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.
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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Morgan, T. H. Evolution and Adaptation (Macmillan, New York, 1903).
Sturtevant, A. H. Essays on evolution. I. On the effects of selection on mutation rate. Q. Rev. Biol. 12, 467–477 (1937). A seminal paper in which the problematic nature of non-zero mutation rate was first posed.
Timofeeff-Ressovsky, N. W. Qualitativer Vergleich der Mutabilität von Drosophila funebris und D. melanogaster. Zeits. Ind. Abst. Vererb. 71, 276–280 (1936) (in German).
Demerec, M. Frequency of spontaneous mutations in certain stocks of Drosophila melanogaster. Genetics 22, 469–478 (1937).
Leigh, E. G. The evolution of mutation rates. Genetics 73, 1–18 (1973).
McVean, G. T. & L. D. Hurst . Evidence for a selectively favourable reduction in the mutation rate of the X chromosome. Nature 386, 388–392 (1997).
Drake, J. W. Chaos and order in spontaneous mutation. Genetics 173, 1–8 (2006).
Fisher, R. A. The Genetical Theory of Natural Selection (Oxford Univ. Press, Oxford, 1930).
Kimura, M. Optimum mutation rate and degree of dominance as determined by the principle of minimum genetic load. J. Genet. 57, 21–34 (1960).
Kimura, M. On evolutionary adjustment of spontaneous mutation rates. Genet. Res. 9, 23–27 (1967). One of the first theoretical treatments of the evolution of mutation rate; the author introduced the idea of the 'cost of fidelity'.
Leigh, E. G. Natural selection and mutability. Am. Nat. 104, 301–305 (1970). Demonstrated that natural selection (almost) always favours a reduced mutation rate in sexual populations but not necessarily among asexuals.
Karlin, S. & McGregor, J. Towards a theory of evolution of modifier genes. Theor. Pop. Biol. 5, 59–103 (1974).
Kondrashov, A. S. Modifiers of mutation-selection balance — general approach and the evolution of mutation rates. Genet. Res. 66, 53–69 (1995). A very general treatment of the evolution of mutation rate, in which the connection between the strength of selection on a modifier of mutation rate and the average effect of a mutation is made explicit.
Kondrashov, A. S. Dynamics of unconditionally deleterious mutations — Gaussian approximation and soft selection. Genet. Res. 65, 113–121 (1995).
Dawson, K. J. Evolutionarily stable mutation rates. J. Theor. Biol. 194, 143–157 (1998).
Johnson, T. Beneficial mutations, hitchhiking and the evolution of mutation rates in sexual populations. Genetics 151, 1621–1631 (1999).
Andre, J. B. & Godelle, B. The evolution of mutation rate in finite asexual populations. Genetics 172, 611–626 (2006).
Sniegowski, P. D., Gerrish, P. J., Johnson, T. & Shaver, A. The evolution of mutation rates: separating causes from consequences. Bioessays 22, 1057–1066 (2000).
Gerrish, P. J., Colato, A., Perelson, A. S. & Sniegowski, P. D. Complete genetic linkage can subvert natural selection. Proc. Natl Acad. Sci. USA 104, 6266–6271 (2007). A theoretical demonstration that fluctuating selection in an asexual organism can cause the population to 'adapt itself to death' by hitchhiking deleterious mutations with beneficial alleles.
Drake, J. W., Charlesworth, B., Charlesworth, D. & Crow, J. F. Rates of spontaneous mutation. Genetics 148, 1667–1686 (1998). Still the most comprehensive review from an evolutionary perspective of the broad field of spontaneous mutation.
Schaaper, R. M. Antimutator mutants in bacteriophage T4 and Escherichia coli. Genetics 148, 1579–1585 (1998).
Haldane, J. B. S. The effect of variation on fitness. Am. Nat. 71, 337–349 (1937).
Hill, W. G. & Robertson, A. The effects of linkage on limits to artificial selection. Genet. Res. 8, 269–294 (1966).
Charlesworth, B., Morgan, M. T. & Charlesworth, D. The effect of deleterious mutations on neutral molecular variation. Genetics 134, 1289–1303 (1993).
Campbell, N. A. Biology 6th edn (Benjamin Cummings, Menlo Park, California, 2004).
Alberts, B. et al. Molecular Biology of the Cell 4th edn (Garland, New York, 2002).
