Reciprocal sign epistasis is a necessary condition for multi-peaked fitness landscapes

Poelwijk, Frank J.; Tănase‐Nicola, Sorin; Kiviet, Daniel J.; Tans, Sander J.

doi:10.1016/j.jtbi.2010.12.015

Cited by 202 publications

(275 citation statements)

References 25 publications

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“…Therefore, the number of pathways accessible by natural selection decreases [2] and successful adaptation becomes contingent upon the identity of first-step mutations [7]. A second, more drastic consequence is the emergence of multiple fitness peaks, which requires a particularly extreme form of epistasis known as reciprocal sign epistasis [9]. Overall, these observations led to the conjecture that natural selection may be limited by pervasive genetic constraints, contributing to explain the surprising degree of repeatability observed in many microbial evolution experiments [10,11].…”

Section: Introductionmentioning

confidence: 99%

Bypass of genetic constraints during mutator evolution to antibiotic resistance

2015

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Genetic constraints can block many mutational pathways to optimal genotypes in real fitness landscapes, yet the extent to which this can limit evolution remains to be determined. Interestingly, mutator bacteria elevate only specific types of mutations, and therefore could be very sensitive to genetic constraints. Testing this possibility is not only clinically relevant, but can also inform about the general impact of genetic constraints in adaptation. Here, we evolved 576 populations of two mutator and one wild-type Escherichia coli to doubling concentrations of the antibiotic cefotaxime. All strains carried TEM-1, a b-lactamase enzyme well known by its low availability of mutational pathways. Crucially, one of the mutators does not elevate any of the relevant first-step mutations known to improve cefatoximase activity. Despite this, both mutators displayed a similar ability to evolve more than 1000-fold resistance. Initial adaptation proceeded in parallel through general multi-drug resistance mechanisms. High-level resistance, in contrast, was achieved through divergent paths; with the a priori inferior mutator exploiting alternative mutational pathways in PBP3, the target of the antibiotic. These results have implications for mutator management in clinical infections and, more generally, illustrate that limits to natural selection in real organisms are alleviated by the existence of multiple loci contributing to fitness.

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Section: Introductionmentioning

confidence: 99%

Bypass of genetic constraints during mutator evolution to antibiotic resistance

2015

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“…This observation illustrates that reciprocal sign epistatic interaction stands at key locations of a multipeaked landscape, and is in line with a theoretical investigation of ours, which indicates that reciprocal sign epistasis is an essential ingredient for the existence of multiple peaks. 34 From Table I, we can also identify several peaks that are in close proximity to each other, being separated by a Hamming distance of only two. Three different situations can be discerned among the 13 cases.…”

Section: Resultsmentioning

confidence: 99%

Multiple peaks and reciprocal sign epistasis in an empirically determined genotype-phenotype landscape

Dawid¹,

Kiviet²,

Kogenaru³

et al. 2010

Chaos: An Interdisciplinary Journal of Nonlinear Science

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Insight into the ruggedness of adaptive landscapes is central to understanding the mechanisms and constraints that shape the course of evolution. While empirical data on adaptive landscapes remain scarce, a handful of recent investigations have revealed genotype-phenotype and genotype-fitness landscapes that appeared smooth and single peaked. Here, we used existing in vivo measurements on lac repressor and operator mutants in Escherichia coli to reconstruct the genotype-phenotype map that details the repression value of this regulatory system as a function of two key repressor residues and four key operator base pairs. We found that this landscape is multipeaked, harboring in total 19 distinct optima. Analysis showed that all direct evolutionary pathways between peaks involve significant dips in the repression value. Consistent with earlier predictions, we found reciprocal sign epistatic interactions at the repression minimum of the most favorable paths between two peaks. These results suggest that the occurrence of multiple peaks and reciprocal epistatic interactions may be a general feature in coevolving systems like the repressor-operator pair studied here.

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“…The relevance of epistasis is determined not just by its presence, but also by the particular forms it takes. For example, reciprocal sign epistasis, such as when two mutations that are individually deleterious are beneficial in combination, leads to rugged, multipeaked fitness landscapes (Poelwijk et al 2011), which can reduce the efficacy of natural selection. Sexual reproduction can be favored over asexual reproduction when deleterious mutations show synergistic epistasis.…”

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confidence: 99%

Environment Determines Epistatic Patterns for a ssDNA Virus

2014

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Despite the accumulation of substantial quantities of information about epistatic interactions among both deleterious and beneficial mutations in a wide array of experimental systems, neither consistent patterns nor causal explanations for these interactions have yet emerged. Furthermore, the effects of mutations depend on the environment in which they are characterized, implying that the environment may also influence epistatic interactions. Recent work with beneficial mutations for the single-stranded DNA bacteriophage ID11 demonstrated that interactions between pairs of mutations could be understood by means of a simple model that assumes that mutations have additive phenotypic effects and that epistasis arises through a nonlinear phenotype-fitness map with a single intermediate optimum.To determine whether such a model could also explain changes in epistatic patterns associated with changes in environment, we measured epistatic interactions for these same mutations under conditions for which we expected to find the wild-type ID11 at different distances from its phenotypic optimum by assaying fitnesses at three different temperatures: 33°, 37°, and 41°. Epistasis was present and negative under all conditions, but became more pronounced as temperature increased. We found that the additive-phenotypes model explained these patterns as changes in the parameters of the phenotype-fitness map, but that a model that additionally allows the phenotypes to vary across temperatures performed significantly better. Our results show that ostensibly complex patterns of fitness effects and epistasis across environments can be explained by assuming a simple structure for the genotype-phenotype relationship.

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Reciprocal sign epistasis is a necessary condition for multi-peaked fitness landscapes

Cited by 202 publications

References 25 publications

Bypass of genetic constraints during mutator evolution to antibiotic resistance

Bypass of genetic constraints during mutator evolution to antibiotic resistance

Multiple peaks and reciprocal sign epistasis in an empirically determined genotype-phenotype landscape

Environment Determines Epistatic Patterns for a ssDNA Virus

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