Mutation rate dynamics in a bacterial population reflect tension between adaptation and genetic load
Open accessAbstract
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.
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TL;DR
In a 20-year *E. coli* evolution experiment, an adapting population first fixed a *mutT* hypermutator that raised the point-mutation rate by ∼150-fold, then was invaded by two independent *mutY* lineages that lowered mutation rates and genetic load. The results support theory that hypermutators decline once adaptation slows and genetic load becomes the dominant selective tension.
Key findings
- Whole-genome phylogenomics and fluctuation tests showed that *mutT* increased the mutation rate by ∼150-fold; later *mutY-E* (L40W) and *mutY-L* (164-stop) reduced rates by ∼56% and ∼36% in maximum-likelihood phylogenomic estimates, with fluctuation tests showing ∼60% and ∼80–90% reductions for 40,000-generation clones.
- Genetic load in the *mutT* background was 0.013 per generation, reduced to 0.0073 with *mutY-E* and 0.0093 with *mutY-L*, implying positive selection coefficients of ∼0.57% and ∼0.37%, respectively.
- The two *mutY* alleles arose independently on separate branches; estimated origins were ∼21,612 generations for *mutT*, ∼26,769 for *mutY-E*, and ∼30,821 for *mutY-L*, and the joint probability of parallel *mutY* mutations by chance was <0.1%.
- Mutational spectra shifted as expected: C:G→A:T substitutions increased from 2/414 in the *mutT*-only background to 38/274 in *mutT mutY-E* and 24/319 in *mutT mutY-L; dN/dS was ∼0.80, implying ∼20% of nonsynonymous mutations were deleterious.
Methods
- Long-term evolution experiment population Ara-1; whole-genome resequencing of 22 evolved clones from generations 2,000–40,000 (16 newly sequenced plus 6 previously sequenced) on the Illumina Genome Analyzer, with mutations identified by BRESEQ against ancestral strain REL606.
- Phylogeny inferred by maximum parsimony in MEGA4; mutation rates, mutator origin times, and branch lengths estimated with maximum likelihood and Metropolis-Hastings MCMC using synonymous substitutions, primarily A:T→C:G and C:G→A:T classes.
- Luria–Delbrück fluctuation tests with Ma–Sandri–Sarkar maximum likelihood estimation measured rifampicin-resistance mutation rates; fitness assays used competition against the ancestor, and genetic load was estimated from dN/dS.
Limitations
- The authors state they did not directly measure selection coefficients because very small coefficients are difficult to measure, isogenic strains are challenging to construct in hypermutable backgrounds, and load-reduction selection requires equilibrium while other beneficial mutations may confound measurements.
- The authors note that fluctuation tests focus on a single gene, the spectrum of rifampicin-resistance mutations and its interaction with lineage-specific mutational biases are unknown, and individual clones could carry other rate-modifying mutations; phylogenomic estimates are considered more accurate.
- Evident from the text: results come from one focal *E. coli* population (Ara-1) in one glucose-limited environment, and mutation-rate estimates assume synonymous mutations are selectively neutral, so generality to other populations or environments is not established.
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- Findingreasoning§ Results and Discussion
The joint probability of these two events is <0.1%.
“The joint probability of these two events is <0.1%”
Quote in the paperSubstantial claim- The authors state this as an assumption: All 426 possible A:T→C:G substitutions in the mutY reading frame that would produce either nonsynonymous or nonsense mutations would lead to a loss of function.
- Findingown data§ Results and Discussion
The proportion of C:G→A:T substitutions increased to 24/319 in the mutT mutY-L lineage.
“and 24/319 in the mutT mutY-L lineage (P = 1.5 × 10−7).”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
The genetic load was reduced to 0.0073 with the addition of the mutY-E mutation.
“and this load was reduced to 0.0073 and 0.0093 with the addition of the mutY-E and mutY-L mutations, respectively (Table 2).”
Quote in the paperSubstantial claim- The authors state this as an assumption: Most nonsynonymous mutations are either neutral or deleterious, whereas most synonymous mutations are neutral.
- Findingreasoning§ Results and Discussion
The calculated genetic load in the mutT background was 0.013 per generation.
“Given the estimated mutation rates, the calculated genetic load in the mutT background was 0.013 per generation”
Quote in the paperSubstantial claim- The authors state this as an assumption: Most nonsynonymous mutations are either neutral or deleterious, whereas most synonymous mutations are neutral.
- Findingown data§ Results and Discussion
The mutation in the mutT gene had not reverted to its ancestral state.
“However, the mutation in the mutT gene had not reverted to its ancestral state, even though that mutation was in a potentially mutable tract of five cytosines.”
Quote in the paperSubstantial claim
- Findingown data§ Results and Discussion
Genome resequencing showed that different mutY mutations had occurred along the two mutT branches sampled at 40,000 generations.
“Indeed, genome resequencing showed that different mutY mutations had occurred along the two mutT branches sampled at 40,000 generations (Fig. 1A).”
Quote in the paperNot a substantial claim - Findingown data§ Abstract
An adapting Escherichia coli population first evolved a mutT hypermutator phenotype.