Jeffreys, A. J., Royle, N. J., Wilson, V. & Wong, Z. Spontaneous mutation rates to new length alleles at tandem-repetitive hypervariable loci in human DNA. Nature 332, 278–281 (1988).
Fileé, J., Forterre, P., Sen-Lin, T. & Laurent, J. Evolution of DNA polymerase families: evidences for multiple gene exchange between cellular and viral proteins. J. Mol. Evol. 54, 763–773 (2002).
Johnson, R. E., Washington, M. T., Prakash, S. & Prakash, L. Fidelity of human DNA polymerase-η. J. Biol. Chem. 275, 7447–7450 (2000).
Landis, G. N. & Tower, J. Superoxide dismutase evolution and lifespan regulation. Mech. Ageing Dev. 126, 365–379 (2005).
Hebert, P. D. N. & Emery, C. J. The adaptive significance of cuticular pigmentation in Daphnia. Funct. Ecol. 4, 703–710 (1990).
Saul, R. L. & Ames, B. N. Background levels of DNA damage in the population. Basic Life Sci. 38, 529–535 (1986).
Lindahl, T. Instability and decay of the primary DNA structure. Nature 362, 709–715 (1993). A broad-based review that covers all the ways in which the DNA molecule can suffer chemical damage to lead to mutation.
Beckman, R. B. & Ames, B. N. Oxidative decay of DNA. J. Biol. Chem. 272, 19633–19636 (1997).
Eisen, J. A. & Hanawalt, P. C. A phylogenomic study of DNA repair genes, proteins, and processes. Mutat. Res. 435, 171–213 (2000).
Taylor, E. M. & Lehmann A. R. Conservation of eukaryotic DNA repair mechanisms. Int. J. Radiat. Biol. 74, 277–286 (1998).
Harfe, B. D. & Jinks-Robertson, S. DNA mismatch repair and genomic instability. Annu. Rev. Genet. 34, 359–399 (2000).
Denver, D. R., Swenson, S. L. & Lynch, M. An evolutionary analysis of the helix–hairpin–helix superfamily of DNA repair glycosylases. Mol. Biol. Evol. 20, 1603–1611 (2003).
Kurowski, M. A., Bhagwat, A. S., Papaj G. & Bujnicki, J. M. Phylogenomic identification of five new human homologs of the DNA repair enzyme AlkB. BMC Genomics 4, 48 (2003).
Weischenfeldt, J., Lykke-Andersen, J. & Porse, B. Messenger RNA surveillance: neutralizing natural nonsense. Curr. Biol. 15, R559–R562 (2005).
Rutherford, S. L. & Lindquist, S. Hsp90 as a capacitor for morphological evolution. Nature 396, 336–342 (1998). The first report of a protein's ability to buffer the phenotypic effects of mutations.
Rutherford, S. L. Between genotype and phenotype: protein chaperones and evolvability. Nature Rev. Genet. 4, 263–274 (2003).
Selker, E. U. Premeiotic instability of repeated sequences in Neurospora crassa. Annu. Rev. Genet. 24, 579–613 (1990).
Freitag, M., Williams, R. L., Kothe, G. O. & Selker, E. U. A cytosine methyltransferase homologue is essential for repeat-induced point mutation in Neurospora crassa. Proc. Natl Acad. Sci. USA 99, 8802–8807 (2002).
Mukai, T. & Cockerham, C. C. Spontaneous mutation rates at enzyme loci in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 74, 2514–2517 (1977).
Russell, L. B. & Russell, W. L. Spontaneous mutations recovered as mosaics in the mouse specific-locus test. Proc. Natl Acad. Sci. USA 93, 13072–13077 (1996).
Kondrashov, A. S. Direct estimates of human per nucleotide mutation rates at 20 loci causing Mendelian diseases. Hum. Mutat. 21, 12–27 (2003).
Nachman, M. W. & Crowell, S. L. Estimate of the mutation rate per nucleotide in humans. Genetics 156, 297–304 (2000).
Denver, D. R., Morris, K., Lynch, M. & Thomas, W. K. High mutation rate and predominance of insertions in the Caenorhabditis elegans nuclear genome. Nature 430, 679–682 (2004).
Haag-Liautard, C. et al. Direct estimation of per nucleotide and genomic deleterious mutation rates in Drosophila. Nature 445, 82–85 (2007). The authors report significant mutation rate variation among three distinct Drosophila mutation-accumulation line lineages.
