Abstract
BackgroundEthnic differences in human DNA methylation have been shown for a number of CpG sites, but the genome-wide patterns and extent of these differences are largely unknown. In addition, whether the genetic control of polymorphic DNA methylation is population-specific has not been investigated.ResultsHere we measure DNA methylation near the transcription start sites of over 14, 000 genes in 180 cell lines derived from one African and one European population. We find population-specific patterns of DNA methylation at over a third of all genes. Furthermore, although the methylation at over a thousand CpG sites is heritable, these heritabilities also differ between populations, suggesting extensive divergence in the genetic control of DNA methylation. In support of this, genetic mapping of DNA methylation reveals that most of the population specificity can be explained by divergence in allele frequencies between populations, and that there is little overlap in genetic associations between populations. These population-specific genetic associations are supported by the patterns of DNA methylation in several hundred brain samples, suggesting that they hold in vivo and across tissues.ConclusionsThese results suggest that DNA methylation is highly divergent between populations, and that this divergence may be due in large part to a combination of differences in allele frequencies and complex epistasis or gene × environment interactions.
Highlights
Ethnic differences in human DNA methylation have been shown for a number of CpG sites, but the genome-wide patterns and extent of these differences are largely unknown
lymphoblastoid cell line (LCL) can acquire changes in gene expression and DNA methylation during transformation and cell culture [20,21], it has been shown that the inter-individual variation - which is what is relevant for the current work - is nearly always conserved [21]
These 180 cell lines were grown in identical conditions and their genomic DNA was subjected to quantitative beadarray-based DNA methylation analysis at 27, 578 CpG sites near the transcription start sites of 14, 495 genes (Materials and methods)
Summary
Ethnic differences in human DNA methylation have been shown for a number of CpG sites, but the genome-wide patterns and extent of these differences are largely unknown. The great diversity of cell types is maintained by mitotically heritable differences in gene expression, which are in part regulated by epigenetic mechanisms [1] These include histone modifications, histone variants, RNA-based mechanisms, and DNA methylation [2]. DNA methylation is a very stable epigenetic mark, numerous environmental influences have been associated with variation in DNA methylation as well as other epigenetic marks [2,6] These include nutritional factors, exposure to environmental pollutants, and social environment. Most primary material available from human populations consists of mixtures of different cell types with distinct epigenomes, making it difficult to assess the association of epigenetic changes with environmental exposure and phenotype.
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