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 542363
Title Unraveling the causes of adaptive benefits of synonymous mutations in TEM-1 β-lactamase
Author(s) Zwart, Mark P.; Schenk, Martijn F.; Hwang, Sungmin; Koopmanschap, Bertha; Lange, Niek de; Pol, Lion van de; Nga, Tran T.T.; Szendro, Ivan G.; Krug, Joachim; Visser, J.A.G.M. de
Source Heredity 121 (2018)5. - ISSN 0018-067X - p. 406 - 421.
DOI https://doi.org/10.1038/s41437-018-0104-z
Department(s) Laboratory of Genetics
Physical Chemistry and Soft Matter
PE&RC
Publication type Refereed Article in a scientific journal
Publication year 2018
Abstract

While synonymous mutations were long thought to be without phenotypic consequences, there is growing evidence they can affect gene expression, protein folding, and ultimately the fitness of an organism. In only a few cases have the mechanisms by which synonymous mutations affect the phenotype been elucidated. We previously identified 48 mutations in TEM-1 β-lactamase that increased resistance of Escherichia coli to cefotaxime, 10 of which were synonymous. To better understand the molecular mechanisms underlying the beneficial effect of these synonymous mutations, we made a series of measurements for a panel containing the 10 synonymous together with 10 non-synonymous mutations as a reference. Whereas messenger levels were unaffected, we found that total and functional TEM protein levels were higher for 5 out of 10 synonymous mutations. These observations suggest that some of these mutations act on translation or a downstream process. Similar effects were observed for some small-benefit non-synonymous mutations, suggesting a similar causal mechanism. For the synonymous mutations, we found that the cost of resistance scales with TEM protein levels. A resistance landscape for four synonymous mutations revealed strong epistasis: none of the combinations of mutations exceeded the resistance of the largest-effect mutation and there were synthetically neutral combinations. By considering combined effects of these mutations, we could infer that functional TEM protein level is a multi-dimensional phenotype. These results suggest that synonymous mutations may have beneficial effects by increasing the expression of an enzyme with low substrate activity, which may be realized via multiple, yet unknown, post-transcriptional mechanisms.

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