scholarly journals Mutation accumulation and fitness in mutator subpopulations of Escherichia coli

2013 ◽  
Vol 9 (1) ◽  
pp. 20120961 ◽  
Author(s):  
Ram P. Maharjan ◽  
Bin Liu ◽  
Yang Li ◽  
Peter R. Reeves ◽  
Lei Wang ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Significant Proportion ◽  
Mutation Accumulation ◽  
Mutation Rates ◽  
Deleterious Mutations ◽  
Wild Type ◽  
Beneficial Mutations ◽  
Bacterial Populations ◽  
Neutral Mutations ◽  
Over Time

Bacterial populations in clinical and laboratory settings contain a significant proportion of mutants with elevated mutation rates (mutators). Mutators have a particular advantage when multiple beneficial mutations are needed for fitness, as in antibiotic resistance. Nevertheless, high mutation rates potentially lead to increasing numbers of deleterious mutations and subsequently to the decreased fitness of mutators. To test how fitness changed with mutation accumulation, genome sequencing and fitness assays of nine Escherichia coli mutY mutators were undertaken in an evolving chemostat population at three time points. Unexpectedly, the fitness in members of the mutator subpopulation became constant despite a growing number of mutations over time. To test if the accumulated mutations affected fitness, we replaced each of the known beneficial mutations with wild-type alleles in a mutator isolate. We found that the other 25 accumulated mutations were not deleterious. Our results suggest that isolates with deleterious mutations are eliminated by competition in a continuous culture, leaving mutators with mostly neutral mutations. Interestingly, the mutator–non-mutator balance in the population reversed after the fitness plateau of mutators was reached, suggesting that the mutator–non-mutator ratio in populations has more to do with competition between members of the population than the accumulation of deleterious mutations.

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

Genetics ◽  
2002 ◽  
Vol 162 (2) ◽  
pp. 557-566 ◽  
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.

Enrichment and Elimination of mutY Mutators in Escherichia coli Populations

Genetics ◽  
2002 ◽  
Vol 162 (3) ◽  
pp. 1055-1062 ◽  
Author(s):  
Lucinda Notley-McRobb ◽  
Shona Seeto ◽  
Thomas Ferenci
Keyword(s):  
Escherichia Coli ◽  
The Other ◽  
Mutation Rates ◽  
Beneficial Mutation ◽  
Glucose Limitation ◽  
Epistatic Interactions ◽  
Beneficial Mutations ◽  
Bacterial Populations ◽  
Kinetics Of ◽  
Selection Event

Abstract The kinetics of mutator sweeps was followed in two independent populations of Escherichia coli grown for up to 350 generations in glucose-limited continuous culture. A rapid elevation of mutation rates was observed in both populations within 120-150 generations, as was apparent from major increases in the proportion of the populations with unselected mutations in fhuA. The increase in mutation rates was due to sweeps by mutY mutators. In both cultures, the enrichment of mutators resulted from hitchhiking with identified beneficial mutations increasing fitness under glucose limitation; mutY hitchhiked with mgl mutations in one culture and ptsG in the other. In both cases, mutators were enriched to constitute close to 100% of the population before a periodic selection event reduced the frequency of unselected mutations and mutators in the cultures. The high proportion of mutators persisted for 150 generations in one population but began to be eliminated within 50 generations in the other. The persistence of mutator, as well as experimental data showing that mutY bacteria were as fit as near-isogenic mutY+ bacteria in competition experiments, suggest that mutator load by deleterious mutations did not explain the rapidly diminishing proportion of mutators in the populations. The nonmutators sweeping out mutators were also unlikely to have arisen by reversion or antimutator mutations; the mutY mutations were major deletions in each case and the bacteria sweeping out mutators contained intact mutY. By following mgl allele frequencies in one population, we discovered that mutators were outcompeted by bacteria that had rare mgl mutations previously as well as additional beneficial mutation(s). The pattern of appearance of mutY, but not its elimination, conforms to current models of mutator sweeps in bacterial populations. A mutator with a narrow mutational spectrum like mutY may be lost if the requirement for beneficial mutations is for changes other than GC → TA transversions. Alternatively, epistatic interactions between mutator mutation and beneficial mutations need to be postulated to explain mutator elimination.

scholarly journals Revisiting the Notion of Deleterious Sweeps

Genetics ◽  
2021 ◽  
Author(s):  
Parul Johri ◽  
Brian Charlesworth ◽  
Emma K Howell ◽  
Michael Lynch ◽  
Jeffrey D Jensen
Keyword(s):  
Positive Selection ◽  
Selective Sweep ◽  
Significant Proportion ◽  
Functional Genomic ◽  
Deleterious Mutations ◽  
Beneficial Mutations ◽  
Mating Population ◽  
Fixation Probabilities ◽  
Genomic Regions ◽  
Genomic Scans

