Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Record number 441443
Title Patterns of epistasis between beneficial mutations in an antibiotic resistance gene
Author(s) Schenk, M.F.; Szendro, I.G.; Salverda, M.L.M.; Krug, J.; Visser, J.A.G.M. de
Source Molecular Biology and Evolution 30 (2013)8. - ISSN 0737-4038 - p. 1779 - 1787.
DOI https://doi.org/10.1093/molbev/mst096
Department(s) Laboratory of Genetics
PE&RC
Publication type Refereed Article in a scientific journal
Publication year 2013
Keyword(s) escherichia-coli population - metabolic-control-theory - fitness landscape model - tem-1 beta-lactamase - deleterious mutations - sign epistasis - diminishing returns - natural evolution - sequence space - protein
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 ß-lactamase. Mutations in these sets either have 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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