Evolutionary Accessibility of Mutational Pathways

Franke, Jasper; Klözer, Alexander; Visser, Jaap; Krug, Joachim

doi:10.1371/journal.pcbi.1002134

Cited by 204 publications

(385 citation statements)

References 50 publications

(89 reference statements)

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“…Several reports have documented both inter- [4,5,56] and intralocus [27,57,58] sign epistasis in different model systems. These observations promoted the idea that genetic constraints could be prevalent and hence adaptation could proceed through very few mutational paths to optimal genotypes [8,11].…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

Bypass of genetic constraints during mutator evolution to antibiotic resistance

2015

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“…Although some models have recognized the importance of deleterious intermediates and the crossing of fitness valleys to the overall adaptive evolution of pathogens (27,29,42,43) and the possibility that multiple simultaneous mutations can overcome such fitness valleys (44), various other models assume a strong selection-weak mutation paradigm (32)(33)(34)45), ignoring any adaptive trajectories that require the crossing of a fitness valley. Such assumptions might be appropriate for small population sizes or pathogens with low mutation rates (5,30).…”

Section: Discussionmentioning

confidence: 99%

“…A methodological framework that is frequently used to study pathogen evolution and that makes such assumptions is the strong selection-weak mutation (SSWM) approximation (30,31). Models using the SSWM assumption describe the evolutionary trajectory of a population where selective sweeps cause the sequential fixation of advantageous mutations, while deleterious or neutral mutations are disregarded (32)(33)(34).…”

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Expected Effect of Deleterious Mutations on Within-Host Adaptation of Pathogens

Fonville

2015

J Virol

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Adaptation is a common theme in both pathogen emergence, for example, in zoonotic cross-species transmission, and pathogen control, where adaptation might limit the effect of the immune response and antiviral treatment. When such evolution requires deleterious intermediate mutations, fitness ridges and valleys arise in the pathogen's fitness landscape. The effect of deleterious intermediate mutations on within-host pathogen adaptation is examined with deterministic calculations, appropriate for pathogens replicating in large populations with high error rates. The effect of deleterious intermediate mutations on pathogen adaptation is smaller than their name might suggest: when two mutations are required and each individual single mutation is fully deleterious, the pathogen can jump across the fitness valley by obtaining two mutations at once, leading to a proportion of adapted mutants that is 20-fold lower than that in the situation where the fitness of all mutants is neutral. The negative effects of deleterious intermediates are typically substantially smaller and outweighed by the fitness advantages of the adapted mutant. Moreover, requiring a specific mutation order has a substantially smaller effect on pathogen adaptation than the effect of all intermediates being deleterious. These results can be rationalized when the number of routes of mutation available to the pathogen is calculated, providing a simple approach to estimate the effect of deleterious mutations. The calculations discussed here are applicable when the effect of deleterious mutations on the within-host adaptation of pathogens is assessed, for example, in the context of zoonotic emergence, antigenic escape, and drug resistance. IMPORTANCEAdaptation is critical for pathogens after zoonotic transmission into a new host species or to achieve antigenic immune escape and drug resistance. Using a deterministic approach, the effects of deleterious intermediate mutations on pathogen adaptation were calculated while avoiding commonly made simplifications that do not apply to large pathogen populations replicating with high mutation rates. Perhaps unexpectedly, pathogen adaptation does not halt when the intermediate mutations are fully deleterious. The negative effects of deleterious mutations are substantially outweighed by the fitness gains of adaptation. To gain an understanding of the effect of deleterious mutations on pathogen adaptation, a simple approach that counts the number of routes available to the pathogen with and without deleterious intermediate mutations is introduced. This methodology enables a straightforward calculation of the proportion of the pathogen population that will cross a fitness valley or traverse a fitness ridge, without reverting to more complicated mathematical models. The fitness landscape of a pathogen is likely to have a rugged shape and consist of multiple optima. Reductions in fitness occur when underlying combinations of genetic mutations lead to an unfit or deleterious phenotype, creating depressions in the...

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“…As a consequence, a mutational pathway connecting two genotypes is selectively accessible in the SSWM regime only if fitness increases in each step (22). A number of recent studies of empirical fitness landscapes have shown that, in most cases, only a small fraction of possible adaptive pathways are accessible in this sense, which implies a dramatic enhancement of evolutionary predictability (10,11,15,(23)(24)(25)(26)(27). Moreover, the statistical weights of different accessible trajectories often vary widely, further narrowing the range of possibilities to a small number of dominant evolutionary pathways (10,11,15).…”

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confidence: 99%

Predictability of evolution depends nonmonotonically on population size

Szendro

Franke

Visser

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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To gauge the relative importance of contingency and determinism in evolution is a fundamental problem that continues to motivate much theoretical and empirical research. In recent evolution experiments with microbes, this question has been explored by monitoring the repeatability of adaptive changes in replicate populations. Here, we present the results of an extensive computational study of evolutionary predictability based on an experimentally measured eight-locus fitness landscape for the filamentous fungus Aspergillus niger. To quantify predictability, we define entropy measures on observed mutational trajectories and endpoints. In contrast to the common expectation of increasingly deterministic evolution in large populations, we find that these entropies display an initial decrease and a subsequent increase with population size N, governed, respectively, by the scales Nμ and Nμ 2 , corresponding to the supply rates of single and double mutations, where μ denotes the mutation rate. The amplitude of this pattern is determined by μ. We show that these observations are generic by comparing our findings for the experimental fitness landscape to simulations on simple model landscapes.clonal interference | epistasis | experimental evolution E volutionary adaptations arise from an intricate interplay of deterministic selective forces and random reproductive or mutational events, and the relative roles of these two types of influences on the outcome of evolution has been subject to longstanding controversy with significant philosophical implications (1, 2). Although the vision of "replaying the tape of life" on Earth or on some extrasolar planet remains confined to the realm of imagination (3, 4), evolution experiments with microbial populations have begun to address predictability of adaptation on a microevolutionary scale (5-9). In particular, strong signatures of parallel evolution have been observed in the context of the evolution of antibiotic resistance in pathogens, a finding that is of direct relevance to strategies of drug design and deployment (10-14). As lack of knowledge of crucial parameters (e.g., the frequency of beneficial mutations) in such experiments prevents forward predictions, predictability is used in a weaker, a posteriori sense implying repeatability of evolutionary trajectories in replicate populations. For this reason, the two terms will often be used interchangeably in the following (15).The repeatability of adaptive trajectories is expected to depend on the genetic constraints imposed by epistatic interactions as well as on parameters such as population size N, mutation rate μ, and the typical scale s of selection coefficients (16-18). To be specific, consider a population evolving in the regime of strong selection and weak mutation (SSWM), where mutations are so rare that normally not more than one mutant is present simultaneously and the population can be represented as a single entity that performs an adaptive walk in the space of genotypes (19)(20)(21). Such walks are constrained to ...

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Evolutionary Accessibility of Mutational Pathways

Cited by 204 publications

References 50 publications

Bypass of genetic constraints during mutator evolution to antibiotic resistance

Bypass of genetic constraints during mutator evolution to antibiotic resistance

Expected Effect of Deleterious Mutations on Within-Host Adaptation of Pathogens

Predictability of evolution depends nonmonotonically on population size

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