“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.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
The same Escherichia coli population was later invaded by two independent lineages with mutY mutations that reduced genome-wide mutation rates.
“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.”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
The rate of accumulation of base substitutions was 62 per thousand generations using clones 27K-D and 30K-B sampled at 27,000 and 30,000 generations.
“The rate of accumulation of base substitutions was 62 per thousand generations using clones 27K-D and 30K-B that were sampled at 27,000 and 30,000 generations, respectively.”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
The genetic load was reduced to 0.0093 with the addition of the mutY-L mutation.
“and this load was reduced to 0.0073 and 0.0093 with the addition of the mutY-E and mutY-L mutations, respectively (Table 2).”
Quote in the paperSubstantial claim- The authors state this as an assumption: Most nonsynonymous mutations are either neutral or deleterious, whereas most synonymous mutations are neutral.
- Findingown data§ Results and Discussion
Clones sampled from both branches at later times accumulated mutations more slowly than did the earlier mutT isolates.
“clones that were sampled from both branches at later times accumulated mutations more slowly than did the earlier mutT isolates”
Quote in the paperSubstantial claim - Findingreasoning§ Abstract
The mutY mutations caused a corresponding decrease in genetic load.
“with a corresponding decrease in the genetic load.”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
The mutation rate to RifR of a 40,000-generation clone on the first branch (40K-A) was reduced by ∼60% compared with the early mutT clones.
“the mutation rate to RifR of a 40,000-generation clone on the first branch (40K-A) was reduced by ∼60% compared with the early mutT clones”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
In these tests, the two basal mutT clones on average produced mutants resistant to rifampicin at ∼73 times the rate of the ancestral strain.
“In these tests, the two basal mutT clones (27K-D and 30K-B, sampled at 27,000 and 30,000 generations, respectively), on average, produced mutants resistant to the antibiotic rifampicin (RifR phenotype) at ∼73 times the rate of the ancestral strain.”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
Each of the two lineages persisted until at least 40,000 generations.
“and that each lineage persisted until at least 40,000 generations”
Quote in the paperNot a substantial claim - Findingown data§ Results and Discussion
The analysis indicates an increase of ∼150-fold in the mutation rate in the mutT background relative to the ancestor.
“This analysis indicates an increase of ∼150-fold in the mutation rate in the mutT background relative to the ancestor (Fig. 2A)”
Quote in the paperSubstantial claim- The authors state this as an assumption: Synonymous mutations are selectively neutral.
- Findingown data§ Results and Discussion
Rates in two 40,000-generation clones from the other branch (40K-B and 40K-C) were reduced by ∼80-90%.
“and rates in two 40,000-generation clones from the other branch (40K-B and 40K-C) were reduced by ∼80–90%.”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
The proportion of C:G→A:T substitutions increased from 2/414 in the initial mutT genetic background to 38/274 in the mutT mutY-E lineage.
“the proportion of C:G→A:T substitutions increased from only 2/414 in the initial mutT genetic background to 38/274 in the mutT mutY-E lineage (one-tailed Fisher’s exact test, P = 4 × 10−14)”
Quote in the paperSubstantial claim - Findingown data§ Abstract
The mutT mutation increased the point-mutation rate by ∼150-fold.
“inferred that the mutT mutation increased the point-mutation rate by ∼150-fold”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
The probability of one of the 426 possible A:T→C:G substitutions in the mutY reading frame occurring on the mutY-E clade as soon as, or sooner than, the mutations occurred is 1.3%.
“These probabilities are 1.3% and 5.7% for the mutY-E and mutY-L clades, respectively.”
Quote in the paperSubstantial claim- The authors state this as an assumption: All 426 possible A:T→C:G substitutions in the mutY reading frame that would produce either nonsynonymous or nonsense mutations would lead to a loss of function.
- Findingown data§ Results and Discussion
Experimental measurements using Luria-Delbrück fluctuation tests indicated substantial reductions in mutation rates along both evolutionary branches.
“Experimental measurements of mutation rates using Luria–Delbrück fluctuation tests also indicated substantial reductions in mutation rates along both evolutionary branches”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
The Escherichia coli population diverged into two deeply branched lineages by 30,000 generations.
“Phylogenetic analysis of the sequenced genomes revealed that the population had diverged into two deeply branched lineages by 30,000 generations”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
The other branch had a base substitution that introduced a premature termination codon at amino acid 164 (164-stop).
“whereas the other branch had a base substitution that introduced a premature termination codon at amino acid 164 (164-stop).”
Quote in the paperNot a substantial claim - Findingown data§ Results and Discussion
The probability of one of these mutations occurring on the mutY-L clade as soon as, or sooner than, the mutations occurred is 5.7%.
“These probabilities are 1.3% and 5.7% for the mutY-E and mutY-L clades, respectively.”
Quote in the paperSubstantial claim- The authors state this as an assumption: All 426 possible A:T→C:G substitutions in the mutY reading frame that would produce either nonsynonymous or nonsense mutations would lead to a loss of function.
