Abstract
All adaptive alleles in existence today began as mutations, but a common view in ecology, evolution, and genetics is that non-neutral mutations are much more likely to be deleterious than beneficial and will be removed by purifying selection. By dramatically limiting the effectiveness of selection in experimental mutation accumulation lines, multiple studies have shown that new mutations cause a detectable reduction in mean fitness. However, a number of exceptions to this pattern have now been observed in multiple species, including in highly replicated, intensive analyses. We briefly review these cases and discuss possible explanations for the inconsistent fitness outcomes of mutation accumulation experiments. We propose that variation in the outcomes of these studies is of interest and understanding the underlying causes of these diverse results will help shed light on fundamental questions about the evolutionary role of mutations.
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References
Bataillon T, Bailey SF (2014) Effects of new mutations on fitness: insights from models and data. Ann N Y Acad Sci 1320:76–92
Belfield EJ, Ding ZJ, Jamieson FJ, Visscher AM, Zheng SJ, Mithani A, Harberd NP (2018) DNA mismatch repair preferentially protects genes from mutation. Genome Res 28(1):66–74
Böndel KB, Kraemer SA, Samuels T, McClean D, Lachapelle J, Ness RW, … Keightley PD(2019) Inferring the distribution of fitness effects of spontaneous mutations in Chlamydomonas reinhardtii.PLoS biology, 17(6), e3000192
Böndel KB, Samuels T, Craig RJ, Ness RW, Colegrave N, Keightley PD (2021) The distribution of fitness effects of spontaneous mutations in Chlamydomonas reinhardtii inferred using frequency changes under experimental evolution. bioRxiv. Chen, X. & Zhang, J. (2013) No gene-specific optimization of mutation rate in Escherichia coli. Mol. Biol. Evol. 30(7) 1559–62
Cruzan MB, Streisfeld MA, Schwoch JA(2022) Fitness effects of somatic mutationsaccumulating during vegetative growth. BioRxiv, 392175. https://doi.org/10.1007/s10682-022-10188-3
Dillon MM, Cooper VS (2016) The fitness effects of spontaneous mutations nearly unseen by selection in a bacterium with multiple chromosomes. Genetics 204(3):1225–1238
Dickinson WJ (2008) Synergistic fitness interactions and a high frequency of beneficial
changes among mutations accumulated under relaxed selection in Saccharomyces
cerevisiae.Genetics, 178(3),1571–1578
Estes S, Phillips PC, Denver DR, Thomas WK, Lynch M (2004) Mutation accumulation in populations of varying size: the distribution of mutational effects for fitness correlates in Caenorhabditis elegans. Genetics 166(3):1269–1279
Eyre-Walker A, Keightley PD (2007) The distribution of fitness effects of new mutations. Nat Rev Genet 8(8):610–618
Fisher KJ, Buskirk SW, Vignogna RC, Marad DA, Lang GI(2018) Adaptive genome duplication affects patterns of molecular evolution in Saccharomyces cerevisiae.PLoS genetics, 14(5), e1007396
Frankham R, Loebel DA (1992) Modeling problems in conservation genetics using captive Drosophila populations: rapid genetic adaptation to captivity. Zoo Biol 11(5):333–342
Frigola J, Sabarinathan R, Mularoni L, Muinos F, Gonzalez-Perez A, Lopez-Bigas N (2017) Reduced mutation rate in exons due to differential mismatch repair. Nat Genet 49:1684–1692
Fry JD (2004) On the rate and linearity of viability declines in Drosophila mutation- accumulation experiments: genomic mutation rates and synergistic epistasis revisited. Genetics 166(2):797–806
Fry JD, Keightley PD, Heinsohn SL, Nuzhdin SV (1999) New estimates of the rates and effects of mildly deleterious mutation in Drosophila melanogaster. Proceedings of the National Academy of Sciences, 96(2), 574–579
Funchain P, Yeung A, Lee Stewart J, Lin R, Slupska MM, Miller JH (2000) 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(3):959–970
