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Mutation rate variation in multicellular eukaryotes: causes and consequences

Key Points

  • Basic knowledge about the rate and range of mutation is central to our understanding of numerous evolutionary processes that include maintaining sexual reproduction and rates of molecular evolution. Although mutation rates are known to vary among species, little is known about the forces that underlie this variation at an empirical level, particularly in multicellular eukaryotes.

  • The theoretical framework for mutational variation is based primarily on the 'cost of fidelity' and 'modifier allele' theories. The former argues that the mutation rate does not evolve to zero, despite the much greater frequency of deleterious mutations, because there is an opposing metabolic cost. The latter models mutational variation as the interaction between a mutator locus that affects the mutation rate for a fitness locus (or loci).

  • Natural selection can potentially modulate the mutation rate through four main points of control: DNA replication fidelity, mutagen exposure, DNA repair efficiencies and the buffering of mutational effects.

  • Molecular mutation rates are generally estimated through three approaches: gene-specific methods, mutation-accumulation lines and pedigrees. Although most empirical mutational knowledge derives from the first method, the other two probably provide more accurate estimates. Per-nucleotide mutation rates that are on the order of 10−8 per generation are observed in Caenorhabditis elegans and Drosophila melanogaster mutation-accumulation experiments.

  • Studies on the differences in mutation rates within and between genomic systems have the potential to provide a framework for understanding natural mutational variation. Animal mitochondrial genomes experience substitution rates that are much greater than those of nuclear genomes, whereas the situation is reversed for most plant species. Rate variation is also observed across different nuclear genomic regions within a species and might be affected by various forces, including base composition, recombination rate, gene expression, gene density and DNA repair domains.

  • Estimates of the deleterious genomic mutation rate (U) are available for a variety of species that derive from fitness assay data and nucleotide substitution rates. Although according to these approaches U varies considerably across groups, the current evidence suggests that this parameter is rarely much less than one in multicellular eukaryotes and that there is as much variation within major lineages as between taxa. The reliability of estimates of U from fitness data suffer from the inability to detect mutations that have very small effects; estimates of U from DNA sequence data are limited by probable loose and uncertain connections between mutation rates and substitution rates.

  • All else being equal, the deleterious genomic mutation rate (U) should be correlated with the per-nucleotide molecular mutation rate (μ). Forces that might cause a decoupling of U and μ include genetic redundancy, robustness and changes in pleiotropy.

  • Mutation rate variation is expected to affect evolutionary rate variation. Three main hypotheses for among-lineage substitution rate variation have been proposed that relate to potential points for modulating mutation rates: the generation-time hypothesis (relates to replication), the metabolic-rate hypothesis (relates to mutagen exposure) and the DNA repair hypothesis (relates variation in DNA repair pathways and/or efficiencies). Evolutionary rate variation can also result from varying selection.

  • Five key questions on the evolution of the mutation rate remain to be answered. First, is the evolution of the mutation rate predictable, given our current theoretical understanding? Second, what is the relationship between μ and U? Third, how faithfully do estimates of μ (and U) from comparative genomic data reflect the actual underlying rate and range of new mutations? Fourth, what are the biological mechanisms that underlie variation in mutation rates? Fifth, to what extent do our most recent mutation rate estimates remain inaccurate? We anticipate that tools resulting from the ongoing genomic revolution, coupled with continued theoretical progress and experimental and comparative approaches, will address these unanswered questions and result in landmark advances in our understanding of natural mutational variation both within and among species.

Abstract

A basic knowledge about mutation rates is central to our understanding of a myriad of evolutionary phenomena, including the maintenance of sex and rates of molecular evolution. Although there is substantial evidence that mutation rates vary among taxa, relatively little is known about the factors that underlie this variation at an empirical level, particularly in multicellular eukaryotes. Here we integrate several disparate lines of theoretical and empirical inquiry into a unified framework to guide future studies that are aimed at understanding why and how mutation rates evolve in multicellular species.

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Figure 1: Points of control in mutation rate evolution.
Figure 2: Experimental methods for molecular mutation rate estimation.

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Acknowledgements

We thank R. Woodruff, A. Kondrashov and two anonymous reviewers for helpful comments on the manuscript.

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Correspondence to Charles F. Baer or Dee R. Denver.

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FURTHER INFORMATION

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Oregon State University Computational and Genome Biology Initiative

University of Florida Genetics Institute

Glossary

Optimizing selection

Selection on a continuously distributed trait such that individuals who have extreme values of the trait have lower fitness than individuals from the middle of the distribution.

Pleiotropy

The genetic effect of a single gene on multiple phenotypic traits.

Linkage disequilibrium

A measure of the non-random association of alleles at two or more loci, which are not necessarily on the same chromosome.

Mutator

An allele that increases the mutation rate.

Fluctuating selection

Selection in which the relative fitness of a genotype or phenotype varies over time in a predictable way.

Selection coefficient (s)

A measure of the intensity of natural selection acting on a particular mutation or genotype in a population.

Coefficient of dominance (h)

The degree to which the phenotype (including fitness) of the heterozygote deviates from the mean of the two homozygotes. For fitness, the fitness of the heterozygote is given by the equation 1 − hs where h is the coefficient of dominance and s is the decrement in fitness of the less fit homozygote relative to the more fit homozygote.

Nonsense-mediated mRNA decay

A cellular mechanism of mRNA surveillance to detect premature nonsense mutations and prevent the expression of truncated or erroneous proteins.

Chaperones

Protein factors, such as heat-shock proteins, that are involved in folding newly made and misfolded proteins.

Repeat-induced point mutation pathway

A pathway that is specific to Neurospora crassa and certain other fungi whereby newly duplicated DNA segments are hypermutated (C:G to T:A transitions) during sexual development.

Denaturing high-performance liquid chromatography

A mutation detection technique that relies on the differential denaturation or reannealing profiles of heteroduplex versus homoduplex DNA molecules.

Joint distribution

The probability that two variables X and Y take on the respective values X = x and Y = y, summed over all possible x and y values.

Standing polymorphism

The steady-state level of genetic or phenotypic variation for a particular gene or trait in a population.

Robustness

The ability of a system's steady state to remain unchanged, or not significantly changed, when parameters that underlie the system change.

Drift

Random fluctuations in allele frequencies as DNA is transmitted from one generation to the next, resulting from sampling in a finite population.

Effective population size

Formally, the size of an ideal population that experiences an equivalent magnitude of genetic drift to the real population in question; heuristically, the number of individuals in a population that contribute genes to the next generation.

Life history

The reproductive strategy of an organism.

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Baer, C., Miyamoto, M. & Denver, D. Mutation rate variation in multicellular eukaryotes: causes and consequences. Nat Rev Genet 8, 619–631 (2007). https://doi.org/10.1038/nrg2158

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