- Findingown data§ Results and Discussion
The analysis indicates secondary reductions of ∼56% and ∼36% in the mutT mutY-E and mutT mutY-L backgrounds, respectively.
“followed by secondary reductions of ∼56% and ∼36% in the mutT mutY-E and mutT mutY-L backgrounds, respectively (Fig. 2B and Table 2).”
Quote in the paperSubstantial claim- The authors state this as an assumption: Synonymous mutations are selectively neutral.
- Findingown data§ Results and Discussion
On one branch, a base substitution changed the amino acid at position 40 in MutY from leucine to tryptophan (L40W).
“On one branch of the tree, a base substitution changed the amino acid at position 40 in MutY from leucine to tryptophan (L40W)”
Quote in the paperNot a substantial claim - Findingown data§ Abstract
The mutY mutations reduced the point-mutation rate by ∼40-60%.
“whereas the mutY mutations reduced the rate by ∼40–60%”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
The mutation rates estimated from the phylogenomic analysis agree reasonably well with those based on the fluctuation tests.
“The mutation rates estimated from this analysis agree reasonably well with those based on the fluctuation tests (Fig. 1C).”
Quote in the paperNot a substantial claim - Findingown data§ Results and Discussion
We observed a dN/dS ratio of ∼0.80 for all mutators.
“We observed a dN/dS ratio of ∼0.80 for all mutators”
Quote in the paperSubstantial claim - Findingcitation§ Results and Discussion
Mutations after the rise of the mutT hypermutator were highly skewed toward the A:T→C:G transversions typical of this defect.
“Mutations after the rise of the mutT hypermutator were highly skewed toward the A:T→C:G transversions typical of this defect (29).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Rotman E, Kuzminov A. The mutT defect does not elevate chromosomal fragmentation in Escherichia coli because of the surprisingly low levels of MutM/MutY-recognized DNA modifications. J Bacteriol. 2007;189(19):6976–6988. doi: 10.1128/JB.00776-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
Not checked in the free run.
- Findingown data§ Materials and Methods
The difference in mutation rates between blocks 3 and 4 for clones 30K-B and 40K-B was not significant at the 0.05 level.
“neither difference was significant at the 0.05 level.”
Quote in the paperNot a substantial claim - Findingown data§ Materials and Methods
A comparison of the two- and three-rate models strongly supports different genomic rates for the mutT-only and the mutT mutY backgrounds.
“a comparison of the two- and three-rate models strongly supports different genomic rates for the mutT-only and the mutT mutY backgrounds (Table S2).”
Quote in the paperSubstantial claim - Findingown data§ Materials and Methods
The maximum likelihood solution indicates that the evolved mutT allele arose around generation 21,612.
“indicates that the evolved mutT allele arose around generation 21,612 (Table 2).”
Quote in the paperNot a substantial claim - Findingown data§ Materials and Methods
The five-rate model did not provide a better fit than the three-rate model after imposing the penalty for additional parameters.
“but it did not provide a better fit than the three-rate model after imposing the penalty for additional parameters (Table S2).”
Quote in the paperNot a substantial claim - Findingown data§ Materials and Methods
The rise of the mutT mutator dramatically changed the branch lengths after 20,000 generations.
“The rise of the mutT mutator dramatically changed the branch lengths after 20,000 generations”
Quote in the paperSubstantial claim - Findingown data§ Materials and Methods
The fluctuation tests showed different mutation rates for the mutT mutY-E and mutT mutY-L backgrounds.
“The fluctuation tests also showed different mutation rates for the mutT mutY-E and mutT mutY-L backgrounds (Fig. 1C)”
Quote in the paperNot a substantial claim - Findingown data§ Materials and Methods
The difference between the mutT mutY-E and mutT mutY-L backgrounds in the fluctuation tests was in the opposite direction to the difference inferred from the phylogenomic analysis.
“although that difference was in the opposite direction to the difference inferred from the phylogenomic analysis (Fig. S2).”
Quote in the paperNot a substantial claim - Findingown data§ Materials and Methods
When using all point mutations, the five-rate model gave a statistically better fit to the data than the best three-rate model, even with the penalty for additional parameters.
“When using all point mutations, the five-rate model gave a statistically better fit to the data than the best three-rate model, even with the penalty for additional parameters (Table S3).”
Quote in the paperSubstantial claim - Findingnone given§ Materials and Methods
These mutators produced a strongly biased spectrum of mutations.
“These mutators produced a strongly biased spectrum of mutations”
Quote in the paperSubstantial claim - Interpretationreasoning§ Results and Discussion
The rates inferred from the phylogenomic data are expected to be more accurate than those from fluctuation tests because they encompass the entire genome across many thousands of generations.
“In general, we expect the rates inferred from the phylogenomic data to be more accurate because they encompass the entire genome across many thousands of generations.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ Abstract
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.
“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.”
Quote in the paperSubstantial claim - Interpretationown data§ Results and Discussion
The nonadaptive explanation for the parallel evolution of reduced mutation rates is rejected.
“and we therefore reject this nonadaptive explanation for the parallel evolution of reduced mutation rates.”
