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. 2011:3:1107-18.
doi: 10.1093/gbe/evr066. Epub 2011 Aug 4.

The lower bound to the evolution of mutation rates

Michael Lynch  1
Affiliations

The lower bound to the evolution of mutation rates

Michael Lynch. Genome Biol Evol. 2011.

Abstract

Despite substantial attention from theoreticians, the evolutionary mechanisms that drive intra- and interspecific variation in the mutation rate remain unclear. It has often been argued that mutation rates associated with the major replicative polymerases have been driven down to their physiological limits, defined as the point at which further enhancement in replication fidelity incurs a cost in terms of reproductive output, but no evidence in support of this argument has emerged for cellular organisms. Here, it is suggested that the lower barrier to mutation rate evolution may ultimately be defined not by molecular limitations but by the power of random genetic drift. As the mutation rate is reduced to a very low level, a point will eventually be reached at which the small advantage of any further reduction is overwhelmed by the power of drift. This hypothesis is consistent with a number of observations, including the inverse relationship between the per-site mutation rate and genome size in microbes, the negative scaling between the per-site mutation rate and effective population size in eukaryotes, and the elevated error rates associated with less frequently deployed polymerases and repair pathways.

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Figures

F<sc>IG</sc>. 1.—
FIG. 1.—
Properties of a mutator allele m in an infinite asexual population, assuming a mutation rate to mutator genotype Mm of 2μ = 10 − 6, and a negligible back mutation rate. Results were obtained by a set of recursion equations that tracked the distributions of deleterious mutation numbers within MM and Mm individuals, until the population achieved mutation–selection equilibrium. Left: Equilibrium frequency of the Mm mutator heterozygotes (dashed line) and average selective disadvantage of the Mm genotype at equilibrium (solid line obtained from recursions; dotted line from eq. (4)). Right: Population average mutation rate at equilibrium.
F<sc>IG</sc>. 2.—
FIG. 2.—
Sample evolutionary trajectories for the average genome-wide deleterious mutation rate (U−) in finite asexual populations with different monomorphic starting conditions. Results are shown for two different population sizes and two different selection coefficients against deleterious mutations, with 48 mutation rate classes differing by a factor of 1.111 between adjacent classes and with the mutation rate to mutator/antimutator genotypes being equal to 0.02 times the total genome-wide mutation rate to deleterious alleles at fitness loci. Mutations to antimutators were relatively rare (10% of the total; fd = 0.1). Note that the quasi-steady-state predictions for U− (given by the horizontal gray lines) are simply the points at which ΔU = 0.1U is equal to 1/N.
F<sc>IG</sc>. 3.—
FIG. 3.—
Mean times (in generations) for transitions from one fixed mutation rate state to another, given for three asexual population sizes. Upwardly bowed curves refer to derived mutators, and downward curves to antimutators. Data points are the averages of 500 stochastic simulations, whereas the curved lines are the expectations based on the theory in the text.
F<sc>IG</sc>. 4.—
FIG. 4.—
In vitro estimates of rates of base misincorporation by polymerases in four species groups (given as averages from multiple estimates from independent studies in Supplementary Material online). Rates are averaged over all nucleotide contexts, and for the error-prone polymerases, some sites are replicated at fidelity rates considerably lower (and others considerably higher) than the average. Note that for Escherichia coli, Pol I is used to replace the small RNA primers that initiate replication, and Pol III is the major replicative polymerase. For eukaryotes, Pol α is used to extend the RNA primers to a DNA length sufficient for Pol δ to take over, and Pols δ and ε are the major replicative polymerases (one for the leading and the other for the lagging strand). Data are limited for archaeal polymerases.
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