Howell, N. et al. The pedigree rate of sequence divergence in the human mitochondrial genome: there is a difference between phylogenetic and pedigree rates. Am. J. Hum. Genet. 72, 659–670 (2003).
Denver, D. R., Morris, K., Lynch, M., Vassilieva, L. L. & Thomas, W. K. High direct estimate of the mutation rate in the mitochondrial genome of Caenorhabditis elegans. Science 289, 2342–2344 (2000).
Lynch, M., Koskella, B. & Schaack, S. Mutation pressure and the evolution of organelle genomic architecture. Science 311, 1727–1730 (2006). The authors propose that the features of genomic architecture are largely determined by the non-adaptive forces of genetic drift and mutation pressure.
Palmer, J. D. & Herbon, L. A. Plant mitochondrial DNA evolves rapidly in structure, but slowly in sequence. J. Mol. Evol. 28, 87–97 (1988). A demonstration that plant mitochondrial genomes experience high rates of structural rearrangement and low rates of nucleotide substitution, unlike animal mitochondrial genomes that generally evolve with low rearrangement rates and high substitution rates.
Filipski, J. Why the rate of silent codon substitutions is variable within a vertebrate genome. J. Theor. Biol. 134, 159–164 (1988).
Wolfe, K. H., Sharp, P. M. & Li, W.-H. Mutation rates differ among regions of the mammalian genome. Nature 337, 283–285 (1989).
Lercher, M. J. & Hurst, L. D. Human SNP variability and mutation rate are higher in regions of high recombination. Trends Genet. 18, 337–340 (2002).
Gaffney, D. J. & Keightley, P. D. The scale of mutational variation in the murid genome. Genome Res. 15, 1086–1094 (2005).
Hardison, R. C. et al. Covariation in frequencies of substitution, deletion, transposition, and recombination during eutherian evolution. Genome Res. 13, 13–26 (2003).
Matassi, G., Sharp, P. M. & Gautier C. Chromosomal location effects on gene sequence evolution in mammals. Curr. Biol. 9, 786–791 (1999).
Williams, E. J. B. & Hurst, L. D. Clustering of tissue-specific genes underlies much of the similarity in rates of protein evolution of linked genes. J. Mol. Evol. 54, 511–518 (2002).
Lercher, M. J., Chamary, J. V. & Hurst, L. D. Genomic regionality in rates of evolution is not explained by clustering of genes of comparable expression profile. Genome Res. 14, 1002–1013 (2004).
Webster, M. T., Smith, N. G. C., Lercher, M. J. & Ellegren, H. Gene expression, synteny, and local similarity in human noncoding mutation rates. Mol. Biol. Evol. 21, 1820–1830 (2004).
Boulikas, T. Evolutionary consequences of nonrandom damage and repair of chromatin domains. J. Mol. Evol. 35, 156–180 (1992).
Denver, D. R., Feinberg, S., Steding, C., Durbin, M. & Lynch, M. The relative roles of three DNA repair pathways in preventing Caenorhabditis elegans mutation accumulation. Genetics 174, 57–65 (2006).
Prendergast, J. G. D. et al. Chromatin structure and evolution in the human genome. BMC Evol. Biol. 7, 72 (2007). The authors show that the mutational milieu varies predictably with chromatin structure, and that groups of functional genes are nonrandomly associated with different mutational domains.
Lichtenauer-Kaligis, E. G. R., van der Velde-van Dijke, T., Dendulk, H., van de Putte, P., Giphart-Gassler, M. & Tasseron-de Jong, J. G. Genomic position influences spontaneous mutagenesis of an integrated retroviral vector containing the hprt cDNA as target for mutagenesis. Hum. Mol. Genet. 2, 173–182 (1993).
Chuang, J. H. & Li, H. Functional bias and spatial organization of genes in mutational hot and cold regions in the human genome. PLoS Biol. 2, 253–263 (2004).
Kondrashov, A. S. Deleterious mutations and the evolution of sexual reproduction. Nature 336, 435–440 (1988).
Keightley, P. D. & Otto S. P. Interference among deleterious mutations favours sex and recombination in finite populations. Nature 443, 89–92 (2006).
Bateman, A. J. The viability of near-normal irradiated chromosomes. Int. J. Radiat. Biol. 1, 170–180 (1959).
Mukai, T. The genetic structure of natural populations of Drosophila melanogaster. I. Spontaneous mutation rate of polygenes controlling viability. Genetics 50, 1–19 (1964).
