Position-dependent correlations between DNA methylation and the evolutionary rates of mammalian coding exons

Abstract

DNA cytosine methylation is a central epigenetic marker that is usually mutagenic and may increase the level of sequence divergence. However, methylated genes have been reported to evolve more slowly than unmethylated genes. Hence, there is a controversy on whether DNA methylation is correlated with increased or decreased protein evolutionary rates. We hypothesize that this controversy has resulted from the differential correlations between DNA methylation and the evolutionary rates of coding exons in different genic positions. To test this hypothesis, we compare human-mouse and human-macaque exonic evolutionary rates against experimentally determined single-base resolution DNA methylation data derived from multiple human cell types. We show that DNA methylation is significantly related to within-gene variations in evolutionary rates. First, DNA methylation level is more strongly correlated with C-to-T mutations at CpG dinucleotides in the first coding exons than in the internal and last exons, although it is positively correlated with the synonymous substitution rate in all exon positions. Second, for the first exons, DNA methylation level is negatively correlated with exonic expression level, but positively correlated with both nonsynonymous substitution rate and the sample specificity of DNA methylation level. For the internal and last exons, however, we observe the opposite correlations. Our results imply that DNA methylation level is differentially correlated with the biological (and evolutionary) features of coding exons in different genic positions. The first exons appear more prone to the mutagenic effects, whereas the other exons are more influenced by the regulatory effects of DNA methylation.methylation-associated mutation | exon evolution | genomics | deep sequencing | bioinformatics D NA methylation is a common form of epigenetic modification that is important for a variety of biological functions, including transcriptional silencing (1), genomic imprinting (2), X-chromosome inactivation (3), the silencing of transposons (4), tumorigenesis (5), and the differentiation of pluripotent cells (6). DNA methylation is unevenly distributed in the human genome. For example, the CpG islands near the promoter regions of active genes tend to be unmethylated (7-10), because methylation in these regions is strongly correlated with transcriptional suppression (8). It has also been reported that exons tend to be more methylated than introns, and that sharp transitions of methylation occur at exonintron boundaries in human (6). Moreover, the level of DNA methylation also varies among exonic regions. The levels of DNA methylation in the first exons were reported to be lower than in downstream exons, and tightly linked to transcriptional silencing (11). In addition, the level of DNA methylation exhibits a slight but sharp step-down at the transcriptional terminal sites (6).In terms of molecular evolution, DNA methylation is relevant in two aspects. First, DNA methylation can significantly increase the rate of spontan...

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