Biophysical determinants of mutational robustness in a viral molecular fitness landscape

2017 ◽  
Author(s):  
Manasi A. Pethe ◽  
Aliza B. Rubenstein ◽  
Dmitri Zorine ◽  
Sagar D. Khare
Keyword(s):  
Fitness Landscape ◽  
Rna Virus ◽  
Fitness Landscapes ◽  
Viral Fitness ◽  
Mutational Robustness ◽  
Hcv Protease ◽  
Viral Polyprotein ◽  
Biophysical Interactions ◽  
Proteins And Peptides

Biophysical interactions between proteins and peptides are key determinants of genotype-fitness landscapes, but an understanding of how molecular structure and residue-level energetics at protein-peptide interfaces shape functional landscapes remains elusive. Combining information from yeast-based library screening, next-generation sequencing and structure-based modeling, we report comprehensive sequence-energetics-function mapping of the specificity landscape of the Hepatitis C Virus (HCV) NS3/4A protease, whose function — site-specific cleavages of the viral polyprotein — is a key determinant of viral fitness. We elucidate the cleavability of 3.2 million substrate variants by the HCV protease and find extensive clustering of cleavable and uncleavable motifs in sequence space indicating mutational robustness, and thereby providing a plausible molecular mechanism to buffer the effects of low replicative fidelity of this RNA virus. Specificity landscapes of known drug-resistant variants are similarly clustered. Our results highlight the key and constraining role of molecular-level energetics in shaping plateau-like fitness landscapes from quasispecies theory.

scholarly journals Data-driven supervised learning of a viral protease specificity landscape from deep sequencing and molecular simulations

2018 ◽  
Vol 116 (1) ◽  
pp. 168-176 ◽  
Author(s):  
Manasi A. Pethe ◽  
Aliza B. Rubenstein ◽  
Sagar D. Khare
Keyword(s):  
Supervised Learning ◽  
Deep Sequencing ◽  
Residue Level ◽  
Viral Fitness ◽  
Supervised Machine Learning ◽  
Support Vector ◽  
Graph Theoretic ◽  
Hcv Protease ◽  
Viral Polyprotein ◽  
Biophysical Interactions

Biophysical interactions between proteins and peptides are key determinants of molecular recognition specificity landscapes. However, an understanding of how molecular structure and residue-level energetics at protein−peptide interfaces shape these landscapes remains elusive. We combine information from yeast-based library screening, next-generation sequencing, and structure-based modeling in a supervised machine learning approach to report the comprehensive sequence−energetics−function mapping of the specificity landscape of the hepatitis C virus (HCV) NS3/4A protease, whose function—site-specific cleavages of the viral polyprotein—is a key determinant of viral fitness. We screened a library of substrates in which five residue positions were randomized and measured cleavability of ∼30,000 substrates (∼1% of the library) using yeast display and fluorescence-activated cell sorting followed by deep sequencing. Structure-based models of a subset of experimentally derived sequences were used in a supervised learning procedure to train a support vector machine to predict the cleavability of 3.2 million substrate variants by the HCV protease. The resulting landscape allows identification of previously unidentified HCV protease substrates, and graph-theoretic analyses reveal extensive clustering of cleavable and uncleavable motifs in sequence space. Specificity landscapes of known drug-resistant variants are similarly clustered. The described approach should enable the elucidation and redesign of specificity landscapes of a wide variety of proteases, including human-origin enzymes. Our results also suggest a possible role for residue-level energetics in shaping plateau-like functional landscapes predicted from viral quasispecies theory.

scholarly journals Host-parasite coevolution promotes innovation through deformations in fitness landscapes

2021 ◽  
Author(s):  
Animesh Gupta ◽  
Luis Zaman ◽  
Hannah M Strobel ◽  
Jenna Gallie ◽  
Alita R Burmeister ◽  
...  
Keyword(s):  
Laboratory Experiments ◽  
Gene Editing ◽  
Direct Evidence ◽  
Fitness Landscape ◽  
Fitness Landscapes ◽  
Ecological Communities ◽  
Bacteriophage Λ ◽  
Evolutionary Novelty ◽  
Host Parasite

During the struggle for survival, populations occasionally evolve new functions that give them access to untapped ecological opportunities. Theory suggests that coevolution between species can promote the evolution of such innovations by deforming fitness landscapes in ways that open new adaptive pathways. We directly tested this idea by using high throughput gene editing-phenotyping technology (MAGE-Seq) to measure the fitness landscape of a virus, bacteriophage λ, as it coevolved with its host, the bacterium Escherichia coli. Through computer simulations of λ's evolution on the empirical fitness landscape, we showed that λ was more likely to evolve to use a new receptor if it experienced a shift in its fitness landscape caused by coevolution. This result was further validated by additional laboratory experiments. This study provides direct evidence for the role of coevolution in driving evolutionary novelty and provides a quantitative framework for predicting evolution in coevolving ecological communities.

scholarly journals Genetic recombination of poliovirus facilitates subversion of host barriers to infection