Keightley, P. D. The distribution of mutation effects on viability in Drosophila melanogaster. Genetics 138, 1315–1322 (1994).
Shaw, F. H., Geyer, C. J. & Shaw, R. G. A comprehensive model of mutations affecting fitness and inferences for Arabidopsis thaliana. Evolution 56, 453–463 (2002).
Kondrashov, A. S. & Crow, J. F. A molecular approach to estimating the human deleterious mutation rate. Hum. Mutat. 2, 229–234 (1993).
Funchain, P. et al. The consequences of growth of a mutator strain of Escherichia coli as measured by loss of function among multiple gene targets and loss of fitness. Genetics 154, 959–970 (2000).
Degtyareva, N. P. et al. Caenorhabditis elegans DNA mismatch repair gene msh-2 is required for microsatellite stability and maintenance of genome integrity. Proc. Natl Acad. Sci. USA 99, 2158–2163 (2002).
Bégin, M. & Schoen, D. J. Low impact of germline transposition on the rate of mildly deleterious mutation in Caenorhabditis elegans. Genetics 174, 2129–2136 (2006).
Woodruff, R. C., Thompson, J. N., Seeger, M. A. & Spivey, W. E. Variation in spontaneous mutation and repair in natural population lines of Drosophila melanogaster. Heredity 53, 223–234 (1984).
Cooper, T. F., Lenski, R. E. & Elena, S. F. Parasites and mutational load: an experimental test of a pluralistic theory for the evolution of sex. Proc. Biol. Sci. 272, 311–317 (2005).
Ohta, T. & Ina, Y. Variation in synonymous substitution rates among mammalian genes and the correlation between synonymous and nonsynonymous divergences. J. Mol. Evol. 41, 717–720 (1995).
Comeron, J. M. & Kreitman, M. The correlation between synonymous and nonsynonymous substutitions in Drosophila: mutation, selection, or relaxed constraints? Genetics 150, 767–775 (1998).
Houle, D. & Kondrashov, A. in Evolutionary Genetics: Concepts and Case Studies (eds Fox, C. W. & Wolf, J. B.) 32–48 (Oxford Univ. Press, New York, 2006).
Wayne, M. & Miyamoto, M. M. in Evolutionary Genetics: Concepts and Case Studies (eds Fox, C. W. & Wolf, J. B.) 14–31 (Oxford Univ. Press, New York, 2006).
Gillespie, J. H. The Causes of Molecular Evolution (Oxford Univ. Press, New York, 1991).
Li, W.-H. Molecular Evolution (Sinauer, Sunderland, Massachusetts, 1997). A valuable general text for the study of molecular evolution, particularly of the patterns and processes of sequence change that are due to mutation, drift and selection.
Page, R. D. M. & Holmes, E. C. Molecular Evolution: A Phylogenetic Approach (Blackwell, Malden, Massachusetts, 1998).
Laird, C. D., McConaughy, B. L. & McCarthy, B. J. Rate of fixation of nucleotide substitution in evolution. Nature 224, 149–154 (1969).
Li, W.-H., Tanimura, M. & Sharp, P. M. An evaluation of the molecular clock hypothesis using mammalian DNA sequences. J. Mol. Evol. 25, 330–342 (1987).
Haldane, J. B. S. The mutation rate of the gene for hemophilia, and its segregation ratios in males and females. Ann. Eugen. 13, 262–271 (1947).
Ellegren, H. & Fridolfsson, A. K. Male-driven evolution of DNA sequences in birds. Nature Genet. 17, 182–184 (1997).
Goetting-Minesky, M. P. & Makova, K. D. Mammalian male mutation bias: impacts of generation time and regional variation in substitution rate. J. Mol. Evol. 63, 537–544 (2006).
Taylor, J., Tyekucheva, S., Zody, M., Chiaromonte, F. & Makova, K. D. Strong and weak male mutation bias at different sites in the primate genomes: insights from the human–chimpanzee comparison. Mol. Biol. Evol. 23, 565–573 (2006).
Lercher, M. J., Williams, E. J. & Hurst, L. D. Local similarity in evolutionary rates extends over whole chromosomes in human–rodent and mouse–rat comparisons: implications for understanding the mechanistic basis of the male mutation bias. Mol. Biol. Evol. 18, 2032–2039 (2001).
