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.

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 Lexical landscapes as largein silicodata for examining advanced properties of fitness landscapes

2019 ◽  
Author(s):  
Victor A. Meszaros ◽  
Miles D. Miller-Dickson ◽  
C. Brandon Ogbunugafor
Keyword(s):  
Evolutionary Theory ◽  
Empirical Data ◽  
In Silico ◽  
Evolutionary Biology ◽  
Fitness Landscape ◽  
Evolutionary Genetics ◽  
Higher Order ◽  
Fitness Landscapes ◽  
Adaptive Landscape ◽  
Data Sets

In silicoapproaches have served a central role in the development of evolutionary theory for generations. This especially applies to the concept of the fitness landscape, one of the most important abstractions in evolutionary genetics, and one which has benefited from the presence of large empirical data sets only in the last decade or so. In this study, we propose a method that allows us to generate enormous data sets that walk the line betweenin silicoand empirical: word usage frequencies as catalogued by the Google ngram corpora. These data can be codified or analogized in terms of a multidimensional empirical fitness landscape towards the examination of advanced concepts—adaptive landscape by environment interactions, clonal competition, higher-order epistasis and countless others. We argue that the greaterLexical Landscapesapproach can serve as a platform that offers an astronomical number of fitness landscapes for exploration (at least) or theoretical formalism (potentially) in evolutionary biology.

NK Simulation Modeling

2016 ◽  
pp. 61-99
Author(s):  
Lucio Biggiero
Keyword(s):  
Biological Networks ◽  
Evolutionary Biology ◽  
Fitness Landscape ◽  
Simulation Modelling ◽  
Boolean Networks ◽  
Point Of View ◽  
Computational Point ◽  
General Aspects ◽  
Sharp Criticism ◽  
Evolutionary Paths

Launched and developed primarily by Kauffman from the end of sixties, NK simulation modelling candidates for capturing networks dynamics. Grounded in reference to biological networks, it has aroused a grate and durable interest in economics and management sciences too. This methodology is split into a version focused on studying proper Boolean networks dynamics, whose trajectories are substantially conditioned by Boolean functions, and a (much more frequented) version focused on systems co-evolutionary paths driven by the search for optimizing its fitness value. Besides the unquestionable value of Kauffman's work for the theoretical implications on evolutionary biology and the strong interest for economics and management sciences, in this chapter failures and limitations of both NK modelling versions are discussed. In particular, it is shown that as applications try to be more realistic, this modeling becomes hardly treatable from a computational point of view. On the other hand, it is underlined that, especially the fitness landscape version, NK simulation modelling is very useful to show general aspects of system's dynamics, and the impossibility to find general optima (excepted for very special and unrealistic cases). This result sounds a sharp criticism to general economic equilibrium, and it is perfectly consistent with Simon's contributions.

scholarly journals Genotypic context modulates fitness landscapes: Effects on the speed and direction of evolution for antimicrobial resistance

2018 ◽  
Author(s):  
C. Brandon Ogbunugafor ◽  
Rafael F. Guerrero ◽  
Margaret J. Eppstein
Keyword(s):  
Public Health ◽  
Drug Resistance ◽  
Antimicrobial Resistance ◽  
Adaptive Evolution ◽  
Evolutionary Biology ◽  
Fitness Landscape ◽  
Genetic Differences ◽  
Fitness Landscapes ◽  
Bacterial Enzyme ◽  
Pathogen Populations