2018 ◽  
Author(s):  
Ashley Acevedo ◽  
Andrew Woodman ◽  
Jamie J. Arnold ◽  
Ming Te Yeh ◽  
David Evans ◽  
...  
Keyword(s):  
Virus Replication ◽  
Genetic Recombination ◽  
Rna Virus ◽  
Small Population ◽  
Viral Fitness ◽  
Primary Role ◽  
Rna Recombination ◽  
Viral Mutant ◽  
The Impact

AbstractThe contribution of RNA recombination to viral fitness and pathogenesis is poorly defined. Here, we isolate a recombination-deficient, poliovirus variant and find that, while recombination is detrimental to virus replication in tissue culture, recombination is important for pathogenesis in infected animals. Notably, recombination-defective virus exhibits severe attenuation following intravenous inoculation that is associated with a significant reduction in population size during intra-host spread. Because the impact of high mutational loads manifests most strongly at small population sizes, our data suggest that the repair of mutagenized genomes is an essential function of recombination and that this function may drive the long-term maintenance of recombination in viral species despite its associated fitness costs.Significance StatementRNA recombination is a widespread but poorly understood feature of RNA virus replication. For poliovirus, recombination is involved in the emergence of neurovirulent circulating vaccine-derived poliovirus, which has hampered global poliovirus eradication efforts. This emergence illustrates the power of recombination to drive major adaptive change; however, it remains unclear if these adaptive events represent the primary role of recombination in virus survival. Here, we identify a viral mutant with a reduced rate of recombination and find that recombination also plays a central role in the spread of virus within animal hosts. These results highlight a novel approach for improving the safety of live attenuated vaccines and further our understanding of the role of recombination in virus pathogenesis and evolution.

scholarly journals The fitness landscape of the codon space across environments

2018 ◽  
Author(s):  
Inès Fragata ◽  
Sebastian Matuszewski ◽  
Mark A. Schmitz ◽  
Thomas Bataillon ◽  
Jeffrey D. Jensen ◽  
...  
Keyword(s):  
Amino Acid ◽  
Evolutionary Dynamics ◽  
Fitness Landscape ◽  
Fitness Landscapes ◽  
Synonymous Mutations ◽  
Landscape Studies ◽  
Fitness Effects ◽  
Bayesian Monte Carlo ◽  
The Relationship

AbstractFitness landscapes map the relationship between genotypes and fitness. However, most fitness landscape studies ignore the genetic architecture imposed by the codon table and thereby neglect the potential role of synonymous mutations. To quantify the fitness effects of synonymous mutations and their potential impact on adaptation on a fitness landscape, we use a new software based on Bayesian Monte Carlo Markov Chain methods and reestimate selection coefficients of all possible codon mutations across 9 amino-acid positions in Saccharomyces cerevisiae Hsp90 across 6 environments. We quantify the distribution of fitness effects of synonymous mutations and show that it is dominated by many mutations of small or no effect and few mutations of larger effect. We then compare the shape of the codon fitness landscape across amino-acid positions and environments, and quantify how the consideration of synonymous fitness effects changes the evolutionary dynamics on these fitness landscapes. Together these results highlight a possible role of synonymous mutations in adaptation and indicate the potential mis-inference when they are neglected in fitness landscape studies.

scholarly journals Recombination and mutational robustness in neutral fitness landscapes

2019 ◽  
Author(s):  
Alexander Klug ◽  
Su-Chan Park ◽  
Joachim Krug
Keyword(s):  
Evolutionary Biology ◽  
Fitness Landscape ◽  
Genetic Recombination ◽  
Fitness Landscapes ◽  
Point Of View ◽  
Genetic Exchange ◽  
Favorable Effect ◽  
Minor Effect ◽  
Moderate Increase ◽  
Mutational Robustness

AbstractMutational robustness quantifies the effect of random mutations on fitness. When mutational robustness is high, most mutations do not change fitness or have only a minor effect on it. From the point of view of fitness landscapes, robust genotypes form neutral networks of almost equal fitness. Using deterministic population models it has been shown that selection favors genotypes inside such networks, which results in increased mutational robustness. Here we demonstrate that this effect is massively enhanced by recombination. Our results are based on a detailed analysis of mesa-shaped fitness landscapes, where we derive precise expressions for the dependence of the robustness on the landscape parameters for recombining and non-recombining populations. In addition, we carry out numerical simulations on different types of random holey landscapes as well as on an empirical fitness landscape. We show that the mutational robustness of a genotype generally correlates with its recombination weight, a new measure that quantifies the likelihood for the genotype to arise from recombination. We argue that the favorable effect of recombination on mutational robustness is a highly universal feature that may have played an important role in the emergence and maintenance of mechanisms of genetic exchange.Author summaryTwo long-standing and seemingly unrelated puzzles in evolutionary biology concern the ubiquity of sexual reproduction and the robustness of organisms against genetic perturbations. Using a theoretical approach based on the concept of a fitness landscape, in this article we argue that the two phenomena may in fact be closely related. In our setting the hereditary information of an organism is encoded in its genotype, which determines it to be either viable or non-viable, and robustness is defined as the fraction of mutations that maintain viability. Previous work has demonstrated that the purging of non-viable genotypes from the population by natural selection leads to a moderate increase in robustness. Here we show that genetic recombination acting in combination with selection massively enhances this effect, an observation that is largely independent of how genotypes are connected by mutations. This suggests that the increase of robustness may be a major driver underlying the evolution of sexual recombination and other forms of genetic exchange throughout the living world.

