Competition between high- and higher-mutating strains of
            Escherichia coli

Experimental studies have shown that a mutator allele can readily hitchhike to fixation with beneficial mutations in an asexual population having a low, wild-type mutation rate. Here, we show that a genotype bearing two mutator alleles can supplant a population already fixed for one mutator allele. Our results provide experimental support for recent theory predicting that mutator alleles will tend to accumulate in asexual populations by hitchhiking with beneficial mutations, causing an ever-higher genomic mutation rate.

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Fitness Evolution and the Rise of Mutator Alleles in Experimental Escherichia coli Populations

Genetics ◽

10.1093/genetics/162.2.557 ◽

2002 ◽

Vol 162 (2) ◽

pp. 557-566 ◽

Cited By ~ 5

Author(s):

Aaron C Shaver ◽

Peter G Dombrowski ◽

Joseph Y Sweeney ◽

Tania Treis ◽

Renata M Zappala ◽

...

Keyword(s):

Escherichia Coli ◽

Genetic Drift ◽

Mutation Rates ◽

Significant Gain ◽

Wild Type ◽

Clonal Interference ◽

Beneficial Mutations ◽

Mutator Allele ◽

Experimental Populations ◽

Rate Of Substitution

Abstract We studied the evolution of high mutation rates and the evolution of fitness in three experimental populations of Escherichia coli adapting to a glucose-limited environment. We identified the mutations responsible for the high mutation rates and show that their rate of substitution in all three populations was too rapid to be accounted for simply by genetic drift. In two of the populations, large gains in fitness relative to the ancestor occurred as the mutator alleles rose to fixation, strongly supporting the conclusion that mutator alleles fixed by hitchhiking with beneficial mutations at other loci. In one population, no significant gain in fitness relative to the ancestor occurred in the population as a whole while the mutator allele rose to fixation, but a substantial and significant gain in fitness occurred in the mutator subpopulation as the mutator neared fixation. The spread of the mutator allele from rarity to fixation took >1000 generations in each population. We show that simultaneous adaptive gains in both the mutator and wild-type subpopulations (clonal interference) retarded the mutator fixation in at least one of the populations. We found little evidence that the evolution of high mutation rates accelerated adaptation in these populations.

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The effect of known mutator alleles in a cluster of clinicalSaccharomyces cerevisiaestrains

10.1101/090498 ◽

2016 ◽

Cited By ~ 2

Author(s):

Daniel A. Skelly ◽

Paul M. Magwene ◽

Brianna Meeks ◽

Helen A. Murphy

Keyword(s):

Mutation Rate ◽

Evolutionary Theory ◽

Phylogenetic Analyses ◽

Mutation Rates ◽

Genetic Modifiers ◽

Beneficial Mutations ◽

Mutator Allele ◽

Genomic Mutation ◽

Asexual Populations ◽

The Relationship

AbstractNatural selection has the potential to act on all phenotypes, including genomic mutation rate. Classic evolutionary theory predicts that in asexual populations, mutator alleles, which cause high mutation rates, can fix due to linkage with beneficial mutations. This phenomenon has been demonstrated experimentally and may explain the frequency of mutators found in bacterial pathogens. In contrast, in sexual populations, recombination decouples mutator alleles from beneficial mutations, preventing mutator fixation. In the facultatively sexual yeastSaccharomyces cerevisiae, segregating alleles ofMLH1andPMS1have been shown to be incompatible, causing a high mutation rate when combined. These alleles had never been found together naturally, but were recently discovered in a cluster of clinical isolates. Here we report that the incompatible mutator allele combination only marginally elevates mutation rate in these clinical strains. Genomic and phylogenetic analyses provide no evidence of a historically elevated mutation rate. We conclude that the effect of the mutator alleles is dampened by background genetic modifiers. Thus, the relationship between mutation rate and microbial pathogenicity may be more complex than once thought. Our findings provide rare observational evidence that supports evolutionary theory suggesting that sexual organisms are unlikely to harbor alleles that increase their genomic mutation rate.

