Fitness Epistasis and Constraints on Adaptation in a Human Immunodeficiency Virus Type 1 Protein Region

Silva, Jack da; Coetzer, Mia; Nedellec, Rebecca; Pastore, Cristina; Mosier, Donald E.

doi:10.1534/genetics.109.112458

Cited by 126 publications

(137 citation statements)

References 81 publications

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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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“…The equations and calculations presented in this work can be used in any situation with fitness valleys and ridges where the deterministic assumptions are fulfilled and the population reproduces asexually. As a result, this method can aid the study of the effects of deleterious mutations in a wide range of pathogens, including, for example, Mycobacterium tuberculosis and HIV (5,40,41). The methodology of counting the number of routes is a straightforward approach to calculate the effect of deleterious intermediate mutations and understand the ways in which pathogen populations traverse fitness valleys and ridges.…”

Section: Discussionmentioning

confidence: 99%

“…Reductions in fitness occur when underlying combinations of genetic mutations lead to an unfit or deleterious phenotype, creating depressions in the fitness landscape. One phenomenon causing sharp peaks and troughs in the fitness landscape is sign epistasis, where a beneficial adaptation involves a combination of individually deleterious mutations (1)(2)(3)(4)(5). In the case where mutants with intermediate mutations are less fit than the wild-type and adapted viruses, a fitness valley, a barrier of disadvantageous mutations hampering the access to other landscape regions, is created (4,6).…”

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confidence: 99%

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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“…Unfortunately, the amount of information about fitness landscapes is still very limited. Empirical fitness landscapes have been explored thoroughly only for another virus, HIV-1, for mutations allowing access to an alternative cell surface chemokine coreceptor (46)(47)(48) and for adaptation to different antiviral drugs (49). In both cases, ruggedness has been proved to be common due to the pervasiveness of epistasis.…”

Section: Figmentioning

confidence: 99%

Effect of Host Species on Topography of the Fitness Landscape for a Plant RNA Virus

Cervera

Lalić

Elena

2016

J Virol

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Adaptive fitness landscapes are a fundamental concept in evolutionary biology that relate the genotypes of individuals to their fitness. In the end, the evolutionary fate of evolving populations depends on the topography of the landscape, that is, the numbers of accessible mutational pathways and possible fitness peaks (i.e., adaptive solutions). For a long time, fitness landscapes were only theoretical constructions due to a lack of precise information on the mapping between genotypes and phenotypes. In recent years, however, efforts have been devoted to characterizing the properties of empirical fitness landscapes for individual proteins or for microbes adapting to artificial environments. In a previous study, we characterized the properties of the empirical fitness landscape defined by the first five mutations fixed during adaptation of tobacco etch potyvirus (TEV) to a new experimental host, Arabidopsis thaliana. Here we evaluate the topography of this landscape in the ancestral host Nicotiana tabacum. By comparing the topographies of the landscapes for the two hosts, we found that some features remained similar, such as the existence of fitness holes and the prevalence of epistasis, including cases of sign and reciprocal sign epistasis that created rugged, uncorrelated, and highly random topographies. However, we also observed significant differences in the fine-grained details between the two landscapes due to changes in the fitness and epistatic interactions of some genotypes. Our results support the idea that not only fitness tradeoffs between hosts but also topographical incongruences among fitness landscapes in alternative hosts may contribute to virus specialization. IMPORTANCEDespite its importance for understanding virus evolutionary dynamics, very little is known about the topography of virus adaptive fitness landscapes, and even less is known about the effects that different host species and environmental conditions may have on this topography. To bridge this gap, we evaluated the topography of a small fitness landscape formed by all genotypes that result from every possible combination of the first five mutations fixed during adaptation of TEV to the novel host A. thaliana. To assess the effect that host species may have on this topography, we evaluated the fitness of every genotype in both the ancestral and novel hosts. We found that both landscapes share some macroscopic properties, such as the existence of holes and being highly rugged and uncorrelated, yet they differ in microscopic details due to changes in the magnitude and sign of fitness and epistatic effects. T he effects of mutations can be influenced by their interactions with other mutations, with the environment, or both. Epistatic interactions among genetic loci determine the ruggedness of fitness landscapes. In the absence of epistasis, landscapes are single peaked and smooth (1). For such simple landscapes, predicting the result of evolution is an easy task. In contrast, epistatic interactions create curvature in the lands...

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Fitness Epistasis and Constraints on Adaptation in a Human Immunodeficiency Virus Type 1 Protein Region

Cited by 126 publications

References 81 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

Effect of Host Species on Topography of the Fitness Landscape for a Plant RNA Virus

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