The cellular, developmental and population-genetic determinants of mutation-rate evolution

Abstract

Although the matter has been subject to considerable theoretical study, there are numerous open questions regarding the mechanisms driving the mutation rate in various phylogenetic lineages. Most notably, empirical evidence indicates that mutation rates are elevated in multicellular species relative to unicellular eukaryotes and prokaryotes, even on a per-cell division basis, despite the need for the avoidance of somatic damage and the accumulation of germline mutations. Here it is suggested that multicellularity discourages selection against weak mutator alleles for reasons associated with both the cellular and the population-genetic environments, thereby magnifying the vulnerability to somatic mutations (cancer) and increasing the risk of extinction from the accumulation of germline mutations. Moreover, contrary to common belief, a cost of fidelity need not be invoked to explain the lower bound to observed mutation rates, which instead may simply be set by the inability of selection to advance very weakly advantageous antimutator alleles in finite populations.

Figure 1.—

Estimates of the error rates associated with the primary polymerases involved in chromosomal replication (polymerases α, δ, and ɛ for eukaryotes and polymerases I, II, and III for prokaryotes). Results are given for base-substitutional changes, averaged over a diversity of in vitro experimental studies (details in supplemental material). Top: the total error rate (not including postreplicative mismatch repair). Center: the baseline misincorporation rate, prior to proofreading and mismatch repair. Bottom: error rate associated with proofreading (the ratio of mutation rates with proofreading-proficient polymerase vs. that with variants lacking the proofreading domain). The latter measures are more phylogenetically restricted than the former.

Figure 2.—

Average estimates of mismatch-repair efficiency for four phylogenetic groups, reported as the inflation in the mutation rate in experimental constructs in which the MMR pathway has been knocked out (relative to control values). Individual bars for different species denote the results for complete MMR knockouts elicited by the removal of alternative essential genes (or pairs of them) in the MMR pathway. Large horizontal bars denote the mean and SEs of these independent lineage-specific estimates. The results are summarized over a variety of in vivo studies involving diverse reporter constructs (details in supplemental material).

Figure 3.—

Inflation of the average induced selective disadvantage of a mutator allele resulting from deleterious mutations at a linked fitness locus relative to that for unlinked loci. hs is the heterozygous effect of the deleterious mutations, and c is the position of the repair locus on a chromosome of 1.0 M. Mutator alleles at the tips of chromosomes are less harmful because they are bounded on only one side by linked mutations.

Figure 4.—

The total selective disadvantage of a mutator allele associated with induced mutations, both linked and unlinked, as a function of the deleterious effect of heterozygous mutations (hs) and the number of chromosomes (L), scaled by the inflation in the mutation rate. The actual selective disadvantage of the mutator allele (s_m) is obtained by multiplying the plotted values by the increase in the haploid genomewide deleterious mutation rate (ΔU). The ratio of the plotted values to the dotted line is the average number of generations that a mutator allele remains associated with the mutations it creates, approximately two when the number of chromosomes is large.

Figure 5.—

The selection coefficient for a mutator allele induced by somatic mutations, as a function of the number of mutational risks prior to the completion of development. u_MM is assumed to equal 10⁻⁶. The vertical dotted line denotes 1/u_MM.

Figure 6.—

Top: equilibrium frequencies of mutator alleles with recessive fitness effects, for populations of effectively infinite size, given for lethal fitness effects (s_m = 1.0) and for mildly deleterious effects (s_m = 0.01), for situations in which the mutation rate to defective alleles is independent of the repair-locus genotype (u_MM = u_Mm) and when the rate is 1000 times higher in heterozygous repair-locus carriers of single defective alleles. Bottom: average mutation rates at a reference locus for populations in mutation–selection equilibrium, obtained from the results in the top assuming random mating. Here it is assumed that the mutation rates of both the mutant heterozygotes and the homozygotes are equal to u_Mm. The solid line is the reference for the situation in which the mutation rate is independent of the genotypic background.

Figure 7.—

Equilibrium frequencies of nonfunctional repair alleles with nonrecessive effects on fitness, for populations of effectively infinite size (as in Figure 6).