Quote in the paperSubstantial claim- The authors state this as an assumption: All 426 possible A:T→C:G substitutions in the mutY reading frame that would produce either nonsynonymous or nonsense mutations would lead to a loss of function.
- Premisecitation§ Abstract
More mutations are deleterious than beneficial.
“More mutations are deleterious than beneficial (2)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Eyre-Walker A, Keightley PD. The distribution of fitness effects of new mutations. Nat Rev Genet. 2007;8(8):610–618. doi: 10.1038/nrg2146. [DOI] [PubMed] [Google Scholar]
Not checked in the free run.
- Interpretationreasoning§ Results and Discussion
The dN/dS ratio implies that ∼20% of all nonsynonymous mutations were deleterious.
“implying that ∼20% of all nonsynonymous mutations were deleterious.”
Quote in the paperSubstantial claim- The authors state this as an assumption: Most nonsynonymous mutations are either neutral or deleterious, whereas most synonymous mutations are neutral.
- Interpretationreasoning§ Results and Discussion
The two independent mutations in mutY achieved their high frequencies because they conferred an advantage.
“Parallel evolution is a hallmark of adaptation, and so it is reasonable to infer that the two independent mutations in mutY achieved their high frequencies because they conferred an advantage.”
Quote in the paperSubstantial claim - Premisecitation§ Results and Discussion
The complementary prediction-that populations should evolve lower rates once they are adapted to their environments-has received only limited and indirect support.
“However, despite long-standing theoretical interest (23–25), 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, 35–38).”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [7] Notley-McRobb L, Seeto S, Ferenci T. Enrichment and elimination of mutY mutators in Escherichia coli populations. Genetics. 2002;162(3):1055–1062. doi: 10.1093/genetics/162.3.1055. [DOI] [PMC free article] [PubMed] [Google Scholar]
Not checked in the free run.
- cites [20] De Visser JA, et al. Diminishing returns from mutation supply rate in asexual populations. Science. 1999;283(5400):404–406. doi: 10.1126/science.283.5400.404. [DOI] [PubMed] [Google Scholar]
Not checked in the free run.
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- cites [37] Tröbner W, Piechocki R. Selection against hypermutability in Escherichia coli during long term evolution. Mol Gen Genet. 1984;198(1):177–178. doi: 10.1007/BF00328720. [DOI] [PubMed] [Google Scholar]
Not checked in the free run.
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Not checked in the free run.
- Premisecitation§ Results and Discussion
Selection can readily act on mutations with effects of this magnitude in the large population studied here.
“Selection can readily act on mutations with effects of this magnitude in the large population studied here (22, 26).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [22] Lenski RE. Phenotypic and genomic evolution during a 20,000-generation experiment with the bacterium Escherichia coli. Plant Breed Rev. 2004;24(2):225–265. [Google Scholar]
Not checked in the free run.
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Not checked in the free run.
- Premisecitation§ Results and Discussion
Loss-of-function mutations in mutY also lead to elevated mutation rates on their own.
“Loss-of-function mutations in mutY, which encodes a DNA repair glycosylase that excises mis-paired bases from DNA helices, also lead to elevated mutation rates on their own (29).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Rotman E, Kuzminov A. The mutT defect does not elevate chromosomal fragmentation in Escherichia coli because of the surprisingly low levels of MutM/MutY-recognized DNA modifications. J Bacteriol. 2007;189(19):6976–6988. doi: 10.1128/JB.00776-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
Not checked in the free run.
- Interpretationown data§ Materials and Methods
With the penalty for additional parameters required to fit an extended model with one or more additional rates, the extended model would be no better than the model with only the two classes of mutation.
“With the penalty for additional parameters required to fit an extended model with one or more additional rates, the extended model would be no better than the model with only the two classes of mutation.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Materials and Methods
The load will be underestimated to the extent that some of the observed nonsynonymous mutations are beneficial.
“Similarly, the load will be underestimated to the extent that some of the observed nonsynonymous mutations are beneficial.”
Quote in the paperNot a substantial claim - Interpretationown data§ Materials and Methods
The results of the analysis would not be substantively affected by using all of the point mutations instead of only the two classes considered here.
“The results of this analysis would not be substantively affected by using all of the point mutations instead of only the two classes considered here.”
Quote in the paperSubstantial claim - Premisecitation§ Results and Discussion
The known function and mechanism of action of the MutY protein do not suggest an obvious advantage.
“However, the known function and mechanism of action of the MutY protein do not suggest an obvious advantage (34).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [34] Fowler RG, et al. Interactions among the Escherichia coli mutT, mutM, and mutY damage prevention pathways. DNA Repair (Amst) 2003;2(2):159–173. doi: 10.1016/s1568-7864(02)00193-3. [DOI] [PubMed] [Google Scholar]
Not checked in the free run.
- Premisecitation§ Results and Discussion
This secondary signature is characteristic of mutY defects.