Abstract It has previously been shown that, conditional on its fixation, the time to fixation of a semi-dominant deleterious autosomal mutation in a randomly mating population is the same as that of an advantageous mutation. This result implies that deleterious mutations could generate selective sweep-like effects. Although their fixation probabilities greatly differ, the much larger input of deleterious relative to beneficial mutations suggests that this phenomenon could be important. We here examine how the fixation of mildly deleterious mutations affects levels and patterns of polymorphism at linked sites - both in the presence and absence of interference amongst deleterious mutations - and how this class of sites may contribute to divergence between-populations and species. We find that, while deleterious fixations are unlikely to represent a significant proportion of outliers in polymorphism-based genomic scans within populations, minor shifts in the frequencies of deleterious mutations can influence the proportions of private variants and the value of FST after a recent population split. As sites subject to deleterious mutations are necessarily found in functional genomic regions, interpretations in terms of recurrent positive selection may require reconsideration.

scholarly journals Escherichia coli with a Tunable Point Mutation Rate for Evolution Experiments

2020 ◽  
Vol 10 (8) ◽  
pp. 2671-2681 ◽  
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.

scholarly journals Benefits of a Recombination-Proficient Escherichia coli System for Adaptive Laboratory Evolution

2016 ◽  
Vol 82 (22) ◽  
pp. 6736-6747 ◽  
Author(s):  
George Peabody ◽  
James Winkler ◽  
Weston Fountain ◽  
David A. Castro ◽  
Enzo Leiva-Aravena ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Strong Support ◽  
Mutational Load ◽  
Adaptive Laboratory Evolution ◽  
Beneficial Mutations ◽  
Laboratory Evolution ◽  
Content Type ◽  
Sexual Recombination ◽  
Simple Kinetic Model ◽  
Neutral Mutations

ABSTRACTAdaptive laboratory evolution typically involves the propagation of organisms asexually to select for mutants with the desired phenotypes. However, asexual evolution is prone to competition among beneficial mutations (clonal interference) and the accumulation of hitchhiking and neutral mutations. The benefits of horizontal gene transfer toward overcoming these known disadvantages of asexual evolution were characterized in a strain ofEscherichia coliengineered for superior sexual recombination (genderless). Specifically, we experimentally validated the capacity of the genderless strain to reduce the mutational load and recombine beneficial mutations. We also confirmed that inclusion of multiple origins of transfer influences both the frequency of genetic exchange throughout the chromosome and the linkage of donor DNA. We built a simple kinetic model to estimate recombination frequency as a function of transfer size and relative genotype enrichment in batch transfers; the model output correlated well with the experimental data. Our results provide strong support for the advantages of utilizing the genderless strain over its asexual counterpart during adaptive laboratory evolution for generating beneficial mutants with reduced mutational load.IMPORTANCEOver 80 years ago Fisher and Muller began a debate on the origins of sexual recombination. Although many aspects of sexual recombination have been examined at length, experimental evidence behind the behaviors of recombination in many systems and the means to harness it remain elusive. In this study, we sought to experimentally validate some advantages of recombination in typically asexualEscherichia coliand determine if a sexual strain ofE. colican become an effective tool for strain development.

scholarly journals GlpD and PlsB Participate in Persister Cell Formation in Escherichia coli

2006 ◽  
Vol 188 (14) ◽  
pp. 5136-5144 ◽  
Author(s):  
Amy L. Spoering ◽  
Marin Vulić ◽  
Kim Lewis
Keyword(s):  
Escherichia Coli ◽  
Cell Formation ◽  
Wild Type ◽  
Expression Library ◽  
Genetic Studies ◽  
Bacterial Populations ◽  
E Coli ◽  
Overexpression Strain ◽  
Multidrug Tolerance ◽  
Glycerol 3 Phosphate Dehydrogenase

ABSTRACT Bacterial populations produce dormant persister cells that are resistant to killing by all antibiotics currently in use, a phenomenon known as multidrug tolerance (MDT). Persisters are phenotypic variants of the wild type and are largely responsible for MDT of biofilms and stationary populations. We recently showed that a hipBA toxin/antitoxin locus is part of the MDT mechanism in Escherichia coli. In an effort to find additional MDT genes, an E. coli expression library was selected for increased survival to ampicillin. A clone with increased persister production was isolated and was found to overexpress the gene for the conserved aerobic sn-glycerol-3-phosphate dehydrogenase GlpD. The GlpD overexpression strain showed increased tolerance to ampicillin and ofloxacin, while a strain with glpD deleted had a decreased level of persisters in the stationary state. This suggests that GlpD is a component of the MDT mechanism. Further genetic studies of mutants affected in pathways involved in sn-glycerol-3-phosphate metabolism have led to the identification of two additional multidrug tolerance loci, glpABC, the anaerobic sn-glycerol-3-phosphate dehydrogenase, and plsB, an sn-glycerol-3-phosphate acyltransferase.

