Selection against hypermutability in Escherichia coli during long term evolution

Tröbner, Wolfgang; Piechocki, Rudolf

doi:10.1007/bf00328720

Cited by 80 publications

(58 citation statements)

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“…Many studies have documented the evolution of higher mutation rates as microbial populations adapt to changed environments (6,(8)(9)(10)(11)(12)35). However, despite long-standing theoretical interest (23)(24)(25), the complementary prediction-that populations should evolve lower rates once they are adapted to their environments-has received only limited and indirect support (7,20,(35)(36)(37)(38). Some of the limitations of earlier studies include reliance on comparative data (36), lack of information on the genetic basis for mutation rate changes (37,38), lack of quantification of effects on rates of sequence evolution (20,37,38), and the use of strains not well adapted to their environment (7,37,38).…”

Section: −7mentioning

confidence: 99%

“…However, despite long-standing theoretical interest (23)(24)(25), the complementary prediction-that populations should evolve lower rates once they are adapted to their environments-has received only limited and indirect support (7,20,(35)(36)(37)(38). Some of the limitations of earlier studies include reliance on comparative data (36), lack of information on the genetic basis for mutation rate changes (37,38), lack of quantification of effects on rates of sequence evolution (20,37,38), and the use of strains not well adapted to their environment (7,37,38). Moreover, reductions in mutation rates were observed surprisingly early in some studies (7,37), and even in nonmutator backgrounds (38), and hence, these results could be seen as counterexamples to the prediction that increased mutation rates should evolve during adaptation to changed conditions, rather than as support for the hypothesis that rates decline when populations become well adapted to their environments.…”

Section: −7mentioning

confidence: 99%

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Mutation rate dynamics in a bacterial population reflect tension between adaptation and genetic load

Wielgoss

Barrick

Tenaillon

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

253

302

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Mutations are the ultimate source of heritable variation for evolution. Understanding how mutation rates themselves evolve is thus essential for quantitatively understanding many evolutionary processes. According to theory, mutation rates should be minimized for well-adapted populations living in stable environments, whereas hypermutators may evolve if conditions change. However, the long-term fate of hypermutators is unknown. Using a phylogenomic approach, we found that an adapting Escherichia coli population that first evolved a mutT hypermutator phenotype was later invaded by two independent lineages with mutY mutations that reduced genome-wide mutation rates. Applying neutral theory to synonymous substitutions, we dated the emergence of these mutations and inferred that the mutT mutation increased the point-mutation rate by ∼150-fold, whereas the mutY mutations reduced the rate by ∼40-60%, with a corresponding decrease in the genetic load. Thus, the long-term fate of the hypermutators was governed by the selective advantage arising from a reduced mutation rate as the potential for further adaptation declined. experimental evolution | genomics | mutators | phylogenomics M utations are the ultimate source of heritable variation for evolution. Therefore, understanding how selection can change mutation rates is crucial for quantitatively describing evolutionary processes (1). More mutations are deleterious than beneficial (2), and organisms from bacteria to eukaryotes encode proofreading and repair enzymes that reduce mutation rates (3). If selection for beneficial mutations is weak relative to selection against deleterious mutations, then the rate of adaptation in asexual populations is maximized at some intermediate mutation rate (4). However, when populations encounter new environments, selection for beneficial mutations can be strong (5), and much higher mutation rates may evolve. Indeed, surveys of laboratory populations of microbes (6-10), clinical isolates of bacterial pathogens (11,12), and some types of eukaryotic tumors (13) have revealed a surprisingly high proportion of lineages that have evolved genetic defects in repair pathways. These hypermutators often have 10-to 100-fold increased mutation rates, and such elevated mutation rates can accelerate the progression of chronic diseases and the evolution of resistance to therapeutic agents.Hypermutable mutants can become established in asexual populations while they adapt to changed environments owing to their higher per capita probability of discovering rare beneficial mutations compared with nonmutators (14-18). Although hypermutable genotypes should produce beneficial mutations at a higher rate than their less mutable counterparts, they do not necessarily increase the rate of adaptation to a corresponding, or even measurable, degree. In large asexual populations, the waiting time for new beneficial mutations to occur may be short relative to the time required for a mutant to increase from one individual to fixation in the population, assuming the be...

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Section: −7mentioning

confidence: 99%

Section: −7mentioning

confidence: 99%

Mutation rate dynamics in a bacterial population reflect tension between adaptation and genetic load

Wielgoss

Barrick

Tenaillon

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

253

302

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“…Antimutators readily emerge from yeast harboring defects in either Pol e or Pol d proofreading (Figure 3) (Herr et al 2011a). Suppressors of diverse mutator phenotypes (proofreading, MMR, and DNA damage repair) also frequently arise in E. coli (Tröbner and Piechocki 1984;Schaaper and Cornacchio 1992;Fijalkowska et al 1993;Fijalkowska and Schaaper 1995;Schaaper 1996;Giraud et al 2001b;NotleyMcRobb et al 2002). Thus, it appears that mutator phenotypes in general are prone to suppression.…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

