The Cellular, Developmental and Population-Genetic Determinants of Mutation-Rate Evolution
Michael Lynch 1
Author Affiliations
Department of Biology, Indiana University, Bloomington, Indiana 47405
1 Author e-mail: milynch@indiana.edu
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.
ALTHOUGH considerable uncertainties remain about the rate of origin and phenotypic consequences of spontaneously arising mutations, it is clear that the vast majority of mutations with effects on fitness are mildly deleterious (LYNCH et al. 1999; CROW2000; BAER et al. 2007; EYRE-WALKER and KEIGHTLEY 2007). Three lines of defense serve to minimize the accumulation of such mutations. First, most replication polymerases have a strong tendency to incorporate bases complementary to those on template strands, while also harboring a proofreading capacity for removing a substantial fraction of the few base misincorporations that do initially occur (FRIEDBERG et al. 2005;KORNBERG and BAKER 2005; MCCULLOCH and KUNKEL 2008). Second, errors remaining after proofreading are scrutinized by postreplicative mismatch-repair (MMR) pathways (HARFE and JINKS-ROBERTSON 2000; LI 2008). Third, natural selection serves as the final arbiter, operating at the population level and eliminating the subset of deleterious germline mutations with selection coefficients large enough to offset the vagaries of random genetic drift (HARTL and CLARK 2007).
Although the relative roles of the various factors molding the evolution of the mutation rate in different organisms remain unresolved, some generalizations seem clear. First, because multicellular species experience numerous germline cell divisions per developmental cycle, their per-generation rate of mutation is expected to be magnified relative to that in unicellular species, unless there is a compensatory increase in the efficiency of recognition and repair of premutations at the DNA level. Second, mutationally aggressive genotypes can experience significant levels of somatic damage in multicellular species, as dramatically illustrated by the numerous hereditary forms of cancer in humans (WEINBERG2006). Third, alleles whose products increase the mutation rate are expected to develop statistical associations with detrimental mutations at linked and unlinked loci, while also inducing the origin of more mutator alleles at the same locus in heterozygous carriers. Finally, because effective population sizes are greatly reduced in multicellular relative to unicellular species, the efficiency of selection for mutation-avoidance mechanisms is expected to be reduced (LYNCH 2006, 2007).
It is frequently argued that mutation rates are optimized by natural selection to enhance the long-term rate of adaptive change (e.g., WILKE et al. 2001; ANDRÉ and GODELLE2006; DENAMUR and MATIC 2006). However, the logic underlying this view applies mainly to asexual populations, where beneficial mutations remain permanently linked to the backgrounds in which they arise (JOHNSON 1999a; SNIEGOWSKI et al. 2000). For sexual populations, it has proved difficult to avoid the conclusion that mutation rates are predominantly driven downward by transient linkage of mutator alleles to their deleterious side effects (STURTEVANT 1937; LEIGH 1970, 1973; JOHNSON 1999b). Here we explore the extent to which phylogenetic variation in rates of mutation can emerge passively in response to factors defined by the cellular, developmental, and population-genetic environments, purely in the context of deleterious-mutation management. Together, these three levels of biological organization define the power of mutation, selection, and drift operating on the molecular machinery responsible for mutational screening. In the following discussion, the term “mutator” allele is used in a generic sense, in that the theory applies to variants at any locus that alter the mutagenic state of the intracellular environment to any degree.
+++++
+++++
