TY - JOUR
T1 - Strong and weak male mutation bias at different sites in the primate genomes
T2 - Insights from the human-chimpanzee comparison
AU - Taylor, James
AU - Tyekucheva, Svitlana
AU - Zody, Michael
AU - Chiaromonte, Francesca
AU - Makova, Kateryna D.
PY - 2006/3
Y1 - 2006/3
N2 - Male mutation bias is a higher mutation rate in males than in females thought to result from the greater number of germ line 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 (α), should reflect the relative excess of male versus female germ line 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: α in the X-autosome comparison was ∼6-7, which was similar to the male-to-female ratio in the number of germ line cell divisions. In contrast, mutations at CpG sites exhibited weak male mutation bias: α 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.
AB - Male mutation bias is a higher mutation rate in males than in females thought to result from the greater number of germ line 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 (α), should reflect the relative excess of male versus female germ line 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: α in the X-autosome comparison was ∼6-7, which was similar to the male-to-female ratio in the number of germ line cell divisions. In contrast, mutations at CpG sites exhibited weak male mutation bias: α 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.
UR - http://www.scopus.com/inward/record.url?scp=33244455058&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33244455058&partnerID=8YFLogxK
U2 - 10.1093/molbev/msj060
DO - 10.1093/molbev/msj060
M3 - Article
C2 - 16280537
AN - SCOPUS:33244455058
SN - 0737-4038
VL - 23
SP - 565
EP - 573
JO - Molecular biology and evolution
JF - Molecular biology and evolution
IS - 3
ER -