MBE Advance Access published online on November 10, 2004
Molecular Biology and Evolution, doi:10.1093/molbev/msi043
Molecular Biology and Evolution © Society for Molecular Biology and Evolution 2004; all rights reserved
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1 Center for Biomedical Genomics and Informatics, Department of Molecular and Microbiology, MS 4D7, George Mason University, Manassas, Virginia, USA
* To whom correspondence should be addressed. CpG dinucleotides mutate at a high rate, because cytosine is vulnerable to deamination, cytosines in CpG dinucleotides are often methylated, and deamination of 5-methylcytosine (5mC) produces thymidine. Previous experiments have shown that DNA melting is the rate-limiting step in cytosine deamination. Here we show, through the analysis of human single nucleotide polymorphisms (SNPs), that the mutation rate produced by 5mC deamination is highly dependent on local GC content. In fact, linear regression analysis showed that the log10 of the 5mC mutation rates (inferred from SNP frequencies) had slopes of -3 when graphed with respect to the GC content of neighboring sequences. This is the ideal slope that would be expected if the correlation between CpG under-representation and GC content had been solely due to DNA melting. Moreover, this same result was obtained regardless of the SNP locations (all SNPs vs. only SNPs in noncoding intergenic regions excluding CpG islands), and regardless of the lengths over which GC content was calculated (SNP sequences with a modal length of 564 bp vs. genomic contigs with a modal length of 163 kb). Several alternative interpretations are discussed.
Research Article
CpG Mutation Rates in the Human Genome are Highly Dependent on Local GC content
Karl J. Fryxell, E-mail: kfryxell{at}gmu.edu
Abstract 
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