“This secondary signature is characteristic of mutY defects (29).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Rotman E, Kuzminov A. The mutT defect does not elevate chromosomal fragmentation in Escherichia coli because of the surprisingly low levels of MutM/MutY-recognized DNA modifications. J Bacteriol. 2007;189(19):6976–6988. doi: 10.1128/JB.00776-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
Not checked in the free run.
- Interpretationown data§ Materials and Methods
Different clones with the same mutator genotype had similar or equal mutation rates.
“Thus, different clones with the same mutator genotype had similar or equal mutation rates.”
Quote in the paperNot a substantial claim - Premisecitation§ Results and Discussion
The 60% reduction in overall mutation rates reported in mutT mutY double mutants compared with mutT single mutants is similar to the rate changes observed in both the phylogenomic analysis and fluctuation tests.
“The 60% reduction in overall mutation rates reported in mutT mutY double mutants compared with mutT single mutants (29) is similar to the rate changes we observed in both the phylogenomic analysis (Fig. 1B) and fluctuation tests (Fig. 1C).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Rotman E, Kuzminov A. The mutT defect does not elevate chromosomal fragmentation in Escherichia coli because of the surprisingly low levels of MutM/MutY-recognized DNA modifications. J Bacteriol. 2007;189(19):6976–6988. doi: 10.1128/JB.00776-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
Not checked in the free run.
- May combine two claims. 20
- Classified as probably not a substantial claim. 14
May combine two claims.
Findingown data§ Results and DiscussionFor the later branches shown in green and purple, the rate of accumulation of base substitutions declined to 22 and 28 per thousand generations, respectively.
“For the later branches shown in green (clones 30K-A and 40K-A) and purple (clones 35K-C, 40K-B, and 40K-C), this rate had declined to 22 and 28 per thousand generations, respectively”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Results and DiscussionThese declines correspond to reductions of ∼65% and ∼55%, respectively.
“which indicate reductions of ∼65% and ∼55%, respectively.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown data§ Materials and MethodsThe five-rate model suggests a difference between the mutT mutY-E and mutT mutY-L backgrounds.
“The five-rate model suggests a difference between the mutT mutY-E and mutT mutY-L backgrounds (Fig. S2)”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Materials and MethodsThe mutation rate estimated for the 35K-C clone bearing the mutT mutY-L alleles was 1.1-fold higher than the rate for the 40K-B mutT mutY-L clone, a difference that was not significant (P = 0.30).
“the mutation rate estimated for the 35K-C clone bearing the mutT mutY-L alleles was 1.1-fold higher than the rate for the 40K-B mutT mutY-L clone, a difference that was not significant (P = 0.30)”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Materials and MethodsFor the mutator backgrounds, there are a total of 142 synonymous mutations, and only two belong to the other four mutation classes combined.
“For the mutator backgrounds, there are a total of 142 synonymous mutations, and only two belong to the other four mutation classes combined (Table 1).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown data§ Materials and MethodsFrom fitness assays, the best-fit trajectory parameters were a = 0.101815 and b = 0.004284 per generation, with a correlation of 0.9898 between the predicted value and the mean of the measurements at the corresponding generation.
“From these data, we estimated a = 0.101815 and b = 0.004284 per generation, with a correlation of 0.9898 between the predicted value and the mean of the measurements at the corresponding generation.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Findingown data§ Materials and MethodsThe classes of mutations clearly (and typically) affected by the mutT and mutY alleles are A:T→C:G and C:G→A:T base substitutions.
“we applied this approach using only the A:T→C:G and C:G→A:T base substitutions because they were the classes of mutations clearly (and typically) affected by the mutT and mutY alleles (Table 1).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Materials and MethodsThe rates for both mutT mutY-L clones (35K-C and 40K-B) differed significantly from the mutT-only 30K-B clone (by 3.4- and 3.2-fold, respectively; each P < 0.001).
“the rates for both of these mutT mutY-L clones differed significantly from the mutT-only 30K-B clone (by 3.4- and 3.2-fold, respectively; each P < 0.001).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Materials and MethodsThe mutation rate estimated for the 27K-D clone bearing the mutT allele differed significantly from the initially tested mutT clone 30K-B (P < 0.001), but the difference was only 1.3-fold.
“The rate estimated for the 27K-D clone bearing the mutT allele differed significantly from the initially tested mutT clone 30K-B (P < 0.001), but the difference was only 1.3-fold”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown data§ Materials and MethodsThe maximum likelihood solution provides a mutation rate per generation, μ, similar to the previous estimate.
“The maximum likelihood solution provides a mutation rate per generation, μ, similar to the previous estimate”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingreasoning§ Results and DiscussionThe fact that the estimated frequencies for the two mutY alleles total slightly over 100% at 40,000 generations is a consequence of sampling variation at different genomic sites.
“The fact that the estimated frequencies for the two mutY alleles total slightly over 100% at 40,000 generations is a consequence of sampling variation at different genomic sites.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Materials and MethodsThe difference between the mutT clones (27K-D and 30K-B) and the mutT mutY-L clone 40K-B was 4.8- and 6.0-fold, respectively (each P < 0.001).
