Abstract
Variation from new mutations is important for several questions in quantitative genetics. Key parameters are the genomic mutation rate and the distribution of effects of mutations (DEM), which determine the amount of new quantitative variation that arises per generation from mutation (V M ). Here, we review methods and empirical results concerning mutation accumulation (MA) experiments that have shed light on properties of mutations affecting quantitative traits. Surprisingly, most data on fitness traits from laboratory assays of MA lines indicate that the DEM is platykurtic in form (i.e., substantially less leptokurtic than an exponential distribution), and imply that most variation is produced by mutations of moderate to large effect. This finding contrasts with results from MA or mutagenesis experiments in which mutational changes to the DNA can be assayed directly, which imply that the vast majority of mutations have very small phenotypic effects, and that the distribution has a leptokurtic form. We compare these findings with recent approaches that attempt to infer the DEM for fitness based on comparing the frequency spectra of segregating nucleotide polymorphisms at putatively neutral and selected sites in population samples. When applied to data for humans and Drosophila, these analyses also indicate that the DEM is strongly leptokurtic. However, by combining the resultant estimates of parameters of the DEM with estimates of the mutation rate per nucleotide, the predicted V M for fitness is only a tiny fraction of V M observed in MA experiments. This discrepancy can be explained if we postulate that a few deleterious mutations of large effect contribute most of the mutational variation observed in MA experiments and that such mutations segregate at very low frequencies in natural populations, and effectively are never seen in population samples.
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Ajie BC, Estes S, Lynch M, Phillips PC (2005) Behavioral degradation under mutation accumulation in Caenorhabditis elegans. Genetics 170:655–660. doi:10.1534/genetics.104.040014
Andolfatto P (2005) Adaptive evolution of non-coding DNA in Drosophila. Nature 437:1149–1152. doi:10.1038/nature04107
Ávila V, Chavarrías D, Sánchez E, Manrique A, López-Fanjul C, García-Dorado A (2006) Increase of the spontaneous mutation rate in a long-term experiment with Drosophila melanogaster. Genetics 173:267–277. doi:10.1534/genetics.106.056200
Azevedo RB, Keightley PD, Laurén-Määttä C, Vassilieva LL, Lynch M, Leroi AM (2002) Spontaneous mutational variation for body size in Caenorhabditis elegans. Genetics 162:755–765
Baer CF, Shaw F, Steding C, Baurngartner M, Hawkins A, Houppert A et al (2005) Comparative evolutionary genetics of spontaneous mutations affecting fitness in rhabditid nematodes. Proc Natl Acad Sci USA 102:5785–5790. doi:10.1073/pnas.0406056102
Bataillon T (2000) Estimation of spontaneous genome-wide mutation rate parameters: whither beneficial mutations? Heredity 84:497–501. doi:10.1046/j.1365-2540.2000.00727.x
Bataillon T (2003) Shaking the ‘deleterious mutations’ dogma? Trends Ecol Evol 18:315–317. doi:10.1016/S0169-5347(03)00128-9
Bateman AJ (1959) The viability of near-normal irradiated chromosomes. Int J Radiat Biol 1:170–180. doi:10.1080/09553005914550241
Boyko AR, Williamson SH, Indap AR, Degenhardt JD, Hernandez RD, Lohmueller KE et al (2008) Assessing the evolutionary impact of amino acid mutations in the human genome. PLoS Genet 4:e1000083. doi:10.1371/journal.pgen.1000083
Bubb KL, Bovee D, Buckley D, Haugen E, Kibukawa M, Paddock M et al (2006) Scan of human genome reveals no new loci under ancient balancing selection. Genetics 173:2165–2177. doi:10.1534/genetics.106.055715
Bulmer MG (1989) Maintenance of genetic variability by mutation-selection balance: a child’s guide through the jungle. Genome 31:761–767
Burch CL, Guyader S, Samarov D, Shen H (2007) Experimental estimate of the abundance and effects of nearly neutral mutations in the RNA virus ϕ6. Genetics 176:467–476. doi:10.1534/genetics.106.067199