García-Dorado A (1997) The rate and effects distribution of viability mutation in
Gerstein AC, Otto SP(2011) Cryptic fitness advantage: diploids invade haploid populations despite lacking any apparent advantage as measured by standard fitness assays. PloS one, 6(12), e26599
Gerstein AC, Sharp NP (2021) The population genetics of ploidy change in unicellular fungi. FEMS microbiology reviews
Hall DW, Joseph SB (2010) A high frequency of beneficial mutations across multiple fitness components in Saccharomyces cerevisiae. Genetics 185(4):1397–1409
Hall DW, Mahmoudizad R, Hurd AW, Joseph SB (2008) Spontaneous mutations in diploid Saccharomyces cerevisiae : another thousand cell generations. Genetics research, 90(3),229–241
Halligan DL, Keightley PD (2009) Spontaneous mutation accumulation studies in evolutionary genetics. Annu Rev Ecol Evol Syst 40:151–172
Heilbron K, Toll-Riera M, Kojadinovic M, MacLean RC (2014) Fitness is strongly influenced by rare mutations of large effect in a microbial mutation accumulation experiment. Genetics 197(3):981–990
Huang Y, Gu L, Li G-M (2018) H3K36me3-mediated mismatch repair preferentially protects actively transcribed genes from mutation. J. Biol. Chem. 293(20): 7811–7823. Johnson, M. S., Gopalakrishnan, S., Goyal, J., Dillingham, M. E., Bakerlee, C. W., Humphrey
Joseph SB, Hall DW (2004) Spontaneous mutations in diploid Saccharomyces cerevisiae: more beneficial than expected. Genetics 168(4):1817–1825
Katju V, Packard LB, Bu L, Keightley PD, Bergthorsson U (2014) Fitness decline in spontaneous mutation accumulation lines of Caenorhabditis elegans with varyin effective population sizes. Evolution 69(1):104–116
Katju V, Packard LB, Keightley PD (2018) Fitness decline under osmotic stress in Caenorhabditis elegans populations subjected to spontaneous mutation accumulation at varying population sizes. Evolution 72(4):1000–1008
Keightley PD (1994) The distribution of mutation effects on viability in Drosophila melanogaster. Genetics 138(4):1315–1322
Keightley PD, Caballero A (1997) Genomic mutation rates for lifetime reproductive output and lifespan in Caenorhabditis elegans. Proceedings of the National Academy of Sciences, 94(8), 3823–3827
Keightley PD, Lynch M (2003) Toward a realistic model of mutations affecting fitness. Evolution 57(3):683–685
Kibota TT, Lynch M (1996) Estimate of the genomic mutation rate deleterious to overall fitness in E. coll. Nature 381(6584):694–696
Klekowski EJ Jr, Kazarinova-Fukshansky N (1984) Shoot apical meristems and mutations: fixation of selectively neutral cell genotypes and selective loss of disadvantageous cell genotypes. Bioscience 34(3):180–181
Knöppel A, Knopp M, Albrecht LM, Lundin E, Lustig U, Näsvall J, Andersson DI (2018) Genetic adaptation to growth under laboratory conditions in Escherichia coli and Salmonella enterica. Front Microbiol 9:756
Kobel S, Valero A, Latt J, Renaud P, Lutolf M (2010) Optimization of microfluidic single cell trapping for long-term on-chip culture. Lab Chip 10(7):857–863
Kraemer SA, Morgan AD, Ness RW, Keightley PD, Colegrave N (2016) Fitness effects of new mutations in Chlamydomonas reinhardtii across two stress gradients. J Evol Biol 29(3):583–593
Lande R (1994) Risk of population extinction from fixation of new deleterious mutations. Evolution 48(5):1460–1469
Lenski RE, Rose MR, Simpson SC, Tadler SC (1991) Long-term experimental evolution in Escherichia coli. I. Adaptation and divergence during 2,000 generations. Am Nat 138(6):1315–1341
Liu H, Zhang J (2019) Yeast spontaneous mutation rate and spectrum vary with environment. Curr Biol 29(10):1584–1591
Loewe L, Textor V, Scherer S (2003) High deleterious genomic mutation rate in stationary phase of Escherichia coli. Science 302(5650):1558–1560
