CpG methylation influences mutation rates

DNA Sequence Itself Influences Mutation Rate, New Research Indicates

Natural selection, accomplished by mutations and heritability, is the driving force of evolution. Neutral selection defines any region of DNA which is changing at a random rate, and not under any selection preferences. Thus, scientists are usually more interested in those regions which do experience selection, and often overlook the neutral sequences. But what makes these regions neutral? Not all regions under selection are in genes, or affect phenotypic expression; thus why is there neutrality or selection at all?

This paper recognizes that there is a need to look at the neutral mutation rate, since this rate is important in keeping genomic stability. A lot of errors/mutations are caught in the proofreading processes of transcription and replication. Seemingly random, they seem inconsequential. But according to Walser and Furano, mutation rates in mammals differ at methylated cytosines, with 10-50 times more mutations at these sites.

Methylation of cytosine (CpG) in endogenous DNA sequences is critical for many organisms. Euchromatin activation is driven by methylation, and in plants, methylation is indicative of host genome recognition against foreign pathogen DNA. The high CpG rate results from the spontaneous deamination of methyl-C to T and incomplete restoration of the ensuing T:G mismatches to C:Gs (Walser et al. 2010). The concentration and ratio of CpG seems to positively correlate with the rate of mutation. However chemically modified CpG are prone to mutation as well, and the age of the mutation can be assessed.

Interestingly enough, in older inactive retrotransposons latent within the primate genome, the overall mutation rates have dropped and are now neutrally evolving. However this is not due to chromosomal location (by the centromere, etc.), but due to the inherent DNA sequence itself. The article concludes that these methylated areas promote mutations at the methylated sites, as well as the surrounding DNA. Future studies of methylated mutation rates will probably still continue to focus on genomic stability and repair.

Science Daily article: http://www.sciencedaily.com/releases/2010/05/100524092348.htm

Walser J, Furano A. The mutational spectrum of non-CpG DNA varies with CpG content. Genome Research, 2010; DOI: 10.1101/gr.103283.109