Bürger R (2000) The mathematical theory of selection, recombination and mutation. Wiley, Chichester
Charlesworth B, Langley CH (1989) The population genetics of Drosophila transposable elements. Annu Rev Genet 23:251–287. doi:10.1146/annurev.ge.23.120189.001343
Charlesworth B, Charlesworth D (1999) The genetic basis of inbreeding depression. Genet Res 74:329–340. doi:10.1017/S0016672399004152
Clayton G, Robertson A (1955) Mutation and quantitative variation. Am Nat 89:151–158. doi:10.1086/281874
Crow JF, Simmons MJ (1983). The mutation load in Drosophila. pp 1–35. In: Ashburner M, Carson HL, Thompson JN (eds) The genetics and biology of Drosophila, vol 3C. Academic Press, London
Davies EK, Peters AD, Keightley PD (1999) High frequency of cryptic deleterious mutations in Caenorhabditis elegans. Science 285:1745–1747. doi:10.1126/science.285.5434.1748
Denver DR, Morris K, Lynch M, Thomas WK (2004) High mutation rate and predominance of insertions in the Caenorhabditis elegans nuclear genome. Nature 430:679–682. doi:10.1038/nature02697
Denver DR, Feinberg S, Estes S, Thomas WK, Lynch M (2005) Mutation rates, spectra, and hotspots in mismatch repair-deficient Caenorhabditis elegans. Genetics 170:107–113. doi:10.1534/genetics.104.038521
Elena SF, Moya A (1999) Rate of deleterious mutation and the distribution of its effects on fitness in vesicular stomatitis virus. J Evol Biol 12:1078–1088. doi:10.1046/j.1420-9101.1999.00110.x
Estes S, Lynch M (2003) Rapid fitness recovery in mutationally degraded lines of Caenorhabditis elegans. Evolution 57:1022–1030
Estes S, Phillips PC, Denver DR, Thomas KW, Lynch M (2004) Mutation accumulation in populations of varying sizes: the distribution of mutational effects for fitness correlates in Caenorhabditis elegans. Genetics 166:1269–1279. doi:10.1534/genetics.166.3.1269
Eyre-Walker A, Keightley PD (2007) The distribution of fitness effects of new mutations. Nat Rev Genet 8:610–618. doi:10.1038/nrg2146
Eyre-Walker A, Keightley PD, Smith NGC, Gaffney D (2002) Quantifying the slightly deleterious model of molecular evolution. Mol Biol Evol 19:2142–2149
Eyre-Walker A, Woolfit M, Phlelps T (2006) The distribution of fitness of new deleterious amino acid mutations in humans. Genetics 173:891–900. doi:10.1534/genetics.106.057570
Falconer DS, Mackay TFC (1996) Introduction to quantitative genetics, 4th edn. Longman, London
Fernández J, López-Fanjul C (1996) Spontaneous mutational variances and covariances for fitness-related traits in Drosophila melanogaster. Genetics 143:829–837
Fry JD, Keightley PD, Heinsohn SL, Nuzhdin SV (1999) New estimates of rates and effects of mildly deleterious mutation in Drosophila melanogaster. Proc Natl Acad Sci USA 96:574–579. doi:10.1073/pnas.96.2.574
García-Dorado A (1997) The rate and effects distribution of viable mutation in Drosophila: minimum distance estimation. Evolution 51:1130–1139. doi:10.2307/2411042
García-Dorado A, Marin JM (1998) Minimum distance estimation of mutational parameters for quantitative traits. Biometrics 54:1097–1114. doi:10.2307/2533860
García-Dorado A, Gallego A (2003) Comparing analysis methods for mutation-accumulation data: A simulation study. Genetics 164:807–819
García-Dorado A, López-Fanjul C, Caballero A (1999) Properties of spontaneous mutations affecting quantitative traits. Genet Res 74:341–350. doi:10.1017/S0016672399004206
Gilligan DM, Woodworth LM, Montgomery ME, Briscoe DA, Frankham R (1997) Is mutation accumulation a threat to the survival of endangered populations? Conserv Biol 11:1235–1241. doi:10.1046/j.1523-1739.1997.96215.x
Haag-Liautard C, Dorris M, Maside X, Macaskill S, Halligan DL, Charlesworth B et al (2007) Direct estimation of per nucleotide and genomic deleterious mutation rates in Drosophila. Nature 445:82–85. doi:10.1038/nature05388
Halligan DL, Keightley PD (2006) Ubiquitous selective constraints in the Drosophila genome revealed by a genome-wide interspecies comparison. Genome Res 16:875–884. doi:10.1101/gr.5022906
