ArticleMolecular biology and evolution2013
Patterns of Epistasis between beneficial mutations in an antibiotic resistance gene.
Article in Molecular biology and evolution, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers, 1 of them a synthesis that pooled it.
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Who cites it
81 citing papers in PubMed, 1 synthesis or guideline pooled it, 149 citations in OpenAlex.
- Detecting fitness epistasis in recently admixed populations with genome-wide data.BMC genomics · 2020Pooled it
- Review
- Epistasis: Just say no!The Journal of biological chemistry · 2026Review
- Origins and breadth of pairwise epistasis in an α-helix of β-lactamase TEM-1.Nature communications · 2026Article
- Cryptic phenotypic variation emerges rapidly during the adaptive evolution of a carbapenemase.Nature ecology & evolution · 2026Article
- Mistranslation suppresses mistranscription in eukaryotes.Nature communications · 2026Article
- Phosphate ions modulate enzyme activity and epistatic effects in two clavulanic acid-resistant β-lactamase mutants.Protein science : a publication of the Protein Society · 2025Article
- Epistasis-mediated compensatory evolution in a fitness landscape with adaptational tradeoffs.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Real-time monitoring of replication errors' fate reveals the origin and dynamics of spontaneous mutations.Nature communications · 2024Article
- Positive epistasis drives clavulanic acid resistance in double mutant libraries of BlaC β-lactamase.Communications biology · 2024Article
- Article
- Genotype-phenotype landscapes for immune-pathogen coevolution.Trends in immunology · 2023Review
- Genetic complementation fosters evolvability in complex fitness landscapes.Scientific reports · 2023Article
- Population dynamics of cross-protection against β-lactam antibiotics in droplet microreactors.Frontiers in microbiology · 2023Article
- Experimental andACS infectious diseases · 2022Article
- On the incongruence of genotype-phenotype and fitness landscapes.PLoS computational biology · 2022Article
- Mutational robustness changes during long-term adaptation in laboratory budding yeast populations.eLife · 2022Article
- Environmental selection and epistasis in an empirical phenotype-environment-fitness landscape.Nature ecology & evolution · 2022Article
- Evolution of resistance under alternative models of selective interference.Journal of evolutionary biology · 2021Article
- Mistranslation can promote the exploration of alternative evolutionary trajectories in enzyme evolution.Journal of evolutionary biology · 2021Article
21 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Understanding epistasis is central to biology. For instance, epistatic interactions determine the topography of the fitness landscape and affect the dynamics and determinism of adaptation. However, few empirical data are available, and comparing results is complicated by confounding variation in the system and the type of mutations used. Here, we take a systematic approach by quantifying epistasis in two sets of four beneficial mutations in the antibiotic resistance enzyme TEM-1 β-lactamase. Mutations in these sets have either large or small effects on cefotaxime resistance when present as single mutations. By quantifying the epistasis and ruggedness in both landscapes, we find two general patterns. First, resistance is maximal for combinations of two mutations in both fitness landscapes and declines when more mutations are added due to abundant sign epistasis and a pattern of diminishing returns with genotype resistance. Second, large-effect mutations interact more strongly than small-effect mutations, suggesting that the effect size of mutations may be an organizing principle in understanding patterns of epistasis. By fitting the data to simple phenotype resistance models, we show that this pattern may be explained by the nonlinear dependence of resistance on enzyme stability and an unknown phenotype when mutations have antagonistically pleiotropic effects. The comparison to a previously published set of mutations in the same gene with a joint benefit further shows that the enzyme's fitness landscape is locally rugged but does contain adaptive pathways that lead to high resistance.
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