Abstract
The extent of variation in DNA methylation patterns in healthy individuals is not yet well documented. Identification of inter-individual epigenetic variation is important for understanding phenotypic variation and disease susceptibility. Using neutrophils from a cohort of healthy individuals, we generated base-resolution DNA methylation maps to document inter-individual epigenetic variation. We identified 12851 autosomal inter-individual variably methylated fragments (iVMFs). Gene promoters were the least variable, whereas gene body and upstream regions showed higher variation in DNA methylation. The iVMFs were relatively enriched in repetitive elements compared to non-iVMFs, and were associated with genome regulation and chromatin function elements. Further, variably methylated genes were disproportionately associated with regulation of transcription, responsive function and signal transduction pathways. Transcriptome analysis indicates that iVMF methylation at differentially expressed exons has a positive correlation and local effect on the inclusion of that exon in the mRNA transcript.
Highlights
Mixed cell types can confound discovery of inter-individual variation[21]
We explored methylation variation in different elements of the genome and integrated them with gene regulatory features (such as transcription factor binding sites (TFBS), histone marks and enhancers) and repetitive elements to gain a perspective on the potential role of methylation variation in genome regulation
To investigate DNA methylation variation, we chose MspI fragments as the unit of analysis[24], since biological relevance tends to be associated with regional methylation and since the use of fragments integrates the information from multiple CpG sites, thereby minimising sampling variation[38]
Summary
Mixed cell types can confound discovery of inter-individual variation[21]. Few studies have attempted to investigate DNA methylation variation in an individual cell type[22,23]. We present single-nucleotide resolution DNA methylation maps from 11 healthy individuals, using Reduced Representation Bisulfite Sequencing (RRBS). Implementing a novel fragment-based analysis approach[24], we identified genomic regions that showed significant inter-individual variation in DNA methylation. We explored methylation variation in different elements of the genome (promoters, gene body and regions far upstream of the gene) and integrated them with gene regulatory features (such as transcription factor binding sites (TFBS), histone marks and enhancers) and repetitive elements to gain a perspective on the potential role of methylation variation in genome regulation. We determined that variable methylation is associated with differential gene expression and exon usage, providing a mechanism by which variable methylation might affect the phenotype of these individuals
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