AbstractUnderstanding the forces that drive the dynamics of adaptive evolution is a goal of many subfields within evolutionary biology. The fitness landscape analogy has served as a useful abstraction for addressing these topics across many systems, and recent treatments have revealed how different environments can frame the particulars of adaptive evolution by changing the topography of fitness landscapes. In this study, we examine how the larger, ambient genotypic context in which the fitness landscape being modeled is embedded affects fitness landscape topography and subsequent evolution. Using simulations on empirical fitness landscapes, we discover that genotypic context, defined by genetic variability in regions outside of the locus under study (in this case, an essential bacterial enzyme target of antibiotics), influences the speed and direction of evolution in several surprising ways. These findings have implications for how we study the evolution of drug resistance in nature, and for presumptions about how biological evolution might be expected to occur in genetically-modified organisms. More generally, the findings speak to theory surrounding how “difference can beget difference” in adaptive evolution: that small genetic differences between organisms can greatly alter the specifics of how evolution occurs, which can rapidly drive even slightly diverged populations further apart.Author summaryTechnological advances enable scientists to engineer individual mutations at specific sites within an organism’s genome with increasing ease. These breakthroughs have provided scientists with tools to study how different engineered mutations affect the function of a given gene or protein, yielding useful insight into genotype-phenotype mapping and evolution. In this study, we use engineered strains of bacteria to show how the dynamics (speed and direction) of evolution of drug resistance in an enzyme depends on the species-type of that bacterial enzyme, and on the presence/absence of mutations in other genes in the bacterial genome. These findings have broad implications for public health, genetic engineering, and theories of speciation. In the context of public health and biomedicine, our results suggest that future efforts in managing antimicrobial resistance must consider genetic makeup of different pathogen populations before predicting how resistance will occur, rather than assuming that the same resistance pathways will appear in different pathogen populations. With regard to broader theory in evolutionary biology, our results show how even small genetic differences between organisms can alter how future evolution occurs, potentially causing closely-related populations to quickly diverge.

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 Genetic Algorithms as a method to study adaptive walks in biological landscapes

2020 ◽  
Author(s):  
Edith Invernizzi ◽  
Graeme D Ruxton
Keyword(s):  
Genetic Algorithms ◽  
Evolutionary Biology ◽  
Fitness Landscape ◽  
Evolutionary Process ◽  
Simulation Modelling ◽  
Fitness Landscapes ◽  
Mathematical Methods ◽  
Reproductive Process ◽  
Modelling Framework ◽  
Phenotypic Fitness

AbstractThe metaphor of fitness landscapes is common in evolutionary biology, as a way to visualise the change in allele or phenotypic frequencies of a population under selection. Understanding how different factors in the evolutionary process affect the trajectory of the population across the landscape is of interest to both theoretical and empirical evolutionary biologists. However, fitness landscape studies often have to rely heavily on mathematical methods that are not easy to access by biologically trained researchers. Here, we used a method borrowed from engineering - genetic algorithms - to simulate the evolutionary process and study how different components affect the path taken through a phenotypic fitness landscape. In a simple study, we compare five selection models that reflect different degrees of dependency of fitness on trait quality: this includes strengths of selection, trait-quality dependent reproductive hierarchy and the amount of stochasticity in the reproductive process. We include an analysis of other evolutionary variables such as population size and mutation rate. We analyse a game theory problem, as a test landscape, that lends itself to analysis through a deterministic mathematical simulation, which we use for comparison. Our results show that there are differences in the speed with which different models of selection lead to the fitness optimum.Author summaryEvolution and adaptation in biology occurs in fitness landscapes, multidimensional spaces representing all possible genotypic or phenotypic combinations, where population adapt by following the cline of the fitness dimension. The study of adaptation on complex fitness landscapes has so far been limited by the need for mathematically heavy methods. Here, we present a simulation modelling framework, genetic algorithms, that can be used for evolutionary simulations of a population on a fitness landscape of chosen features and with custom evolutionary parameters.

scholarly journals On the (un-)predictability of a large intragenic fitness landscape

2016 ◽  
Author(s):  
Claudia Bank ◽  
Sebastian Matuszewski ◽  
Ryan T. Hietpas ◽  
Jeffrey D. Jensen
Keyword(s):  
Amino Acid ◽  
Fitness Landscape ◽  
Fitness Landscapes ◽  
Specific Information ◽  
Theoretical Approaches ◽  
Elevated Salinity ◽  
Theoretical Predictions ◽  
Experimental Approaches ◽  
Deterministic Processes ◽  
Negative Epistasis