Emergence of DNA Polymerase ε Antimutators That Escape Error-Induced Extinction in Yeast

2013

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DNA polymerases (Pols) e and d perform the bulk of yeast leading-and lagging-strand DNA synthesis. Both Pols possess intrinsic proofreading exonucleases that edit errors during polymerization. Rare errors that elude proofreading are extended into duplex DNA and excised by the mismatch repair (MMR) system. Strains that lack Pol proofreading or MMR exhibit a 10-to 100-fold increase in spontaneous mutation rate (mutator phenotype), and inactivation of both Pol d proofreading (pol3-01) and MMR is lethal due to replication error-induced extinction (EEX). It is unclear whether a similar synthetic lethal relationship exists between defects in Pol e proofreading (pol2-4) and MMR. Using a plasmid-shuffling strategy in haploid Saccharomyces cerevisiae, we observed synthetic lethality of pol2-4 with alleles that completely abrogate MMR (msh2D, mlh1D, msh3D msh6D, or pms1D mlh3D) but not with partial MMR loss (msh3D, msh6D, pms1D, or mlh3D), indicating that high levels of unrepaired Pol e errors drive extinction. However, variants that escape this error-induced extinction (eex mutants) frequently emerged. Five percent of pol2-4 msh2D eex mutants encoded second-site changes in Pol e that reduced the pol2-4 mutator phenotype between 3-and 23-fold. The remaining eex alleles were extragenic to pol2-4. The locations of antimutator amino-acid changes in Pol e and their effects on mutation spectra suggest multiple mechanisms of mutator suppression. Our data indicate that unrepaired leading-and lagging-strand polymerase errors drive extinction within a few cell divisions and suggest that there are polymerase-specific pathways of mutator suppression. The prevalence of suppressors extragenic to the Pol e gene suggests that factors in addition to proofreading and MMR influence leading-strand DNA replication fidelity.O RGANISMS must accurately duplicate their genomes to avoid loss of long-term fitness. Consequently, cells employ high-fidelity DNA polymerases (Pols) equipped with proofreading exonucleases to replicate their DNA (reviewed in McCulloch and Kunkel 2008;Reha-Krantz 2010). Mismatch repair (MMR) further ensures the integrity of genetic information by targeting mismatches for excision from newly replicated DNA (reviewed in Kolodner and Marsischky 1999;Iyer et al. 2006;Hsieh and Yamane 2008). These polymerase error-correcting mechanisms, together with DNA damage repair (Friedberg et al. 2006), maintain the genome with less than one mutation per 10 9 nucleotides per cell division (Drake et al. 1998). Defects in proofreading or MMR result in mutator phenotypes characterized by increased rates of spontaneous mutation (Kolodner and Marsischky 1999;Iyer et al. 2006;Hsieh and Yamane 2008;McCulloch and Kunkel 2008; RehaKrantz 2010).Mutator phenotypes can be an important source of genetic diversity, which facilitates adaptation to environmental change. In bacterial and yeast populations, unstable environments favor mutator strains that readily acquire adaptive mutations (Chao and Cox 1983;Mao et al. 1997;Sniegowski et al. 1997...

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“…However, once the population has reached a high fitness level, high mutation rates are detrimental because most mutations will now be deleterious, and in such a situation, the mutation rate is expected to decrease (Liberman and Feldman 1986). Indeed, in some experiments (Tröbner and Piechocki 1984; Notley‐McRobb et al. 2002; McDonald et al.…”

Section: Introductionmentioning

confidence: 99%

Fixation probability of rare nonmutator and evolution of mutation rates

James

Jain

2016

Ecology and Evolution

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Although mutations drive the evolutionary process, the rates at which the mutations occur are themselves subject to evolutionary forces. Our purpose here is to understand the role of selection and random genetic drift in the evolution of mutation rates, and we address this question in asexual populations at mutation‐selection equilibrium neglecting selective sweeps. Using a multitype branching process, we calculate the fixation probability of a rare nonmutator in a large asexual population of mutators and find that a nonmutator is more likely to fix when the deleterious mutation rate of the mutator population is high. Compensatory mutations in the mutator population are found to decrease the fixation probability of a nonmutator when the selection coefficient is large. But, surprisingly, the fixation probability changes nonmonotonically with increasing compensatory mutation rate when the selection is mild. Using these results for the fixation probability and a drift‐barrier argument, we find a novel relationship between the mutation rates and the population size. We also discuss the time to fix the nonmutator in an adapted population of asexual mutators, and compare our results with experiments.

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Selection against hypermutability in Escherichia coli during long term evolution

Cited by 80 publications

References 8 publications

Mutation rate dynamics in a bacterial population reflect tension between adaptation and genetic load

Mutation rate dynamics in a bacterial population reflect tension between adaptation and genetic load

Emergence of DNA Polymerase ε Antimutators That Escape Error-Induced Extinction in Yeast

Fixation probability of rare nonmutator and evolution of mutation rates

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