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Molecular clock in neutral protein evolution

Wilke, Claus O. (2004) Molecular clock in neutral protein evolution. BMC Genetics, 5 . Art. No. 25. ISSN 1471-2156. PMCID PMC517495.

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Background: A frequent observation in molecular evolution is that amino-acid substitution rates show an index of dispersion (that is, ratio of variance to mean) substantially larger than one. This observation has been termed the overdispersed molecular clock. On the basis of in silico protein-evolution experiments, Bastolla and coworkers recently proposed an explanation for this observation: Proteins drift in neutral space, and can temporarily get trapped in regions of substantially reduced neutrality. In these regions, substitution rates are suppressed, which results in an overall substitution process that is not Poissonian. However, the simulation method of Bastolla et al. is representative only for cases in which the product of mutation rate μ and population size Ne is small. How the substitution process behaves when μNe is large is not known. Results: Here, I study the behavior of the molecular clock in in silico protein evolution as a function of mutation rate and population size. I find that the index of dispersion decays with increasing μNe, and approaches 1 for large μNe . This observation can be explained with the selective pressure for mutational robustness, which is effective when μNe is large. This pressure keeps the population out of low-neutrality traps, and thus steadies the ticking of the molecular clock. Conclusions: The molecular clock in neutral protein evolution can fall into two distinct regimes, a strongly overdispersed one for small μNe, and a mostly Poissonian one for large μNe. The former is relevant for the majority of organisms in the plant and animal kingdom, and the latter may be relevant for RNA viruses.

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Wilke, Claus O.0000-0002-7470-9261
Additional Information:© 2004 Wilke; licensee BioMed Central Ltd. This is an open-access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Received: 09 June 2004; Accepted: 27 August 2004; Published: 27 August 2004. This work was supported in part by the NSF under Contract No. DEB-9981397. I thank Ugo Bastolla for helpful comments on an earlier version of this paper. Authors' contributions: COW carried out all aspects of this study.
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PubMed Central ID:PMC517495
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Deposited On:22 Nov 2005
Last Modified:02 Oct 2019 22:38

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