Patterns of Epistasis between Beneficial Mutations in an Antibiotic Resistance Gene
| Autor: | Ivan G. Szendro, M.F. Schenk, J. Arjan G. M. de Visser, Joachim Krug, Merijn L. M. Salverda |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
epistasis
antibiotic resistance fitness landscape Genotype Fitness landscape metabolic-control-theory natural evolution Epistasis and functional genomics Genetic Fitness fitness landscape model Fast Tracks deleterious mutations Cefotaxime Biology medicine.disease_cause Laboratorium voor Erfelijkheidsleer beta-Lactamases Drug Resistance Bacterial Genetics medicine Escherichia coli sign epistasis Molecular Biology Ecology Evolution Behavior and Systematics Mutation Epistasis Genetic PE&RC β-lactamase Phenotype Biological Evolution beneficial mutations Anti-Bacterial Agents sequence space tem-1 beta-lactamase Epistasis Laboratory of Genetics escherichia-coli population Adaptation protein diminishing returns |
| Zdroj: | Molecular Biology and Evolution Molecular Biology and Evolution, 30(8), 1779-1787 Molecular Biology and Evolution 30 (2013) 8 |
| ISSN: | 1537-1719 0737-4038 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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