Martin, A. P. & Palumbi, S. R. Body size, metabolic rate, generation time, and the molecular clock. Proc. Natl Acad. Sci. USA 90, 4087–4091 (1993).
Britten, R. J. Rates of DNA sequence evolution differ between taxonomic groups. Science 231, 1393–1398 (1986).
Saparbaev, M. & Laval, J. Excision of hypoxanthine from DNA containing dIMP residues by the Escherichia coli, yeast, rat, and human alkylpurine DNA glycosylases. Proc. Natl Acad. Sci. USA 91, 5873–5877 (1994).
Ohta, T. Slightly deleterious mutant substitutions in evolution. Nature 246, 96–98 (1973).
Keightley, P. D. & Caballero, A. Genomic mutation rates for lifetime reproductive output and lifespan in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 94, 3823–3827 (1997).
Kondrashov, F. A., Ogurtsov, A. Y. & Kondrashov, A. S. Selection in favor of nucleotides G and C diversifies evolution rates and levels of polymorphism in mammalian synonymous sites. J. Theor. Biol. 240, 616–626 (2006). This paper provides a basis for the use of | s | < 1 / 4 N e as the cut off between effectively neutral and effectively selected mutations.
Gillooly, J. F., Allen, A. P., West, G. B. & Brown, J. H. The rate of DNA evolution: effects of body size and temperature on the molecular clock. Proc. Natl Acad. Sci. USA 102, 140–145 (2005).
Halligan, D. L. & Keightley, P. D. Ubiquitous selective constraints in the Drosophila genome revealed by a genome-wide interspecies comparison. Genome Res. 16, 875–884 (2006).
Nöthel, H. Adaptation of Drosophila melanogaster populations to high mutation pressure: evolutionary adjustment of mutation rates. Proc. Natl Acad. Sci. USA 84, 1045–1049 (1987).
Baer, C. F. et al. Comparative evolutionary genetics of spontaneous mutations affecting fitness in rhabditid nematodes. Proc. Natl Acad. Sci. USA 102, 5785–5790 (2005).
Mardis, E. R. Anticipating the 1,000 dollar genome. Genome Biol. 7, 112 (2006). A review of the ongoing race for highly parallel and inexpensive new DNA sequencing methods that have already resulted in breakthrough technologies, enabling a new scale of mutational analysis.
Gibson, G. Mutation accumulation of the transcriptome. Nature Genet. 37, 458–460 (2005).
Lynch, M. & Conery, J. S. The origins of genome complexity. Science 302, 401–404 (2003).
Dacks, J. & Roger, A. J. The first sexual lineage and the relevance of facultative sex. J. Mol. Evol. 48, 779–783 (1999).
Butterfield, N. J. Bangiomorpha pubescens n. gen., n. sp.: implications for the evolution of sex, multicellularity, and the Mesoproterozoic/Neoproterozoic radiation of eukaryotes. Paleobiology 26, 386–404 (2000).
Taddei, F. et al. Role of mutator alleles in adaptive evolution. Nature 387, 700–702 (1997).
Tenaillon, O., Toupance, B., Le Nagard, H., Taddei, F. & Godelle, B. Mutators, population size, adaptive landscape and the adaptation of asexual populations of bacteria. Genetics 152, 485–493 (1999).
Chao, L. & Cox, E. C. Competition between high and low mutating strains of Escherichia coli. Evolution 37, 125–134 (1983).
Matic, I. et al. Highly variable mutation rates in commensal and pathogenic Escherichia coli. Science 277, 1833–1834 (1997).
Sniegowski, P. D., Gerrish, P. J. & Lenski, R. E. Evolution of high mutation rates in experimental populations of E. coli. Nature 387, 703–705 (1997).
Bjedov, I. et al. Stress-induced mutagenesis in bacteria. Science 300, 1404–1409 (2003).
Denamur, E. & Matic, I. Evolution of mutation rates in bacteria. Mol. Microbiol. 60, 820–827 (2006).
Keightley, P. D. & Caballero, A. Genomic mutation rates for lifetime reproductive output and lifespan in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 94, 3823–3827 (1997).
Kimura, M. On probability of fixation of mutant genes in a population. Genetics 47, 713–719 (1962).
Lynch, M. & Walsh, B. Genetics and Analysis of Quantitative Traits (Sinauer, Sunderland, Massachusetts, 1998).