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

2016 ◽  
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.

scholarly journals Transient mutators: a semiquantitative analysis of the influence of translation and transcription errors on mutation rates.

Genetics ◽  
1991 ◽  
Vol 129 (3) ◽  
pp. 957-962 ◽  
Author(s):  
J Ninio
Keyword(s):  
Steady State ◽  
Synonymous Codon ◽  
Experimental Manipulation ◽  
Mutation Rates ◽  
Wild Type ◽  
Lethal Mutations ◽  
Nearly Neutral Mutations ◽  
Neutral Mutations ◽  
Translation Errors ◽  
State Composition

Abstract A population of bacteria growing in a nonlimiting medium includes mutator bacteria and transient mutators defined as wild-type bacteria which, due to occasional transcription or translation errors, display a mutator phenotype. A semiquantitative theoretical analysis of the steady-state composition of an Escherichia coli population suggests that true strong genotypic mutators produce about 3 x 10(-3) of the single mutations arising in the population, while transient mutators produce at least 10% of the single mutations and more than 95% of the simultaneous double mutations. Numbers of mismatch repair proteins inherited by the offspring, proportions of lethal mutations and mortality rates are among the main parameters that influence the steady-state composition of the population. These results have implications for the experimental manipulation of mutation rates and the evolutionary fixation of frequent but nearly neutral mutations (e.g., synonymous codon substitutions).

scholarly journals Compensatory mutations modulate the competitiveness and dynamics of plasmid-mediated colistin resistance in Escherichia coli clones

2020 ◽  
Vol 14 (3) ◽  
pp. 861-865 ◽  
Author(s):  
Qiu E. Yang ◽  
Craig MacLean ◽  
Andrei Papkou ◽  
Manon Pritchard ◽  
Lydia Powell ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Fitness Landscape ◽  
Fitness Cost ◽  
Colistin Resistance ◽  
Bacterial Populations ◽  
Compensatory Evolution ◽  
Neutral Mutations ◽  
The Cost ◽  
Negative Epistasis

AbstractThe emergence of mobile colistin resistance (mcr) threatens to undermine the clinical efficacy of the last antibiotic that can be used to treat serious infections caused by Gram-negative pathogens. Here we measure the fitness cost of a newly discovered MCR-3 using in vitro growth and competition assays. mcr-3 expression confers a lower fitness cost than mcr-1, as determined by competitive ability and cell viability. Consistent with these findings, plasmids carrying mcr-3 have higher stability than mcr-1 plasmids across a range of Escherichia coli strains. Crucially, mcr-3 plasmids can stably persist, even in the absence of colistin. Recent compensatory evolution has helped to offset the cost of mcr-3 expression, as demonstrated by the high fitness of mcr-3.5 as opposed to mcr-3.1. Reconstructing all of the possible evolutionary trajectories from mcr-3.1 to mcr-3.5 reveals a complex fitness landscape shaped by negative epistasis between compensatory and neutral mutations. Our findings highlight the importance of fitness costs and compensatory evolution in driving the dynamics and stability of mobile colistin resistance in bacterial populations, and they highlight the need to understand how processes (other than colistin use) impact mcr dynamics.

scholarly journals The effect of spatial structure on adaptation in Escherichia coli

2007 ◽  
Vol 4 (1) ◽  
pp. 57-59 ◽  
Author(s):  
Lilia Perfeito ◽  
M. Inês Pereira ◽  
Paulo R.A Campos ◽  
Isabel Gordo
Keyword(s):  
Escherichia Coli ◽  
Spatial Structure ◽  
Experimental Evolution ◽  
Petri Dish ◽  
Mutation Rates ◽  
Wild Type ◽  
Clonal Interference ◽  
Genetic Studies ◽  
Significant Difference ◽  
The Cost

Populations of organisms are generally organized in a given spatial structure. However, the vast majority of population genetic studies are based on populations in which every individual competes globally. Here we use experimental evolution in Escherichia coli to directly test a recently made prediction that spatial structure slows down adaptation and that this cost increases with the mutation rate. This was studied by comparing populations of different mutation rates adapting to a liquid (unstructured) medium with populations that evolved in a Petri dish on solid (structured) medium. We find that mutators adapt faster to both environments and that adaptation is slower if there is spatial structure. We observed no significant difference in the cost of structure between mutator and wild-type populations, which suggests that clonal interference is intense in both genetic backgrounds.

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