Optimization of DNA polymerase mutation rates during bacterial evolution
Open accessAbstract
Mutation rate is an important determinant of evolvability. The optimal mutation rate for different organisms during evolution has been modeled in silico and tested in vivo, predominantly through pairwise comparisons. To characterize the fitness landscape across a broad range of mutation rates, we generated a panel of 66 DNA polymerase I mutants in Escherichia coli with comparable growth properties, yet with differing DNA replication fidelities, spanning 10 3 -fold higher and lower than that of wild type. These strains were competed for 350 generations in six replicate cultures in two different environments. A narrow range of mutation rates, 10- to 47-fold greater than that of wild type, predominated after serial passage. Mutants exhibiting higher mutation rates were not detected, nor were wild-type or antimutator strains. Winning clones exhibited shorter doubling times, greater maximum culture densities, and a growth advantages in pairwise competition relative to their precompetition ancestors, indicating the acquisition of adaptive phenotypes. To investigate the basis for mutator selection, we undertook a large series of pairwise competitions between mutator and wild-type strains under conditions where, in most cases, one strain completely overtook the culture within 18 days. Mutators were the most frequent winners but wild-type strains were also observed winning, suggesting that the competitive advantage of mutators is due to a greater probability of developing selectably advantageous mutations rather than from an initial growth advantage conferred by the polymerase variant itself. Our results indicate that under conditions where organism fitness is not yet maximized for a particular environment, competitive adaptation may be facilitated by enhanced mutagenesis.
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This mechanism may be a way to address the 'yin-yang' of low error rates: low mutation rates permit greater complexity because more information can be retained, but low rates also imply low adaptive evolvability in case a sequence is far from its fitness optimum (or if environmental conditions change).
“Indeed, this mechanism may be a way to address the ‘yin-yang’ of low error rates: that is, low mutation rates permit greater complexity because more information can be retained, but low rates also imply low adaptive evolvability in case a sequence is far from its fitness optimum (or if environmental conditions change).51”
From Cascade of reduced speed and accuracy after errors in enzyme-free copying of nucleic acid sequences (2013) · cites this paper as [51]
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Patil, S. D., & Kondabagil, K. R. (2021) · Molecular Biology and Evolution · doi:10.1093/molbev/msab003 · Cited by 12 · see citing works
Suppression of Beneficial Mutations in Dynamic Microbial Populations
Bittihn, P., Hasty, J., & Tsimring, L. S. (2017) · Physical Review Letters · doi:10.1103/physrevlett.118.028102 · Cited by 9 · see citing works
Phenotype switching of the mutation rate facilitates adaptive evolution
Lobinska, G., Pilpel, Y., & Ram, Y. (2023) · Genetics · doi:10.1093/genetics/iyad111 · Cited by 8 · see citing works
The disparity mutagenesis model predicts rescue of living things from catastrophic errors
Furusawa, M. (2014) · Frontiers in Genetics · doi:10.3389/fgene.2014.00421 · Cited by 7 · see citing works
A road map for in vivo evolution experiments with blood‐borne parasitic microbes
Rodríguez‐Pastor, R., Shafran, Y., Knossow, N., Gutiérrez, R., Harrus, S., Zaman, L., Lenski, R. E., Barrick, J. E., & Hawlena, H. (2022) · Molecular Ecology Resources · doi:10.1111/1755-0998.13649 · Cited by 7 · see citing works
Fidelity in Archaeal Information Processing
de Koning, B., Blombach, F., Brouns, S. J. J., & John van der, O. O. S. T. (2010) · Archaea · doi:10.1155/2010/960298 · Cited by 6 · see citing works
Systems and Methods for Continuous Evolution of Enzymes
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A Mutation Model from First Principles of the Genetic Code
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Betancurt-Anzola, L., O’Connell, K. C., Potapov, V., Ong, J. L., Tanner, N. A., Sauguet, L., & Zatopek, K. M. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf1143 · Cited by 3 · see citing works
Alternate mutation modalities in models of population dynamics
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Spontaneous Mutation: Real-Time in Living Cells
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Pourquoi le taux de mutation n’est-il jamais égal à zéro ?
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Somatic maintenance impacts the evolution of mutation ratePreprint
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Rapid Evolution of Ionic Silver Resistance in Escherichia Phage T7
Kiki, L. C., Ntonifor, M., LaDelle, W., Morikwe, U. C., Ezeanowai, F. C., McGee, L. W., Ewunkem, A. J., Graves, J. L., & Jeffers-Francis, L. K. (2026) · Microorganisms · doi:10.3390/microorganisms14061243
Reproductive mode and the evolution of mutation ratePreprint
Lafond, J., Saravanakumar, S., Neiman, M., Zufall, R. A., Wright, S., & Azevedo, R. B. R. (2026) · doi:10.32942/x2nt2j
- Authors
- Loh, E., Salk, J. J., & Loeb, L. A.
- Affiliations
- University of Washington (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-12-28
- Volume
- 107
- Issue
- 3
- Pages
- 1154-1159
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2824296
- OpenAlex
- W2031939238
- Cited by
- 81
- References
- 43
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 2 · 2022: 4 · 2021: 6 · 2020: 1 · 2019: 5 · 2018: 5 · 2017: 6 · 2016: 2 · 2015: 8 · 2014: 9 · 2013: 6 · 2012: 8
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG033485, F30AG033485)
- National Cancer Institute (CA-102029, CA115802, R01CA102029, R01CA115802)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- mutation rate, DNA polymerase I, DNA replication fidelity, Escherichia coli, fitness landscape, pairwise competition, evolvability, adaptive evolution, serial passage, growth rate
- MeSH terms
- DNA Polymerase I, Escherichia coli, Biological Evolution, Mutation
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