Universität zu Köln

Zwart, Mark P., Schenk, Martijn F., Hwang, Sungmin, Koopmanschap, Bertha, de lange, Niek, de Pol, Lion van, Szendro, Ivan G., Krug, Joachim ORCID: 0000-0002-2143-6490 and de Visser, J. Arjan G. M. (2018). Unraveling the causes of adaptive benefits of synonymous mutations in TEM-1 beta-lactamase. Heredity, 121 (5). S. 406 - 422. LONDON: NATURE PUBLISHING GROUP. ISSN 1365-2540

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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 beta-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Zwart, Mark P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schenk, Martijn F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hwang, Sungmin UNSPECIFIED UNSPECIFIED UNSPECIFIED Koopmanschap, Bertha UNSPECIFIED UNSPECIFIED UNSPECIFIED de lange, Niek UNSPECIFIED UNSPECIFIED UNSPECIFIED de Pol, Lion van UNSPECIFIED UNSPECIFIED UNSPECIFIED Szendro, Ivan G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Krug, Joachim UNSPECIFIED orcid.org/0000-0002-2143-6490 UNSPECIFIED de Visser, J. Arjan G. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-168614
DOI:	10.1038/s41437-018-0104-z
Journal or Publication Title:	Heredity
Volume:	121
Number:	5
Page Range:	S. 406 - 422
Date:	2018
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1365-2540
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Physics > Institut für Biologische Physik
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SINGLE-NUCLEOTIDE POLYMORPHISM; ESCHERICHIA-COLI; MESSENGER-RNA; CODON BIAS; PROTEIN EXPRESSION; FITNESS LANDSCAPES; NATURAL EVOLUTION; ORDER EPISTASIS; GENES; RECOMBINATION Multiple languages Ecology; Evolutionary Biology; Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16861