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This article is part of the supplement: The International Conference on Intelligent Biology and Medicine (ICIBM) – Genomics

Open Access Research

Investigating the relationship of DNA methylation with mutation rate and allele frequency in the human genome

Junfeng Xia1, Leng Han1 and Zhongming Zhao1234*

Author Affiliations

1 Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA

2 Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA

3 Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA

4 Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA

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BMC Genomics 2012, 13(Suppl 8):S7  doi:10.1186/1471-2164-13-S8-S7

Published: 17 December 2012

Abstract

Background

DNA methylation, which mainly occurs at CpG dinucleotides, is a dynamic epigenetic regulation mechanism in most eukaryotic genomes. It is already known that methylated CpG dinucleotides can lead to a high rate of C to T mutation at these sites. However, less is known about whether and how the methylation level causes a different mutation rate, especially at the single-base resolution.

Results

In this study, we used genome-wide single-base resolution methylation data to perform a comprehensive analysis of the mutation rate of methylated cytosines from human embryonic stem cell. Through the analysis of the density of single nucleotide polymorphisms, we first confirmed that the mutation rate in methylated CpG sites is greater than that in unmethylated CpG sites. Then, we showed that among methylated CpG sites, the mutation rate is markedly increased in low-intermediately (20-40% methylation level) to intermediately methylated CpG sites (40-60% methylation level) of the human genome. This mutation pattern was observed regardless of DNA strand direction and the sequence coverage over the site on which the methylation level was calculated. Moreover, this highly non-random mutation pattern was found more apparent in intergenic and intronic regions than in promoter regions and CpG islands. Our investigation suggested this pattern appears primarily in autosomes rather than sex chromosomes. Further analysis based on human-chimpanzee divergence confirmed these observations. Finally, we observed a significant correlation between the methylation level and cytosine allele frequency.

Conclusions

Our results showed a high mutation rate in low-intermediately to intermediately methylated CpG sites at different scales, from the categorized genomic region, whole chromosome, to the whole genome level, thereby providing the first supporting evidence of mutation rate variation at human methylated CpG sites using the genome-wide sing-base resolution methylation data.