Luijckx P, Ho EK, Stanić A, Agrawal AF (2018) Mutation accumulation in populations of varying size: large effect mutations cause most mutational decline in the rotifer Brachionus calyciflorus under UV-C radiation. J Evol Biol 31(6):924–932
Lynch M, Latta L, Hicks J, Giorgianni M (1998) Mutation, selection, and the maintenance of life-history variation in a natural population. Evolution 52(3):727–733
Lynch M, Walsh B, Saadé JL, Le FE, Bureau QH, Schoen DJ (1998) (2005). Genomic mutation in lines of Arabidopsis thaliana exposed to ultraviolet-B radiation. Genetics, 171(2), 715–723
Mahilkar A, Kemkar S, Saini S (2021) Selection in a growing bacterial/yeast colony biases results of mutation accumulation experiments. bioRxiv. Martin, G., & Lenormand, T. (2006). The fitness effect of mutations across environments: a survey in light of fitness landscape models. Evolution, 60(12), 2413–2427
Martin G, Lenormand T (2008) The distribution of beneficial and fixed mutation fitness effects close to an optimum. Genetics 179(2):907–916
Martin G, Lenormand T (2015) The fitness effect of mutations across environments: Fisher’s geometrical model with multiple optima. Evolution 69(6):1433–1447
Martincorena I, Seshasayee ASN, Luscombe NM (2012) Evidence of non-random mutation rates suggests an evolutionary risk management strategy. Nature 485, 95–98. Monroe, J., Srikant, T., Carbonell-Bejerano, P., Becker, C., Lensink, M., Exposito-Alonso, M., … Weigel, D. (2022). Mutation bias reflects natural selection in Arabidopsis thaliana. Nature, 1–5
Mukai T, Mustonen V, Lassig M (1964) The genetic structure of natural populations of Drosophila melanogaster. I. Spontaneous mutation rate of polygenes controlling viability. Genetics, 50(1), 1. Mulcahy, D. L., Sari-Gorla, M., & Mulcahy, G. B. (1996). Pollen selection—past, present and future. Sexual Plant Reproduction, 9(6), 353–356. Mustonen V, Lassig M (2009) From fitness landscapes to seascapes: non-equilibrium dynamics of selection and adaptation. Trends Genet. 25(3), 111–119
Orr HA (2006) The distribution of fitness effects among beneficial mutations in Fisher’s geometric model of adaptation. J Theor Biol 238(2):279–285
Otto SP, Hastings IM (1998) Mutation and selection within the individual. Genetica 102:507–524
Otto SP, Orive ME (1995) Evolutionary consequences of mutation and selection within an individual. Genetics 141(3):1173–1187
Otto SP, Scott MF, Immler S (2015) Evolution of haploid selection in predominantly diploid organisms. Proceedings of the National Academy of Sciences, 112(52), 15952- 15957
Pletcher SD, Houle D, Curtsinger JW (1998) Age-specific properties of spontaneous mutations affecting mortality in Drosophila melanogaster. Genetics 148(1):287–303
Roles AJ, Conner JK (2008) Fitness effects of mutation accumulation in a natural outbred population of wild radish (Raphanus raphanistrum): comparison of field and greenhouse environments. Evolution: Int J Org Evol 62(5):1066–1075
Roles AJ, Rutter MT, Dworkin I, Fenster CB, Conner JK (2016) Field measurements of genotype by environment interaction for fitness caused by spontaneous mutations in Arabidopsis thaliana. Evolution 70(5):1039–1050
Rutter MT, Shaw FH, Fenster CB (2010) Spontaneous mutation parameters for Arabidopsis thaliana measured in the wild. Evolution: Int J Org Evol 64(6):1825–1835
Rutter MT, Roles A, Conner JK, Shaw RG, Shaw FH, Schneeberger K, Fenster CB (2012) Fitness of Arabidopsis thaliana mutation accumulation lines whose spontaneous mutations are known. Evolution: Int J Org Evol 66(7):2335–2339
Rutter MT, Roles AJ, Fenster CB (2018) Quantifying natural seasonal variation in
mutation parameters with mutation accumulation lines.Ecology and evolution, 8(11),5575–5585
Sandell L, Sharp NP(2021) Submitted. Fitness effects of mutations: An assessment of PROVEAN predictions using mutation accumulation data.
