DNA Methylation and Mutation


Single‐gene and genome sequencing studies have identified base substitution mutations as a causative mechanism in human genetic diseases and cancer. These mutations do not occur randomly but are often enriched at specific DNA (deoxyribonucleic acid) sequences. The genome of most human cells contains about 50 million 5‐methylcytosine bases, the majority of them occurring at the CpG dinucleotide sequence. Methylated CpG dinucleotides are the targets of many of the mutations, mostly transition mutations (C→T or G→A), found in genetic disorders and in malignant tumours. The mechanisms that increase mutations at CpG sites include spontaneous deamination of 5‐methylcytosine and preferential interaction of such sequences with physical or chemical carcinogens. As a consequence of enhanced mutagenesis at methylated CpGs, the CpG frequency in mammalian genomes has been strongly depleted over evolutionary time.

Key Concepts

  • Methylated CpG sequences are preferentially mutated.
  • Deamination of 5‐methylcytosine leads to transition mutations at CpGs.
  • Exogenous carcinogens target methylated CpGs.
  • CpG mutations are frequent in genetic diseases and cancer.
  • DNA repair may be affected by methylation of CpG sequences.

Keywords: DNA methylation; mutation; CpG sequence; 5‐methylcytosine; DNA damage

Figure 1. Two mechanisms that operate at methylated CpG sequences to produce mutational hot spots. Deamination of 5‐methylcytosine can lead to C to T transition mutations after DNA (deoxyribonucleic acid) replication. Preferential modification of guanines at methylated CpG sequences (indicated by x) can lead to G to T transversions after DNA replication. A double‐stranded methylated CpG sequence is shown.


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Further Reading

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Pfeifer GP, Tang M and Denissenko MF (2000) Mutation hotspots and DNA methylation. Current Topics in Microbiology and Immunology 249: 1–19.

Zuo S, Boorstein RJ and Teebor GW (1995) Oxidative damage to 5‐methylcytosine in DNA. Nucleic Acids Research 25: 3239–3243.

Web Links

Human Gene Mutation Database: http://www.hgmd.cf.ac.uk/ac/index.php

International Agency for Research on Cancer: http://www.iarc.fr/

Tumor protein p53 (TP53); LocusID: 7157. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=7157

Tumor protein p53 (TP53); http://omim.org/entry/191170

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Pfeifer, Gerd P(Jun 2017) DNA Methylation and Mutation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006159.pub2]