MBE Advance Access published online on June 4, 2008
Molecular Biology and Evolution, doi:10.1093/molbev/msn130
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Research Article |
Compensatory evolution in RNA secondary structures increases substitution rate variation among sites
1 Department of Biology, University of North Carolina, Chapel Hill, NC 27599
2 Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599
3 Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC 27599
4 Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599
5 Current affiliation: Department of Laboratory Medicine, University of Washington, Seattle, WA 98195
6 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599
7 The UNC Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599
8 Current affiliation: Department of Ecology and Evolutionary Biology, Brown University, Providence, RI, 02912
Corresponding Author: Jennifer Knies, Department of Ecology and Evolutionary Biology, Box G, Brown University, Providence, RI, 02912, Phone: (401) 863-2749 Fax: (401) 863-2166 E-mail: ennifer_Knies{at}brown.edu
Received for publication October 2, 2007. Revision received March 20, 2008. Revision received April 17, 2008. Revision received May 30, 2008. Accepted for publication May 30, 2008.
There is growing evidence that interactions between biological molecules (e.g. RNA-RNA, protein-protein, RNA-protein) place limits on the rate and trajectory of molecular evolution. Here, by extending Kimura's (1985) model of compensatory evolution at interacting sites, we show that the ratio of transition to transversion substitutions (
) at interacting sites should be equal to the square of the ratio at independent sites. Since transition mutations generally occur at a higher rate than transversions, the model predicts that should be higher at interacting sites than at independent sites. We tested this prediction in ten RNA secondary structures by comparing phylogenetically-derived estimates of in paired sites within stems (p) and unpaired sites within loops (u). Eight of the ten structures showed an excellent match to the quantitative predictions of the model, and nine of the ten structures matched the qualitative prediction p > u. Only the rev response element (RRE) from the HIV genome showed the reverse pattern, with p < u. Although a variety of evolutionary forces could produce quantitative deviations from the model predictions, the reversal in magnitude of p and u could by achieved only by violating the model assumption that the underlying transition (or transversion) mutation rates were identical in paired and unpaired regions of the molecule. We explore the ability of the APOBEC3 enzymes, host defense mechanisms against retroviruses, that induce transition mutations preferentially in single-stranded regions of the HIV genome, to explain this exception to the rule. Taken as a whole, our findings suggest that may have utility as a simple diagnostic to evaluate proposed secondary structures.
Key Words: molecular evolution • RNA secondary structure • compensatory evolution • transition-transversion ratio
* Contributed equally to this work