“the difference between these mutT clones and the mutT mutY-L clone 40K-B (4.8- and 6.0-fold, respectively; each P < 0.001).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown data§ Materials and MethodsThe estimated mutation rate for clone 30K-B was 3.7 × 10−7 in block 3 and 3.7 × 10−7 in block 4.
“The estimated mutation rates were 3.7 × 10−7 (block 3) and 3.7 × 10−7 (block 4) for 30K-B”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown data§ Materials and MethodsThe estimated mutation rate for clone 40K-B was 0.9 × 10−7 in block 3 and 1.1 × 10−7 in block 4.
“and 0.9 × 10−7 (block 3) and 1.1 × 10−7 (block 4) for 40K-B”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Results and DiscussionClone 40K-C seems to have a lower mutation rate than clones 35K-C and 40K-B, even though all three clones lie on the mutY-L branch.
“For example, based on the fluctuation tests, clone 40K-C seems to have a lower mutation rate than clones 35K-C and 40K-B (Fig. 1C), even though all three clones lie on the mutY-L branch (Fig. 1A).”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Premisecitation§ Results and DiscussionMany studies have documented the evolution of higher mutation rates as microbial populations adapt to changed environments.
“Many studies have documented the evolution of higher mutation rates as microbial populations adapt to changed environments (6, 8–12, 35).”
Quote in the paperSubstantial claim0 of 7 sources checked- cites [6] Sniegowski PD, Gerrish PJ, Lenski RE. Evolution of high mutation rates in experimental populations of E. coli. Nature. 1997;387(6634):703–705. doi: 10.1038/42701. [DOI] [PubMed] [Google Scholar] source
Not checked in the free run.
- cites [8] Chao L, Cox EC. Competition between high and low mutating strains of Escherichia coli. Evolution. 1983;37(1):125–134. doi: 10.1111/j.1558-5646.1983.tb05521.x. [DOI] [PubMed] [Google Scholar]
Not checked in the free run.
- cites [9] Mao EF, Lane L, Lee J, Miller JH. Proliferation of mutators in A cell population. J Bacteriol. 1997;179(2):417–422. doi: 10.1128/jb.179.2.417-422.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
Not checked in the free run.
- cites [10] Giraud A, et al. Costs and benefits of high mutation rates: Adaptive evolution of bacteria in the mouse gut. Science. 2001;291(5513):2606–2608. doi: 10.1126/science.1056421. [DOI] [PubMed] [Google Scholar]
Not checked in the free run.
- cites [11] Oliver A, Cantón R, Campo P, Baquero F, Blázquez J. High frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection. Science. 2000;288(5469):1251–1254. doi: 10.1126/science.288.5469.1251. [DOI] [PubMed] [Google Scholar]
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- cites [12] Matic I, et al. Highly variable mutation rates in commensal and pathogenic Escherichia coli. Science. 1997;277(5333):1833–1834. doi: 10.1126/science.277.5333.1833. [DOI] [PubMed] [Google Scholar]
Not checked in the free run.
- cites [35] Gentile CF, Yu S-C, Serrano SA, Gerrish PJ, Sniegowski PD. Competition between high- and higher-mutating strains of Escherichia coli. Biol Lett. 2011;7(3):422–424. doi: 10.1098/rsbl.2010.1036. [DOI] [PMC free article] [PubMed] [Google Scholar]
Not checked in the free run.
May combine two claims.
Interpretationreasoning§ Results and DiscussionThese genetic load reductions imply positive selection coefficients of ∼0.57% and ∼0.37% for mutY-E and mutY-L, respectively.
“These genetic load reductions imply positive selection coefficients of ∼0.57% and ∼0.37% for mutY-E and mutY-L, respectively.”
Quote in the paperSubstantial claim- The authors state this as an assumption: Most nonsynonymous mutations are either neutral or deleterious, whereas most synonymous mutations are neutral.
Probably not a substantial claim: may not pass S4 (based).
Interpretationnone given§ Results and DiscussionA reduction in genetic load is expected for any mutations that compensate for hypermutators.
“In any case, a reduction in genetic load is expected for any mutations that compensate for hypermutators”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Results and DiscussionReductions in mutation rates were observed surprisingly early in some studies, and even in nonmutator backgrounds, 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.
“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”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [7] Notley-McRobb L, Seeto S, Ferenci T. Enrichment and elimination of mutY mutators in Escherichia coli populations. Genetics. 2002;162(3):1055–1062. doi: 10.1093/genetics/162.3.1055. [DOI] [PMC free article] [PubMed] [Google Scholar]
Not checked in the free run.
- cites [37] Tröbner W, Piechocki R. Selection against hypermutability in Escherichia coli during long term evolution. Mol Gen Genet. 1984;198(1):177–178. doi: 10.1007/BF00328720. [DOI] [PubMed] [Google Scholar]
Not checked in the free run.
- cites [38] McDonald MJ, Hsieh Y-Y, Yu Y-H, Chang S-L, Leu J-Y. The evolution of low mutation rates in experimental mutator populations of Saccharomyces cerevisiae. Curr Biol. 2012;22(13):1235–1240. doi: 10.1016/j.cub.2012.04.056. [DOI] [PubMed] [Google Scholar]
Not checked in the free run.