Garcia-Dorado, A. & Gallego, A. Comparing analysis methods for mutation-accumulation data: a simulation study. Genetics 164, 807–819 (2003).
Keightley, P. D. & Bataillon, T. M. Multigeneration maximum-likelihood analysis applied to mutation accumulation experiments in Caenorhabditis elegans. Genetics 154, 1193–1201 (2000).
García-Dorado, A. The rate and effects distribution of viability mutation in Drosophila: minimum distance estimation. Evolution 51, 1130–1139 (1997).
Deng, H-W. & Lynch, M. Estimation of deleterious mutation parameters in natural populations. Genetics 144, 349–360 (1996).
Kimura, M. Evolutionary rate at the molecular level. Nature 217, 624–626 (1968).
Schmalhausen, I. I. Factors of Evolution: the Theory of Stabilizing Selection (Univ. Chicago Press, Chicago, 1949).
Waddington, C. H. Genetic assimilation of an acquired character. Evolution 7, 118–126 (1953).
de Visser, J. A. et al. Perspective: Evolution and detection of genetic robustness. Evolution 57, 1959–1972 (2003).
Flatt, T. The evolutionary genetics of canalization. Q. Rev. Biol. 80, 287–316 (2005).
Wagner, G. P., Booth, G. & Bagheri-Chaichian, H. A population genetic theory of canalization. Evolution 51, 329–347 (1997).
Force, A. et al. Preservation of duplicate genes by complementary, degenerative mutations. Genetics 151, 1531–1545 (1999).
Lynch, M. & Force, A. The probability of duplicate gene preservation by subfunctionalization. Genetics 154, 459–473 (2000).
Kimura, M. 1983. The Neutral Theory of Molecular Evolution (Cambridge Univ. Press, Cambridge, UK, 1983).
Keightley, P. D. & Eyre-Walker, A. Terumi Mukai and the riddle of deleterious mutation rates. Genetics 153, 515–523 (1999).
Keightley, P. D. & Eyre-Walker, A. Deleterious mutations and the evolution of sex. Science 290, 331–333 (2000).
Harada, K., Kusakabe, S., Yamazaki, T. & Mukai, T. Spontaneous mutation rates in null and band-morph mutations of enzyme loci in Drosophila melanogaster. Jpn. J. Genet. 68, 605–616 (1993).
Downie, D. A. Effects of short-term spontaneous mutation accumulation for life history traits in grape phylloera, Daktulosphaira vitifoliae. Genetica 119, 237–251 (2003).
Vassilieva, L. L., Hook, A. M. & Lynch M. The rate of spontaneous mutation for life-history traits in Caenorhabditis elegans. Evolution 151, 119–129 (2000).
Baer, C. F. et al. Cumulative effects of spontaneous mutations for fitness in Caenorhabditis: role of genotype, environment and stress. Genetics 174, 1387–1395 (2006).
Cutter, A. D. & Payseur, B. A. Rates of deleterious mutation and the evolution of sex in Caenorhabditis. J. Evol. Biol. 16, 812–822 (2003).
Lynch, M., Latta, L., Hicks, J. & Giorgianni, M. Mutation, selection, and the maintenance of life-history variation in a natural population. Evolution 52, 727–733 (1988).
Deng, H.-W., Li, J., Pfrender, M. E., Li, J.-L. & Deng, H. Upper limit of the rate and per generation effects of deleterious genomic mutations. Genet. Res. 88, 57–65 (2006).
Schultz, S. T., Lynch, M. & Willis, J. H. Spontaneous deleterious mutation in Arabidopsis thaliana. Proc. Natl Acad. Sci. USA 96, 11393–11398 (1999).
Wright, S. I., Lauga, B. & Charlesworth, D. Rates and patterns of molecular evolution in inbred and outbred Arabidopsis. Mol. Biol. Evol. 19, 1407–1420 (2002).
Schoen, D. J. Deleterious mutation in related species of the plant genus Amsinckia with contrasting mating systems. Evolution 59, 2370–2377 (2005).
Gaffney, D. J. & Keightley, P. D. Genomic selective constraints in murid noncoding DNA. PLoS Genet. 2, 1912–1923 (2006).
We thank R. Woodruff, A. Kondrashov and two anonymous reviewers for helpful comments on the manuscript.
The authors declare no competing financial interests.
- 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.
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.
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.
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.
The ability of a system's steady state to remain unchanged, or not significantly changed, when parameters that underlie the system change.
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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Cite this article
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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