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

2016 ◽  
Vol 90 (22) ◽  
pp. 10160-10169 ◽  
Author(s):  
Héctor Cervera ◽  
Jasna Lalić ◽  
Santiago F. Elena
Keyword(s):  
Host Species ◽  
Evolutionary Biology ◽  
Evolutionary Dynamics ◽  
Fitness Landscape ◽  
Rna Virus ◽  
Fitness Landscapes ◽  
Content Type ◽  
Fine Grained ◽  
Novel Host ◽  
Fitness Tradeoffs

ABSTRACTAdaptive 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 hostNicotiana 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 hostA. 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.

scholarly journals Effective potential reveals evolutionary trajectories in complex fitness landscapes

2019 ◽  
Author(s):  
Matteo Smerlak
Keyword(s):  
Effective Potential ◽  
Evolutionary Dynamics ◽  
Fitness Landscape ◽  
Coarse Graining ◽  
Fitness Landscapes ◽  
Coarse Grained ◽  
Mutational Robustness ◽  
Sequencing Technologies ◽  
Wide Range ◽  
Evolutionary Trajectories

AbstractGrowing efforts to measure fitness landscapes in molecular and microbial systems are premised on a tight relationship between landscape topography and evolutionary trajectories. This relationship, however, is far from being straightforward: depending on their mutation rate, Darwinian populations can climb the closest fitness peak (survival of the fittest), settle in lower regions with higher mutational robustness (survival of the flattest), or fail to adapt altogether (error catastrophes). These bifurcations highlight that evolution does not necessarily drive populations “from lower peak to higher peak”, as Wright imagined. The problem therefore remains: how exactly does a complex landscape topography constrain evolution, and can we predict where it will go next? Here I introduce a generalization of quasispecies theory which identifies metastable evolutionary states as minima of an effective potential. From this representation I derive a coarse-grained, Markov state model of evolution, which in turn forms a basis for evolutionary predictions across a wide range of mutation rates. Because the effective potential is related to the ground state of a quantum Hamiltonian, my approach could stimulate fruitful interactions between evolutionary dynamics and quantum many-body theory.SIGNIFICANCE STATEMENTThe course of evolution is determined by the relationship between heritable types and their adaptive values, the fitness landscape. Thanks to the explosive development of sequencing technologies, fitness landscapes have now been measured in a diversity of systems from molecules to micro-organisms. How can we turn these data into evolutionary predictions? I show that preferred evolutionary trajectories are revealed when the effects of selection and mutations are blended in a single effective evolutionary force. With this reformulation, the dynamics of selection and mutation becomes Markovian, bringing a wealth of classical visualization and analysis tools to bear on evolutionary dynamics. Among these is a coarse-graining of evolutionary dynamics along its metastable states which greatly reduces the complexity of the prediction problem.

scholarly journals The role of epistasis in determining the fitness landscape of HIV proteins

2021 ◽  
Author(s):  
Avik Biswas ◽  
Allan Haldane ◽  
Ronald Levy
Keyword(s):  
Drug Resistance ◽  
Potts Model ◽  
Dynamic Range ◽  
Fitness Landscape ◽  
Rapid Evolution ◽  
Viral Fitness ◽  
Multiple Drug ◽  
Epistatic Interactions ◽  
Limited Precision

The rapid evolution of HIV is constrained by interactions between mutations which affect viral fitness. In this work, we explore the role of epistasis in determining the fitness landscape of HIV for multiple drug target proteins, including Protease, Reverse Transcriptase, and Integrase. Epistatic interactions between residues modulate the mutation patterns involved in drug resistance with unambiguous signatures of epistasis best seen in the comparison of a maximum entropy sequence co-variation (Potts) model predicted and experimental HIV sequence ``prevalences" when expressed as higher-order marginals (beyond triplets) of the sequence probability distribution. In contrast, the evidence for epistasis based on experimental measures of fitness such as replicative capacity is weak;  the correspondence with Potts model ``prevalence"-based predictions is obscured by site conservation and limited precision. Double mutant cycles provide in principle one of the best ways to probe epistatic interactions experimentally without reference to a particular background, and we find they reveal that the most strongly interacting mutations in HIV involve correlated sets of drug-resistance-associated residues, however the analysis is complicated by the small dynamic range of measurements. The use of correlated models for the design of experiments to probe viral fitness can help identify the epistatic interactions involved in mutational escape, and lead to better inhibitor therapies.

scholarly journals The role of mutational robustness in RNA virus evolution

2013 ◽  
Vol 11 (5) ◽  
pp. 327-336 ◽  
Author(s):  
Adam S. Lauring ◽  
Judith Frydman ◽  
Raul Andino
Keyword(s):  
Rna Virus ◽  
Virus Evolution ◽  
Mutational Robustness
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