May combine two claims.
Premisecitation§ Results and DiscussionThe mutY-L allele was not detected at 30,000 generations, but it constituted 69% of the population at 40,000 generations.
“The mutY-L allele was not detected at 30,000 generations, but it constituted 69% (51–83%) of the population at 40,000 generations.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Barrick JE, Lenski RE. Genome-wide mutational diversity in an evolving population of Escherichia coli. Cold Spring Harb Symp Quant Biol. 2009;74:119–129. doi: 10.1101/sqb.2009.74.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
Not checked in the free run.
May combine two claims.
Interpretationown data§ Results and DiscussionThe tension between accelerating adaptive evolution and reducing genetic load depends on the fit between a population and its environment, with the relative importance of load reduction increasing as a population becomes well adapted to its circumstances.
“Our results indicate that the tension between accelerating adaptive evolution and reducing genetic load depends on the fit between a population and its environment, with the relative importance of load reduction increasing as a population becomes well adapted to its circumstances.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ Results and DiscussionThe mutY-E allele was present in 65% of the population at 30,000 generations and 39% at 40,000 generations.
“A previous analysis of mixed-population sequencing data (28) found that the mutY-E allele was present in 65% (51–78%; 95% confidence limits) of the population at 30,000 generations and 39% (25–53%) at 40,000 generations.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Barrick JE, Lenski RE. Genome-wide mutational diversity in an evolving population of Escherichia coli. Cold Spring Harb Symp Quant Biol. 2009;74:119–129. doi: 10.1101/sqb.2009.74.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
Not checked in the free run.
Classified as probably not a substantial claim.
Premisecitation§ AbstractTheory predicts that populations of hypermutators should re-evolve lower mutation rates after they have become well adapted to their current environment.
“theory predicts that populations of hypermutators should re-evolve lower mutation rates after they have become well adapted to their current environment (23–25).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [23] Sturtevant AH. Essays on evolution. I. On the effects of selection on mutation rate. Q Rev Biol. 1937;12(4):464–467. [Google Scholar]
Not checked in the free run.
- cites [24] Kimura M. On the evolutionary adjustment of spontaneous mutation rates. Genet Res. 1967;9(1):23–34. [Google Scholar]
Not checked in the free run.
- cites [25] Leigh EG. Natural selection and mutability. Am Nat. 1970;104(937):301–305. [Google Scholar]
Not checked in the free run.
May combine two claims.
Premisecitation§ Results and DiscussionSome limitations of earlier studies include reliance on comparative data, lack of information on the genetic basis for mutation rate changes, lack of quantification of effects on rates of sequence evolution, and the use of strains not well adapted to their environment.
“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).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [36] Denamur E, et al. Evolutionary implications of the frequent horizontal transfer of mismatch repair genes. Cell. 2000;103(5):711–721. doi: 10.1016/s0092-8674(00)00175-6. [DOI] [PubMed] [Google Scholar]
Not checked in the free run.
- cites [37] Tröbner W, Piechocki R. Selection against hypermutability in Escherichia coli during long term evolution. Mol Gen Genet. 1984;198(1):177–178. doi: 10.1007/BF00328720. [DOI] [PubMed] [Google Scholar]
Not checked in the free run.
- cites [38] McDonald MJ, Hsieh Y-Y, Yu Y-H, Chang S-L, Leu J-Y. The evolution of low mutation rates in experimental mutator populations of Saccharomyces cerevisiae. Curr Biol. 2012;22(13):1235–1240. doi: 10.1016/j.cub.2012.04.056. [DOI] [PubMed] [Google Scholar]
Not checked in the free run.
May combine two claims.
Interpretationown data§ Results and DiscussionAfter the rise of a mutT hypermutator genotype, two distinct mutY alleles with reduced mutation rates independently evolved and invaded this E. coli population, driving the mutT-only lineage extinct (or at least to very low frequency).
“Thus, after the rise of a mutT hypermutator genotype, two distinct mutY alleles with reduced mutation rates independently evolved and invaded this E. coli population, driving the mutT-only lineage extinct (or at least to very low frequency).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Results and DiscussionThe ancestor's mutation rate was previously estimated as 0.00041 per generation based on the accumulation of synonymous substitutions in eight nonmutator lineages.
“The ancestor’s mutation rate was previously estimated as 0.00041 per generation based on the accumulation of synonymous substitutions in eight nonmutator lineages (31).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] Wielgoss S, et al. Mutation rate inferred from synonymous substitutions in a long-term evolution experiment with Escherichia coli. G3 (Bethesda) 2011;1(3):183–186. doi: 10.1534/g3.111.000406. [DOI] [PMC free article] [PubMed] [Google Scholar]
Not checked in the free run.
May combine two claims.
Interpretationown data§ Materials and MethodsThe number of beneficial mutations should be small because the load was estimated only during the later generations of the long-term evolution experiment, after the rate of fitness improvement had greatly decelerated, indicating that beneficial mutations were fewer and of smaller effect than in the early generations.