Halligan DL, Peters AD, Keightley PD (2003) Estimating numbers of EMS-induced mutations affecting life history traits in Caenorhabditis elegans in crosses between inbred sublines. Genet Res 82:191–205. doi:10.1017/S0016672303006499
Hill WG (1982a) Rates of change in quantitative traits from fixation of new mutations. Proc Natl Acad Sci USA 79:142–145. doi:10.1073/pnas.79.1.142
Hill WG (1982b) Predictions of response to artificial selection from new mutations. Genet Res 40:255–278
Hill WG, Rasbash J (1986) Models of long term artificial selection in finite population with recurrent mutation. Genet Res 48:125–131
Houle D, Nuzhdin SV (2004) Mutation accumulation and the effect of copia insertions in Drosophila melanogaster. Genet Res 83:7–18. doi:10.1017/S0016672303006505
Houle D, Hoffmaster D, Assimacopolous S, Charlesworth B (1992) The genomic mutation rate for fitness in Drosophila. Nature 359:58–60. doi:10.1038/359058a0
Houle D, Morikawa B, Lynch M (1996) Comparing mutational variabilities. Genetics 143:1467–1483
Joseph SB, Hall DW (2004) Spontaneous mutations in diploid Saccharomyces cerevisiae: more beneficial than expected. Genetics 168:1817–1825. doi:10.1534/genetics.104.033761
Keightley PD (1994) The distribution of mutation effects on viability in Drosophila melanogaster. Genetics 138:1315–1322
Keightley PD (1998) Inference of genome wide mutation rates and distributions of mutation effects for fitness traits: a simulation study. Genetics 150:1283–1293
Keightley PD (2004a) Mutational variation and long-term selection response. Plant Breed Rev 24(part 1):227–247
Keightley PD (2004b) Comparing analysis methods for mutation-accumulation data. Genetics 167:551–553. doi:10.1534/genetics.167.1.551
Keightley PD, Caballero A (1997) Genomic mutation rates for lifetime reproductive output and lifespan in Caenorhabditis elegans. Proc Natl Acad Sci USA 94:3823–3827. doi:10.1073/pnas.94.8.3823
Keightley PD, Ohnishi O (1998) EMS-induced polygenic mutation rates for nine quantitative characters in Drosophila melanogaster. Genetics 148:753–766
Keightley PD, Bataillon TA (2000) Multi-generation maximum likelihood analysis applied to mutation accumulation experiments in Caenorhabditis elegans. Genetics 154:1193–1201
Keightley PD, Lynch M (2003) Towards a realistic model of mutations affecting fitness. Evolution Int J Org Evolution 57:683–685
Keightley PD, Eyre-Walker A (2007) Joint inference of the distribution of fitness effects of deleterious mutations and population demography based on nucleotide polymorphism frequencies. Genetics 177:2251–2261
Kimura M (1983). The neutral theory of molecular evolution. Cambridge University Press, Cambridge
Lande R (1994) Risk of population extinction from fixation of new deleterious mutations. Evolution 48:1460–1469. doi:10.2307/2410240
Livingston RJ, von Niederhausern A, Jegga AG, Crawford DC, Carlson CS, Rieder MJ et al (2004) Pattern of sequence variation across 213 environmental response genes. Genome Res 14:1821–1831. doi:10.1101/gr.2730004
Loewe L, Charlesworth B, Bartolomé C, Nöel V (2006) Estimating selection on non-synonymous mutations. Genetics 172:1079–1092. doi:10.1534/genetics.105.047217
López MA, López-Fanjul C (1993) Spontaneous mutation for a quantitative trait in Drosophila melanogaster I. Response to artificial selection. Genet Res 61:107–116
Lyman RF, Lawrence F, Nuzhdin SV, Mackay TFC (1996) Effects of single P-element insertions on bristle number and viability in Drosophila melanogaster. Genetics 143:277–292
Lynch M (1988) The rate of polygenic mutation. Genet Res 51:137–148
Lynch M, Hill WG (1986) Phenotypic evolution by neutral mutation. Evolution 40:915–935. doi:10.2307/2408753
Lynch M, Walsh B (1998) Genetics and analysis of quantitative traits. Sinauer, Sunderland, MA, USA
Lynch M, Conery J, Burger R (1995) Mutation accumulation and the extinction of small populations. Am Nat 146:489–518. doi:10.1086/285812
