MBE Advance Access published online on November 9, 2005
Molecular Biology and Evolution, doi:10.1093/molbev/msj060
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1 Department of Computer Science and Engineering, Penn State University, University Park, PA, 16802, USA; Department of the Center for Comparative Genomics and Bioinformatics, Penn State University, University Park, PA, 16802, USA
* To whom correspondence should be addressed. Male mutation bias is a higher mutation rate in males than in females thought to result from the greater number of germline cell divisions in males. If errors in DNA replication cause most mutations, then the magnitude of male mutation bias, measured as the male-to-female mutation rate ratio (
Accepted November 2, 2005
Research Article
Strong and Weak Male Mutation Bias at Different Sites in the Primate Genomes: Insights from the Human-Chimpanzee Comparison
2 Department of Statistics, Penn State University, University Park, PA, 16802, USA; Department of the Center for Comparative Genomics and Bioinformatics, Penn State University, University Park, PA, 16802, USA
3 Department of Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
4 Department of Statistics, Penn State University, University Park, PA, 16802, USA; Department of Health Evaluation Sciences, Penn State University, University Park, PA, 16802, USA; Department of the Center for Comparative Genomics and Bioinformatics, Penn State University, University Park, PA, 16802, USA
5 Department of Biology, Penn State University, University Park, PA, 16802, USA; Department of the Center for Comparative Genomics and Bioinformatics, Penn State University, University Park, PA, 16802, USA
Kateryna D. Makova, E-mail: kdm16{at}psu.edu
Abstract 
), should reflect the relative excess of male vs. female germline cell divisions. Evolutionary rates averaged among all sites in a sequence and compared between mammalian sex chromosomes were shown to be indeed higher in males than in females. However, it is presently unknown whether individual classes of substitutions exhibit such bias. To address this issue, we investigated male mutation bias separately at non-CpG and CpG sites using human-chimpanzee whole-genome alignments. We observed strong male mutation bias at non-CpG sites: in the X-autosome comparison was 
6-7, which was similar to the male-to-female ratio in the number of germline cell divisions. In contrast, mutations at CpG sites exhibited weak male mutation bias: in the X-autosome comparison was only 2-3. This is consistent with the methylation-induced and replication-independent mechanism of CpG transitions, which constitute the majority of mutations at CpG sites. Interestingly, our study also indicated weak male mutation bias for transversions at CpG sites, implying a spontaneous mechanism largely not associated with replication. Male mutation bias was equally strong at CpG and non-CpG sites located within unmethylated CpG islands, suggesting the replication-dependent origin of these mutations. Thus, we found that the strength of male mutation bias is nonuniform in the primate genomes. Importantly, we discovered that male mutation bias depends on the proportion of CpG sites in the loci compared. This might explain the differences in the magnitude of primate male mutation bias observed among studies.
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