Schaack, S., Allen, D. E., Latta IV, L. C., Morgan, K. K., & Lynch, M. (2013). The effect of spontaneous mutations on competitive ability.Journal of evolutionary biology, 26(2),451–456
Schoen DJ, Schultz ST (2019) Somatic mutation and evolution in plants. Annu Rev Ecol Evol Syst 50:49–73
Schultz ST, Lynch M (1997) Mutation and extinction: the role of variable mutational effects, synergistic epistasis, beneficial mutations, and degree of outcrossing. Evolution 51(5):1363–1371
Schultz ST, Lynch M, Willis JH(1999) Spontaneous deleterious mutation in Arabidopsis thaliana. Proceedings of the National Academy of Sciences, 96(20), 11393–11398
Sgrò CM, Partridge L (2000) Evolutionary responses of the life history of wild-caught Drosophila melanogaster to two standard methods of laboratory culture. Am Nat 156(4):341–353
Sgrò CM, Partridge L (2001) Laboratory adaptation of life history in Drosophila. Am Nat 158(6):657–658
Sharp NP, Agrawal AF(2016) Low genetic quality alters key dimensions of the mutational spectrum.PLoS biology, 14(3), e1002419
Sharp NP, Agrawal AF(2018) An experimental test of the mutation-selection balance model for the maintenance of genetic variance in fitness components. Proceedings of the Royal Society B, 285(1890), 20181864
Sharp NP, Sandell L, James CG, Otto SP(2018) The genome-wide rate and spectrum of spontaneous mutations differ between haploid and diploid yeast. Proceedings of the National Academy of Sciences, 115(22), E5046-E5055
Shaw RG, Byers DL, Darmo E (2000) Spontaneous mutational effects on reproductive traits of Arabidopsis thaliana. Genetics 155(1):369–378
Shaw RG, Chang SM (2006) Gene action of new mutations in Arabidopsis thaliana. Genetics 172(3):1855–1865
Shaw FH, Geyer CJ, Shaw RG (2002) A comprehensive model of mutations affecting fitness and inferences for Arabidopsis thaliana. Evolution 56(3):453–463
Shaw RG, Shaw FH, Geyer C (2003) What fraction of mutations reduces fitness? A reply to Keightley and Lynch. Evolution 57(3):686–689
Silander OK, Tenaillon O, Chao L(2007) Understanding the evolutionary fate of finite populations: the dynamics of mutational effects.PLoS biology, 5(4), e94
Stearns FW, Fenster CB (2016) Fisher’s geometric model predicts the effects of random mutations when tested in the wild. Evolution 70(2):495–501
Supek F, Lehner B (2017) Clustered Mutation Signatures Reveal that Error-Prone DNA Repair Targets Mutations to Active Genes. Cell 170(3):534–547
Tenaillon O (2014) The utility of Fisher’s geometric model in evolutionary genetics. Annu Rev Ecol Evol Syst 45:179–201
Trindade S, Perfeito L, Gordo I (2010) Rate and effects of spontaneous mutations that affect fitness in mutator Escherichia coli. Philosophical Trans Royal Soc B: Biol Sci 365(1544):1177–1186
Vassilieva LL, Lynch M (1999) The rate of spontaneous mutation for life-history traits in Caenorhabditis elegans. Genetics 151(1):119–129
Vassilieva LL, Hook AM, Lynch M (2000) The fitness effects of spontaneous mutations in Caenorhabditis elegans. Evolution 54(4):1234–1246
Venkataram S, Dunn B, Li Y, Agarwala A, Chang J, Ebel ER, Petrov DA (2016) Development of a comprehensive genotype-to-fitness map of adaptation-driving mutations in yeast. Cell 166(6):1585–1596
Voordeckers K, Kominek J, Das A, Espinosa-Cantu A, De Maeyer D, Arslan A, … Verstrepen KJ(2015) Adaptation to high ethanol reveals complex evolutionary pathways.PLoS genetics, 11(11), e1005635
Wang AD, Sharp NP, Agrawal AF (2013) Sensitivity of the distribution of mutational fitness effects to environment, genetic background, and adaptedness: a case study with Drosophila. Evolution 68(3):840–853
Wahl LM, Agashe D(2022) Selection bias in mutation accumulation. Evolution. Wei, W., Tuna, S., Keogh, M. J., Smith, K. R., Aitman, T. J., Beales, P. L., … Chinnery, P. F. (2019). Germline selection shapes human mitochondrial DNA diversity. Science, 364(6442), eaau6520
Weng ML, Ågren J, Imbert E, Nottebrock H, Rutter MT, Fenster CB (2021) Fitness effects of mutation in natural populations of Arabidopsis thaliana reveal a complex influence of local adaptation. Evolution 75(2):330–348
Weng ML, Becker C, Hildebrandt J, Neumann M, Rutter MT, Shaw RG, Fenster CB (2019) Fine-grained analysis of spontaneous mutation spectrum and frequency in Arabidopsis thaliana. Genetics 211(2):703–714
Wloch DM, Szafraniec K, Borts RH, Korona R (2001) Direct estimate of the mutation rate and the distribution of fitness effects in the yeast Saccharomyces cerevisiae. Genetics 159(2):441–452
Zeyl C, DeVisser JAG (2001) Estimates of the rate and distribution of fitness effects of spontaneous mutation in Saccharomyces cerevisiae. Genetics 157(1):53–61
Zhu YO, Siegal ML, Hall DW, Petrov DA(2014) Precise estimates of mutation rate and spectrum in yeast. Proceedings of the National Academy of Sciences, 111(22), E2310-E2318
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This work was supported by NIH T32 Predoctoral Training Program in Genetics to KB.
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Bao, K., Melde, R.H. & Sharp, N.P. Are mutations usually deleterious? A perspective on the fitness effects of mutation accumulation. Evol Ecol 36, 753–766 (2022). https://doi.org/10.1007/s10682-022-10187-4
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DOI: https://doi.org/10.1007/s10682-022-10187-4