Abstract
BackgroundA 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.ResultsHere, 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.ConclusionsThe 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.
Highlights
A frequent observation in molecular evolution is that amino-acid substitution rates show an index of dispersion substantially larger than one
Kimura has argued that the majority of nucleotide substitutions that accumulate in genes over time are selectively neutral, and go to fixation purely by chance [1]
The finding for synonymous mutations is not surprising, because changes in the protein's neutrality do not affect the probability with which a synonymous mutation is neutral
Summary
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. On the basis of in silico proteinevolution 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. One major prediction of Kimura's neutral theory is that the substitution process should be a Poisson process, with the mean number of substitutions per unit time equal to the variance In contrast to this theory, empirical studies often find the variance to be significantly larger than the mean [2,3,4,5,6,7,8]. The problem with the fluctuating neutral space model is that it does not offer any argument for why the (page number not for citation purposes)
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