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Known mutator alleles do not markedly increase mutation rate in clinical Saccharomyces cerevisiae strains

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2016.2672 ◽

2017 ◽

Vol 284 (1852) ◽

pp. 20162672 ◽

Cited By ~ 6

Author(s):

Daniel A. Skelly ◽

Paul M. Magwene ◽

Brianna Meeks ◽

Helen A. Murphy

Keyword(s):

Saccharomyces Cerevisiae ◽

Mutation Rate ◽

Evolutionary Theory ◽

Phylogenetic Analyses ◽

Genetic Modifiers ◽

Beneficial Mutations ◽

Mutator Allele ◽

Genomic Mutation ◽

Asexual Populations ◽

The Relationship

Natural selection has the potential to act on all phenotypes, including genomic mutation rate. Classic evolutionary theory predicts that in asexual populations, mutator alleles, which cause high mutation rates, can fix due to linkage with beneficial mutations. This phenomenon has been demonstrated experimentally and may explain the frequency of mutators found in bacterial pathogens. By contrast, in sexual populations, recombination decouples mutator alleles from beneficial mutations, preventing mutator fixation. In the facultatively sexual yeast Saccharomyces cerevisiae , segregating alleles of MLH1 and PMS1 have been shown to be incompatible, causing a high mutation rate when combined. These alleles had never been found together naturally, but were recently discovered in a cluster of clinical isolates. Here we report that the incompatible mutator allele combination only marginally elevates mutation rate in these clinical strains. Genomic and phylogenetic analyses provide no evidence of a historically elevated mutation rate. We conclude that the effect of the mutator alleles is dampened by background genetic modifiers. Thus, the relationship between mutation rate and microbial pathogenicity may be more complex than once thought. Our findings provide rare observational evidence that supports evolutionary theory suggesting that sexual organisms are unlikely to harbour alleles that increase their genomic mutation rate.

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Escherichia coli with a Tunable Point Mutation Rate for Evolution Experiments

G3 Genes|Genome|Genetics ◽

10.1534/g3.120.401124 ◽

2020 ◽

Vol 10 (8) ◽

pp. 2671-2681 ◽

Cited By ~ 1

Author(s):

Nicholas A. Sherer ◽

Thomas E. Kuhlman

Keyword(s):

Escherichia Coli ◽

Point Mutation ◽

Mutation Rate ◽

Fitness Landscape ◽

Genetically Engineered ◽

Mutation Rates ◽

Nucleotide Polymorphisms ◽

Beneficial Mutations ◽

Beneficial Effects ◽

Evolution Experiment

The mutation rate and mutations’ effects on fitness are crucial to evolution. Mutation rates are under selection due to linkage between mutation rate modifiers and mutations’ effects on fitness. The linkage between a higher mutation rate and more beneficial mutations selects for higher mutation rates, while the linkage between a higher mutation rate and more deleterious mutations selects for lower mutation rates. The net direction of selection on mutations rates depends on the fitness landscape, and a great deal of work has elucidated the fitness landscapes of mutations. However, tests of the effect of varying a mutation rate on evolution in a single organism in a single environment have been difficult. This has been studied using strains of antimutators and mutators, but these strains may differ in additional ways and typically do not allow for continuous variation of the mutation rate. To help investigate the effects of the mutation rate on evolution, we have genetically engineered a strain of Escherichia coli with a point mutation rate that can be smoothly varied over two orders of magnitude. We did this by engineering a strain with inducible control of the mismatch repair proteins MutH and MutL. We used this strain in an approximately 350 generation evolution experiment with controlled variation of the mutation rate. We confirmed the construct and the mutation rate were stable over this time. Sequencing evolved strains revealed a higher number of single nucleotide polymorphisms at higher mutations rates, likely due to either the beneficial effects of these mutations or their linkage to beneficial mutations.

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Genetic background affects epistatic interactions between two beneficial mutations

Biology Letters ◽

10.1098/rsbl.2012.0328 ◽

2013 ◽

Vol 9 (1) ◽

pp. 20120328 ◽

Cited By ~ 29

Author(s):

Yinhua Wang ◽

Carolina Díaz Arenas ◽

Daniel M. Stoebel ◽

Tim F. Cooper

Keyword(s):

