Why are CpG sites more prone to mutation? - (May/20/2007 )
Why are CpG sites (not islands) more prone to mutation?
All I can find is that it has something to do with methylation?
It is to do with the methylation of CpG's and their spontaneous deamination.
I may have this the wrong way around and correct me please!!
Unmethylated C deaminates to uracil spontaneously and this is corrected by the mismatch repair machinery because uracil is not a DNA nucleotide.
Methylated C deaminates to thymidine, here the mismatch repair machinery would not be able to tell which base is the mistake on complementary strands thus you have higher mutation rates of C in the context of CG outside of an island, assumed to be methylated, mutating to T
It has something to do with the mismatch repair machinery and i may have the bases mixed up, if so, sing out!
Curr Top Microbiol Immunol. 2006;301:259-81. Links
Mutagenesis at methylated CpG sequences.Pfeifer GP.
Division of Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. firstname.lastname@example.org
5-Methylcytosine in DNA is genetically unstable. Methylated CpG (mCpG) sequences frequently undergo mutation resulting in a general depletion of this dinucleotide sequence in mammalian genomes. In human genetic disease- and cancer-relevant genes, mCpG sequences are mutational hotspots. It is an almost universally accepted dogma that these mutations are caused by random deamination of 5-methylcytosines. However, it is plausible that mCpG transitions are not caused simply by spontaneous deamination of 5-methylcytosine in double-stranded DNA but by other processes including, for example, mCpG-specific base modification by endogenous or exogenous mutagens or, alternatively, by secondary factors operating at mCpG sequences and promoting deamination. We also discuss that mCpG sequences are favored targets for specific exogenous mutagens and carcinogens. When adjacent to another pyrimidine, 5-methylcytosine preferentially undergoes sunlight-induced pyrimidine dimer formation. Certain polycyclic aromatic hydrocarbons form guanine adducts and induce G to T transversion mutations with high selectivity at mCpG sequences.
PMID: 16570852 [PubMed - indexed for MEDLINE]
...about the evolutionary aspect of this topic look at the works of Giorgio Bernardi (for example: DNA methylation and body temperature in fishes, Gene 385 (2006) 111–121, and some others)...
yes. there is some very interesting reads that deal with genetic conservation, and the evolutionary purpose of methylation...