AbstractThe study of fitness landscapes, which aims at mapping genotypes to fitness, is receiving ever-increasing attention. Novel experimental approaches combined with NGS methods enable accurate and extensive studies of the fitness effects of mutations – allowing us to test theoretical predictions and improve our understanding of the shape of the true underlying fitness landscape, and its implications for the predictability and repeatability of evolution.Here, we present a uniquely large multi-allelic fitness landscape comprised of 640 engineered mutants that represent all possible combinations of 13 amino-acid changing mutations at six sites in the heat-shock protein Hsp90 in Saccharomyces cerevisiae under elevated salinity. Despite a prevalent pattern of negative epistasis in the landscape, we find that the global fitness peak is reached via four positively epistatic mutations. Combining traditional and extending recently proposed theoretical and statistical approaches, we quantify features of the global multi-allelic fitness landscape. Using subsets of the data, we demonstrate that extrapolation beyond a known part of the landscape is difficult owing to both local ruggedness and amino-acid specific epistatic hotspots, and that inference is additionally confounded by the non-random choice of mutations for experimental fitness landscapes.Author SummaryThe study of fitness landscapes is fundamentally concerned with understanding the relative roles of stochastic and deterministic processes in adaptive evolution. Here, the authors present a uniquely large and complete multi-allelic intragenic fitness landscape of 640 systematically engineered mutations in yeast Hsp90. Using a combination of traditional and recently proposed theoretical approaches, they study the accessibility of the global fitness peak, and the potential for predictability of the fitness landscape topography. They report local ruggedness of the landscape and the existence of epistatic hotspot mutations, which together make extrapolation and hence predictability inherently difficult, if mutation-specific information is not considered.

scholarly journals The distribution of epistasis on simple fitness landscapes

2018 ◽  
Author(s):  
Christelle Fraïsse ◽  
John J. Welch
Keyword(s):  
Evolutionary Dynamics ◽  
Fitness Landscape ◽  
Null Model ◽  
Large Data ◽  
Fitness Landscapes ◽  
Mutational Bias ◽  
Data Set ◽  
Epistatic Interactions ◽  
Standing Variation ◽  
Mean And Variance

AbstractFitness interactions between mutations can influence a population’s evolution in many different ways. While epistatic effects are difficult to measure precisely, important information about the overall distribution is captured by the mean and variance of log fitnesses for individuals carrying different numbers of mutations. We derive predictions for these quantities from simple fitness landscapes, based on models of optimizing selection on quantitative traits. We also explore extensions to the models, including modular pleiotropy, variable effects sizes, mutational bias, and maladaptation of the wild-type. We illustrate our approach by reanalysing a large data set of mutant effects in a yeast snoRNA. Though characterized by some strong epistatic interactions, these data give a good overall fit to the non-epistatic null model, suggesting that epistasis might have little effect on the evolutionary dynamics in this system. We also show how the amount of epistasis depends on both the underlying fitness landscape, and the distribution of mutations, and so it is expected to vary in consistent ways between new mutations, standing variation, and fixed mutations.

scholarly journals Biophysical principles predict fitness landscapes of drug resistance

2016 ◽  
Vol 113 (11) ◽  
pp. E1470-E1478 ◽  
Author(s):  
João V. Rodrigues ◽  
Shimon Bershtein ◽  
Anna Li ◽  
Elena R. Lozovsky ◽  
Daniel L. Hartl ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Protein Quality ◽  
Fitness Landscape ◽  
Catalytic Efficiency ◽  
Fitness Landscapes ◽  
Resistance Mutations ◽  
Chlamydia Muridarum ◽  
Complete Set ◽  
Essential Enzyme

Fitness landscapes of drug resistance constitute powerful tools to elucidate mutational pathways of antibiotic escape. Here, we developed a predictive biophysics-based fitness landscape of trimethoprim (TMP) resistance for Escherichia coli dihydrofolate reductase (DHFR). We investigated the activity, binding, folding stability, and intracellular abundance for a complete set of combinatorial DHFR mutants made out of three key resistance mutations and extended this analysis to DHFR originated from Chlamydia muridarum and Listeria grayi. We found that the acquisition of TMP resistance via decreased drug affinity is limited by a trade-off in catalytic efficiency. Protein stability is concurrently affected by the resistant mutants, which precludes a precise description of fitness from a single molecular trait. Application of the kinetic flux theory provided an accurate model to predict resistance phenotypes (IC50) quantitatively from a unique combination of the in vitro protein molecular properties. Further, we found that a controlled modulation of the GroEL/ES chaperonins and Lon protease levels affects the intracellular steady-state concentration of DHFR in a mutation-specific manner, whereas IC50 is changed proportionally, as indeed predicted by the model. This unveils a molecular rationale for the pleiotropic role of the protein quality control machinery on the evolution of antibiotic resistance, which, as we illustrate here, may drastically confound the evolutionary outcome. These results provide a comprehensive quantitative genotype–phenotype map for the essential enzyme that serves as an important target of antibiotic and anticancer therapies.

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