Lynch M, Blanchard J, Houle D, Kibota T, Schultz S, Vassilieva L et al (1999) Perspective: spontaneous deleterious mutation. Evolution Int J Org Evolution 53:645–663. doi:10.2307/2640707
Mackay TFC (1988) Transposable element-induced quantitative genetic variation in Drosophila. In: Weir BS, Eisen EJ, Goodman MM, Namkoong G (eds) Proceedings of the second international conference on quantitative genetics. Sinauer, Sunderland, Massachusetts
Mukai T (1964) The genetic structure of natural populations of Drosophila melanogaster I. Spontaneous mutation rate of polygenes controlling viability. Genetics 50:1–19
Mukai T, Chigusa SI, Mettler LE, Crow JF (1972) Mutation rate and dominance of genes affecting viability in Drosophila melanogaster. Genetics 72:333–355
Nielsen R, Yang Z (2003) Estimating the distribution of selection coefficients from phylogenetic data with applications to mitochondrial and viral DNA. Mol Biol Evol 20:1231–1239. doi:10.1093/molbev/msg147
Ohnishi O (1977) Spontaneous and ethyl methanesulfonate-induced mutations controlling viability in Drosophila melanogaster II. Homozygous effect of polygenic mutations. Genetics 87:529–545
Otto SP, Lenormand T (2002) Resolving the paradox of sex and recombination. Nat Rev Genet 3:252–261. doi:10.1038/nrg761
Piganeau GV, Eyre-Walker A (2003) Estimating the distribution of fitness effects from DNA sequence data: implications for the molecular clock. Proc Natl Acad Sci USA 100:10335–10340. doi:10.1073/pnas.1833064100
Robertson A (1967) The nature of quantitative genetic variation. In: Brink RB (ed) Heritage from Mendel. University of Wisconsin Press, Madison, Milwaukee and London, pp 265–280
Sawyer SA, Kulathinal RJ, Bustamante CD, Hartl DL (2003) Bayesian analysis suggests that most amino acid replacements in Drosophila are driven by positive selection. J Mol Evol 57:S154–S164. doi:10.1007/s00239-003-0022-3
Schoen DJ (2005) Deleterious mutation in related species of the plant genus Amsinckia with contrasting mating systems. Evolution 59:2370–2377
Shapiro JA, Huang W, Zhang C, Hubisz MJ, Lu J, Turissini DA et al (2007) Adaptive genic evolution in the Drosophila genomes. Proc Natl Acad Sci USA 104:2271–2276. doi:10.1073/pnas.0610385104
Shaw RG, Chang SM (2006) Gene action of new mutations in Arabidopsis thaliana. Genetics 172:1855–1865. doi:10.1534/genetics.105.050971
Shaw RG, Byers DL, Darmo E (2000) Spontaneous mutational effects on reproductive traits of Arabidopsis thaliana. Genetics 155:369–378
Shaw FH, Geyer CJ, Shaw RG (2002) A comprehensive model of mutations affecting fitness and inferences for Arabidopsis thaliana. Evolution Int J Org Evolution 56:453–463
Shaw RG, Shaw FH, Geyer C (2003) What fraction of mutations reduces fitness? A reply to Keightley and Lynch. Evolution 57:686–689
Smith NGC, Eyre-Walker A (2002) Adaptive protein evolution in Drosophila. Nature 415:1022–1024. doi:10.1038/4151022a
Vassilieva LL, Lynch M (1999) The rate of spontaneous mutation for life-history traits in Caenorhabditis elegans. Genetics 151:119–129
Vassilieva LL, Hook AM, Lynch M (2000) The fitness effects of spontaneous mutations in Caenorhabditis elegans. Evolution 54:1234–1246
Webb CT, Shabalina SA, Ogurtsov AY, Kondrashov AS (2002) Analysis of similarity within 142 pairs of orthologous intergenic regions of Caenorhabditis elegans and Caenorhabditis briggsae. Nucleic Acids Res 30:1233–1239. doi:10.1093/nar/30.5.1233
Zhang XS, Hill WG (2005) Genetic variability under mutation selection balance. Trends Ecol Evol 20:468–470. doi:10.1016/j.tree.2005.06.010
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We thank Penny Haddrill, Bill Hill and Mark Kirkpatrick for helpful comments.
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Keightley, P.D., Halligan, D.L. Analysis and implications of mutational variation. Genetica 136, 359–369 (2009). https://doi.org/10.1007/s10709-008-9304-4
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DOI: https://doi.org/10.1007/s10709-008-9304-4