Escherichia Coli ◽

Genetic Background ◽

General Pattern ◽

Experimental Studies ◽

Natural Isolate ◽

Phenotypic Effect ◽

Fitness Effect ◽

Epistatic Interactions ◽

Beneficial Mutations ◽

E Coli

The phenotypic effect of mutations can depend on their genetic background, a phenomenon known as epistasis. Many experimental studies have found that epistasis is pervasive, and some indicate that it may follow a general pattern dependent on the fitness effect of the interacting mutations. These studies have, however, typically examined the effect of interactions between a small number of focal mutations in a single genetic background. Here, we extend this approach by considering how the interaction between two beneficial mutations that were isolated from a population of laboratory evolved Escherichia coli changes when they are added to divergent natural isolate strains of E. coli . We find that interactions between the focal mutations and the different genetic backgrounds are common. Moreover, the pair-wise interaction between the focal mutations also depended on their genetic background, being more negative in backgrounds with higher absolute fitness. Together, our results indicate the presence of interactions between focal mutations, but also caution that these interactions depend quantitatively on the wider genetic background.

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Tempo and mode of genome evolution in a 50,000-generation experiment

10.1101/036806 ◽

2016 ◽

Cited By ~ 5

Author(s):

Olivier Tenaillon ◽

Jeffrey E. Barrick ◽

Noah Ribeck ◽

Daniel E. Deatherage ◽

Jeffrey L. Blanchard ◽

...

Keyword(s):

Escherichia Coli ◽

Genome Evolution ◽

Mutation Rate ◽

Beneficial Mutations ◽

Insertions And Deletions ◽

Constant Rate ◽

Shifting Balance ◽

Balance Of Forces ◽

Neutral Mutations

Adaptation depends on the rates, effects, and interactions of many mutations. We analyzed 264 genomes from 12 Escherichia coli populations to characterize their dynamics over 50,000 generations. The trajectories for genome evolution in populations that retained the ancestral mutation rate fit a model where most fixed mutations are beneficial, the fraction of beneficial mutations declines as fitness rises, and neutral mutations accumulate at a constant rate. We also compared these populations to lines evolved under a mutation-accumulation regime that minimizes selection. Nonsynonymous mutations, intergenic mutations, insertions, and deletions are overrepresented in the long-term populations, supporting the inference that most fixed mutations are favored by selection. These results illuminate the shifting balance of forces that govern genome evolution in populations adapting to a new environment.

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Mutations that improve efficiency of a weak-link enzyme are rare compared to adaptive mutations elsewhere in the genome

eLife ◽

10.7554/elife.53535 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 3

Author(s):

Andrew B Morgenthaler ◽

Wallis R Kinney ◽

Christopher C Ebmeier ◽

Corinne M Walsh ◽

Daniel J Snyder ◽

...

Keyword(s):

Escherichia Coli ◽

Metabolic Pathway ◽

Weak Link ◽

Experimental Studies ◽

Wild Type ◽

Gene Encoding ◽

Evolutionary Trajectory ◽

Adaptive Mutations ◽

E Coli ◽

Essential Function

New enzymes often evolve by gene amplification and divergence. Previous experimental studies have followed the evolutionary trajectory of an amplified gene, but have not considered mutations elsewhere in the genome when fitness is limited by an evolving gene. We have evolved a strain of Escherichia coli in which a secondary promiscuous activity has been recruited to serve an essential function. The gene encoding the ‘weak-link’ enzyme amplified in all eight populations, but mutations improving the newly needed activity occurred in only one. Most adaptive mutations occurred elsewhere in the genome. Some mutations increase expression of the enzyme upstream of the weak-link enzyme, pushing material through the dysfunctional metabolic pathway. Others enhance production of a co-substrate for a downstream enzyme, thereby pulling material through the pathway. Most of these latter mutations are detrimental in wild-type E. coli, and thus would require reversion or compensation once a sufficient new activity has evolved.

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Spontaneously Arising mutL Mutators in Evolving Escherichia coli Populations Are the Result of Changes in Repeat Length

Journal of Bacteriology ◽

10.1128/jb.185.20.6076-6082.2003 ◽

2003 ◽

Vol 185 (20) ◽

pp. 6076-6082 ◽

Cited By ~ 35

Author(s):

Aaron C. Shaver ◽

Paul D. Sniegowski

Keyword(s):

