at hypomethylated CpGs. This finding suggests that individual-specific environmental and stochastic influences account for more variation in DNA methylation in CpG-poor regions. Our findings also indicate that it is worthwhile to examine heritable and shared environmental influences on buccal DNA methylation in larger studies that also include dizygotic twins.

Highlights

To date, hundreds of genetic risk variants for complex traits and diseases have been identified, for most of these variants, the biological mechanisms remain to be elucidated [1].Interestingly, the majority of disease-associated genetic variation is located in regulatory regions of the genome [2], including transcription-factor-occupied regions and DNase I hypersensitive sites [3]
To further examine DNA methylation at regulatory regions in the genome, we focused on CpGs located within DNase I hypersensitive sites (DHS) and CpGs within transcription factor binding sites (TFBS) identified by the ENCODE project
As we observed that DNA methylation in MZ twins is overall less similar at CpGs in non-CpG islands (CGIs) regions, CGI shores and shelves, these regions are of particular interest to studies examining environmental exposures, as these regions may show the strongest effects of environmental influences

Summary

Introduction

The majority of disease-associated genetic variation is located in regulatory regions of the genome [2], including transcription-factor-occupied regions and DNase I hypersensitive sites (which correspond to open chromatin) [3]. This suggests that mechanisms that control the activity of genes, including epigenetic mechanisms, may represent an important link between DNA sequence variation and common disease susceptibility [4]. DNA methylation patterns may vary, and differential methylation has been demonstrated to occur across age [10], cell types, tissues [7,11] and disease states [12,13], and it has become clear that widespread variation in methylation patterns exist between individuals [14]. Twin studies provide insight into the proportion of inter-individual variation in DNA methylation that is due to genetic variation, environmental effects and stochastic variation [19]

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