“the number of beneficial mutations should be small because we are estimating the load only during the later generations of the long-term evolution experiment, after the rate of fitness improvement had greatly decelerated (Fig. 1B), indicating that beneficial mutations were fewer and of smaller effect than in the early generations of the experiment.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based).
Interpretationnone given§ Results and DiscussionThe scarcity of evidence for mutation rate reductions in evolving asexual populations is due not to flaws in the theory but to the need for evolution to proceed in a test environment long enough that the scope for further adaptation is reduced to a level commensurate with the load of deleterious mutations.
“In our view, the paucity of evidence for mutation rate reductions in evolving asexual populations lies not in flaws with the theory, but rather in the necessity for evolution to proceed in a test environment for a sufficiently long time that the scope for further adaptation is reduced to a level commensurate with the load of deleterious mutations.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown data§ Results and DiscussionConfounding factors had negligible effects in our study and left no signatures in the evolved genomes.
“However, these factors had negligible effects in our study and left no signatures in the evolved genomes (SI Text).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationreasoning§ Materials and MethodsThe calculation may lead to a slight underestimate of the load if some deleterious mutations, not yet eliminated by selection, are included among the observed nonsynonymous mutations.
“This calculation may lead to a slight underestimate of the load if some deleterious mutations, not yet eliminated by selection, are included among the observed nonsynonymous mutations (n).”
Quote in the paperNot a substantial claim
The authors state this as an assumption.
Synonymous mutations are selectively neutral.
“If one assumes that synonymous mutations are selectively neutral, then the expected number of such mutations in an evolved clone relative to its progenitor is equal to the product of the intrinsic substitution rate, the number of genomic sites at risk for synonymous mutations, and the number of elapsed generations (30, 31).”
The authors state this as an assumption.
All 426 possible A:T→C:G substitutions in the mutY reading frame that would produce either nonsynonymous or nonsense mutations would lead to a loss of function.
“There are 426 possible A:T→C:G substitutions in the mutY reading frame that would produce either nonsynonymous or nonsense mutations, and we made the conservative assumption that all of them would have led to a loss of function.”
The authors state this as an assumption.
Most nonsynonymous mutations are either neutral or deleterious, whereas most synonymous mutations are neutral.
“Assuming that most nonsynonymous mutations are either neutral or deleterious, whereas most synonymous mutations are neutral, the fraction of nonsynonymous changes that are deleterious can be estimated from the ratio of the rates of nonsynonymous (dN) to synonymous (dS) substitutions.”
The authors state this as an assumption.
Mutations at synonymous sites are neutral and mutations at nonsynonymous sites are either neutral or deleterious.
“If mutations at synonymous sites are neutral and mutations at nonsynonymous sites are either neutral or deleterious”
The paper relies on this without support.
Selection acting on the mutations is independent of the mechanisms that produced them.
“However, selection acting on the mutations should be independent of the mechanisms that produced them.”
The paper relies on this without support.
The arabinose-utilization marker used to distinguish competitors is neutral in the conditions of the fitness assays.
“The competitors were distinguished by using an arabinose-utilization marker that is neutral in these conditions.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Many typical ALE experiments were performed in shake flasks and similar growth conditions with cell densities in the range of 10^7 to 10^9 cells per mL for typical microbial cultures.
“Many typical ALE experiments were performed in shake flasks and similar growth conditions with cell densities in the range of 107 to 109 cells per mL for typical microbial cultures [124,125]”
From Adaptive laboratory evolution—Principles and applications for biotechnology (2013) · cites this paper as [125]
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Adaptive laboratory evolution—Principles and applications for biotechnology
Dragosits, M., & Mattanovich, D. (2013) · Microbial Cell Factories · doi:10.1186/1475-2859-12-64 · Cited by 827 · see citing works
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- Authors
- Wielgoss, S., Barrick, J. E., Tenaillon, O., Wiser, M. J., Dittmar, W. J., Cruveiller, S., Chane-Woon-Ming, B., Médigue, C., Lenski, R. E., & Schneider, D.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- The University of Texas at Austin (US)
- Inserm (FR)
- Michigan State University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-12-17
- Volume
- 110
- Issue
- 1
- Pages
- 222-227
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3538217
- OpenAlex
- W2087601214
- Cited by
- 292
- References
- 47
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 20 · 2023: 32 · 2022: 18 · 2021: 21 · 2020: 15 · 2019: 20 · 2018: 20 · 2017: 28 · 2016: 25 · 2015: 26 · 2014: 22 · 2013: 13
- FWCI
- 11.57
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-08-GENM-0023)
- National Institute of General Medical Sciences (R00GM087550)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- mutation rate evolution, hypermutators, MutT, MutY, Escherichia coli, genetic load, adaptation, invasion dynamics, neutral theory, synonymous substitutions, phylogenomics
- MeSH terms
- Adaptation, Biological, Escherichia coli, Biological Evolution, Models, Genetic, Phylogeny, Population Dynamics, Pyrophosphatases, Likelihood Functions, Escherichia coli Proteins, Genetic Load, DNA Glycosylases, Mutation Rate
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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