MBE Advance Access published online on October 29, 2008
Molecular Biology and Evolution, doi:10.1093/molbev/msn245
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Research Article |
Transcription-induced mutational strand bias and its effect on substitution rates in human genes
1 Institute of Chemistry, Karl-Franzens University Graz, Graz, Austria
2 Max-Planck Institute for Neurological Research, Cologne, Germany
Corresponding Author: Martin Peifer, Max-Planck Institute for Neurological Research, Gleueler Str. 50, 50931 Cologne, Germany, Phone: +49-221-4726-342, Fax: +49-221-4726-298, Email: peifer{at}nf.mpg.de
Received for publication June 25, 2008. Revision received September 29, 2008. Accepted for publication October 7, 2008.
If substitution rates are not the same on the two complementary DNA strands, a substitution is considered strand-asymmetric. Such substitutional strand asymmetries are determined here for the three most frequent types of substitution on the human genome (C 
T, A G and G T). Substitution rate differences between both strands are estimated for 4590 human genes by aligning all repeats occuring within the introns with their ancestral consensus sequences. For 1630 of these genes, both coding-strand and non-coding-strand rates could be compared to rates in gene-flanking regions. All three rates considered are found to be on average higher on the coding strand and lower on the transcribed strand in comparison to their values in the gene-flanking regions. This finding points to the simultaneous action of rate-increasing effects on the coding strand – such as increased adenine and cytosine deamination – and transcription-coupled repair as a rate-reducing effect on the transcribed strand. The common behavior of the three rates lead to strong correlations of the rate asymmetries: whenever one rate is strand-biased, the other two rates are likely to show the same bias. Furthermore, we determine all three rate asymmetries as a function of time: the A G and G T rate asymmetries are both found to be constant in time while the C T rate asymmetry shows a pronounced time-dependence, an observation which explains the difference between our results and those of an earlier work by Green et al. Finally, we show that in addition to transcription also the replication process biases the substitution rates in genes.
Key Words: substitution rate asymmetries • transcription-coupled repair • cytosine deamination