Escherichia Coli ◽

Mismatch Repair ◽

Mutation Rate ◽

Mismatch Repair Gene ◽

Dna Repeats ◽

Wild Type ◽

Repair Gene ◽

Mutator Strains ◽

Experimental Populations

ABSTRACT Over the course of thousands of generations of growth in a glucose-limited environment, 3 of 12 experimental populations of Escherichia coli spontaneously and independently evolved greatly increased mutation rates. In two of the populations, the mutations responsible for this increased mutation rate lie in the same region of the mismatch repair gene mutL. In this region, a 6-bp repeat is present in three copies in the gene of the wild-type ancestor of the experimental populations but is present in four copies in one of the experimental populations and two copies in the other. These in-frame mutations either add or delete the amino acid sequence LA in the MutL protein. We determined that the replacement of the wild-type sequence with either of these mutations was sufficient to increase the mutation rate of the wild-type strain to a level comparable to that of the mutator strains. Complementation of strains bearing the mutator mutations with wild-type copies of either mutL or the mismatch repair gene uvrD rescued the wild-type mutation rate. The position of the mutator mutations—in the region of MutL known as the ATP lid—suggests a possible deficiency in MutL's ATPase activity as the cause of the mutator phenotype. The similarity of the two mutator mutations (despite the independent evolutionary histories of the populations that gave rise to them) leads to a discussion of the potential adaptive role of DNA repeats.

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Beneficial Mutations, Hitchhiking and the Evolution of Mutation Rates in Sexual Populations

Genetics ◽

10.1093/genetics/151.4.1621 ◽

1999 ◽

Vol 151 (4) ◽

pp. 1621-1631 ◽

Cited By ~ 6

Author(s):

Toby Johnson

Keyword(s):

Mutation Rate ◽

Indirect Selection ◽

Mutation Rates ◽

Deleterious Mutations ◽

Heritable Variation ◽

Asexual Population ◽

Beneficial Mutations ◽

Long Term Effect ◽

The Cost ◽

Substantial Change

Abstract Natural selection acts in three ways on heritable variation for mutation rates. A modifier allele that increases the mutation rate is (i) disfavored due to association with deleterious mutations, but is also favored due to (ii) association with beneficial mutations and (iii) the reduced costs of lower fidelity replication. When a unique beneficial mutation arises and sweeps to fixation, genetic hitchhiking may cause a substantial change in the frequency of a modifier of mutation rate. In previous studies of the evolution of mutation rates in sexual populations, this effect has been underestimated. This article models the long-term effect of a series of such hitchhiking events and determines the resulting strength of indirect selection on the modifier. This is compared to the indirect selection due to deleterious mutations, when both types of mutations are randomly scattered over a given genetic map. Relative to an asexual population, increased levels of recombination reduce the effects of beneficial mutations more rapidly than those of deleterious mutations. However, the role of beneficial mutations in determining the evolutionarily stable mutation rate may still be significant if the function describing the cost of high-fidelity replication has a shallow gradient.

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Increased Episomal Replication Accounts for the High Rate of Adaptive Mutation in recD Mutants of Escherichia coli

Genetics ◽

10.1093/genetics/152.1.15 ◽

1999 ◽

Vol 152 (1) ◽

pp. 15-30 ◽

Cited By ~ 1

Author(s):

Patricia L Foster ◽

William A Rosche

Keyword(s):

Escherichia Coli ◽

Mutation Rate ◽

Copy Number ◽

Frameshift Mutation ◽

High Rate ◽

Adaptive Mutation ◽

Lacz Gene ◽

Exonuclease Activity ◽

Wild Type ◽

Mutant Cells

Abstract Adaptive mutation has been studied extensively in FC40, a strain of Escherichia coli that cannot metabolize lactose (Lac-) because of a frameshift mutation affecting the lacZ gene on its episome. recD mutants of FC40, in which the exonuclease activity of RecBCD (ExoV) is abolished but its helicase activity is retained, have an increased rate of adaptive mutation. The results presented here show that, in several respects, adaptive mutation to Lac+ involves different mechanisms in recD mutant cells than in wild-type cells. About half of the apparent increase in the adaptive mutation rate of recD mutant cells is due to a RecA-dependent increase in episomal copy number and to growth of the Lac- cells on the lactose plates. The remaining increase appears to be due to continued replication of the episome, with the extra copies being degraded or passed to recD+ recipients. In addition, the increase in adaptive mutation rate in recD mutant cells is (i) dependent on activities of the single-stranded exonucleases, RecJ and ExoI, which are not required for (in fact, slightly inhibit) adaptive mutation in wild-type cells, and (ii) enhanced by RecG, which opposes adaptive mutation in wild-type cells.

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