Initial mutations direct alternative pathways of protein evolution
| Autor: | John van der Oost, Eynat Dellus, Florien A. Gorter, J. Arjan G. M. de Visser, Alfons J. M. Debets, Dan S. Tawfik, Rolf F. Hoekstra, Merijn L. M. Salverda |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
0106 biological sciences
epistasis Cancer Research natural evolution Cooperativity Cefotaxime adaptation 01 natural sciences Microbiologie Genetics (clinical) Genetics 0303 health sciences Drug Resistance Microbial PE&RC Adaptation Physiological Genetics and Genomics/Microbial Evolution and Genomics antibiotic-resistance Evolutionary Biology/Microbial Evolution and Genomics sequence space tem-1 beta-lactamase Mutation (genetic algorithm) Laboratory of Genetics Sequence space (evolution) Plasmids Research Article lcsh:QH426-470 Epistasis and functional genomics Biology in-vitro Laboratorium voor Erfelijkheidsleer 010603 evolutionary biology Microbiology beta-Lactamases Evolution Molecular 03 medical and health sciences Escherichia coli trajectories Amino Acid Sequence Selection Genetic Allele Molecular Biology Alleles Ecology Evolution Behavior and Systematics 030304 developmental biology VLAG Models Genetic Evolutionary Biology/Evolutionary and Comparative Genetics Mechanism (biology) Epistasis Genetic lcsh:Genetics Mutation escherichia-coli Epistasis empirical fitness landscapes Adaptation |
| Zdroj: | PLoS Genetics, Vol 7, Iss 3, p e1001321 (2011) Plos Genetics 7 (2011) 3 Plos Genetics, 7(3) PLoS Genetics |
| ISSN: | 1553-7404 1553-7390 |
| Popis: | Whether evolution is erratic due to random historical details, or is repeatedly directed along similar paths by certain constraints, remains unclear. Epistasis (i.e. non-additive interaction between mutations that affect fitness) is a mechanism that can contribute to both scenarios. Epistasis can constrain the type and order of selected mutations, but it can also make adaptive trajectories contingent upon the first random substitution. This effect is particularly strong under sign epistasis, when the sign of the fitness effects of a mutation depends on its genetic background. In the current study, we examine how epistatic interactions between mutations determine alternative evolutionary pathways, using in vitro evolution of the antibiotic resistance enzyme TEM-1 β-lactamase. First, we describe the diversity of adaptive pathways among replicate lines during evolution for resistance to a novel antibiotic (cefotaxime). Consistent with the prediction of epistatic constraints, most lines increased resistance by acquiring three mutations in a fixed order. However, a few lines deviated from this pattern. Next, to test whether negative interactions between alternative initial substitutions drive this divergence, alleles containing initial substitutions from the deviating lines were evolved under identical conditions. Indeed, these alternative initial substitutions consistently led to lower adaptive peaks, involving more and other substitutions than those observed in the common pathway. We found that a combination of decreased enzymatic activity and lower folding cooperativity underlies negative sign epistasis in the clash between key mutations in the common and deviating lines (Gly238Ser and Arg164Ser, respectively). Our results demonstrate that epistasis contributes to contingency in protein evolution by amplifying the selective consequences of random mutations. Author Summary A long-term goal of evolutionary biology is to understand the factors that govern the outcome of evolution. Epistasis (i.e. the situation in which the fitness effect of a mutation depends on its genetic background) is one such factor. Epistasis not only affects the dynamics of evolution, it may also direct its outcome by affecting the type and order of selected mutations. This effect is particularly strong under sign epistasis, which occurs when the sign of a mutation's fitness effect depends on its genetic background. Here, we demonstrate how epistasis causes divergence of mutational pathways of an antibiotic resistance enzyme, TEM-1 β-lactamase. First, we use in vitro mutagenesis followed by selection for cefotaxime resistance to demonstrate that alternative mutational pathways towards highly resistant variants exist in addition to the main pathway that was previously described. Next, to test whether negative interactions between alternative initial substitutions govern this diversification, we start identical evolution experiments with alleles containing initial substitutions from the deviating lines. These alleles consistently evolve to lower adaptive peaks and acquire different mutations than those in the main pathway. Our results demonstrate that sign epistasis between alternative initial substitutions may force evolution to follow different mutational pathways. |
| Databáze: | OpenAIRE |
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