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

2016 ◽  
Vol 113 (49) ◽  
pp. 14085-14090 ◽  
Author(s):  
Claudia Bank ◽  
Sebastian Matuszewski ◽  
Ryan T. Hietpas ◽  
Jeffrey D. Jensen
Keyword(s):  
Amino Acid ◽  
Fitness Landscape ◽  
Fitness Landscapes ◽  
Fitness Effects ◽  
Elevated Salinity ◽  
Theoretical Predictions ◽  
Experimental Approaches ◽  
Next Generation Sequencing Ngs ◽  
Negative Epistasis ◽  
Generation Sequencing

The study of fitness landscapes, which aims at mapping genotypes to fitness, is receiving ever-increasing attention. Novel experimental approaches combined with next-generation sequencing (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 multiallelic fitness landscape comprising 640 engineered mutants that represent all possible combinations of 13 amino acid-changing mutations at 6 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 multiallelic 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 nonrandom choice of mutations for experimental fitness landscapes.

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 The distribution of epistasis on simple fitness landscapes

2019 ◽  
Vol 15 (4) ◽  
pp. 20180881 ◽  
Author(s):  
Christelle Fraïsse ◽  
John J. Welch
Keyword(s):  
Evolutionary Dynamics ◽  
Fitness Landscape ◽  
Null Model ◽  
Fitness Landscapes ◽  
Mutational Bias ◽  
Variable Effect ◽  
Epistatic Effects ◽  
Standing Variation ◽  
Mean And Variance ◽  
Nucleolar Rna

Fitness interactions between mutations can influence a population’s evolution in many different ways. While epistatic effects are difficult to measure precisely, important information is captured by the mean and variance of log fitnesses for individuals carrying different numbers of mutations. We derive predictions for these quantities from a class of simple fitness landscapes, based on models of optimizing selection on quantitative traits. We also explore extensions to the models, including modular pleiotropy, variable effect sizes, mutational bias and maladaptation of the wild type. We illustrate our approach by reanalysing a large dataset of mutant effects in a yeast snoRNA (small nucleolar RNA). Though characterized by some large epistatic effects, these data give a good overall fit to the non-epistatic null model, suggesting that epistasis might have limited influence 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 is expected to vary in consistent ways between new mutations, standing variation and fixed mutations.

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 On Cellular Darwinism: Mitochondria

2016 ◽  
Vol 22 (1) ◽  
pp. 112-118 ◽  
Author(s):  
Larry Bull
Keyword(s):  
Significant Role ◽  
Genetic Variant ◽  
Relative Rate ◽  
Evolutionary Process ◽  
Fitness Landscapes ◽  
Rate Of Evolution ◽  
The Relationship

The significant role of mitochondria within cells is becoming increasingly clear. This letter uses the NKCS model of coupled fitness landscapes to explore aspects of organelle-nucleus coevolution. The phenomenon of mitochondrial diversity is allowed to emerge under a simple intracellular evolutionary process, including varying the relative rate of evolution by the organelle. It is shown how the conditions for the maintenance of more than one genetic variant of mitochondria are similar to those previously suggested as needed for the original symbiotic origins of the relationship using the NKCS model.

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 The distribution of fitness effects among synonymous mutations in a gene under selection

2019 ◽  
Author(s):  
E. Lebeuf-Taylor ◽  
N. McCloskey ◽  
S.F. Bailey ◽  
A. Hinz ◽  
R. Kassen
Keyword(s):  
Amino Acid ◽  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Compelling Evidence ◽  
Competitive Fitness ◽  
Synonymous Substitutions ◽  
Synonymous Mutations ◽  
Fitness Effects ◽  
Growing Body ◽  
Direct Measures

AbstractThe fitness effects of synonymous mutations, nucleotide changes that do not alter the encoded amino acid, have often been assumed to be neutral, but a growing body of evidence suggests otherwise. We used site-directed mutagenesis coupled with direct measures of competitive fitness to estimate the distribution of fitness effects among synonymous mutations for a gene under selection. Synonymous mutations had highly variable fitness effects, both deleterious and beneficial, resembling those of nonsynonymous mutations in the same gene. This variation in fitness was underlain by changes in transcription linked to the creation of internal promoter sites. A positive correlation between fitness and the presence of synonymous substitutions across a phylogeny of related Pseudomonads suggests these mutations may be common in nature. Taken together, our results provide the most compelling evidence to date that synonymous mutations with non-neutral fitness effects may in fact be commonplace.

scholarly journals Within-patient mutation frequencies reveal fitness costs of CpG dinucleotides and drastic amino acid changes in HIV

2016 ◽  
Author(s):  
Kristof Theys ◽  
Alison F. Feder ◽  
Maoz Gelbart ◽  
Marion Hartl ◽  
Adi Stern ◽  
...  
Keyword(s):  
Amino Acid ◽  
Mutation Rate ◽  
Fitness Landscape ◽  
Fitness Costs ◽  
Nonsense Mutations ◽  
Cpg Dinucleotides ◽  
Synonymous Mutations ◽  
The Cost ◽  
Patient Mutation

AbstractHIV has a high mutation rate, which contributes to its ability to evolve quickly. However, we know little about the fitness costs of individual HIV mutationsin vivo, their distribution and the different factors shaping the viral fitness landscape. We calculated the mean frequency of transition mutations at 870 sites of thepolgene in 160 patients, allowing us to determine the cost of these mutations. As expected, we found high costs for non-synonymous and nonsense mutations as compared to synonymous mutations. In addition, we found that non-synonymous mutations that lead to drastic amino acid changes are twice as costly as those that do not and mutations that create new CpG dinucleotides are also twice as costly as those that do not. We also found that G→A and C→T mutations are more costly than A→G mutations. We anticipate that our newin vivofrequency-based approach will provide insights into the fitness landscape and evolvability of not only HIV, but a variety of microbes.Author summaryHIV’s high mutation rate allows it to evolve quickly. However, most mutations probably reduce the virus’ ability to replicate – they are costly to the virus. Until now, the actual cost of mutations is not well understood. We used within-patient mutation frequencies to estimate the cost of 870 HIV mutationsin vivo. As expected, we found high costs for non-synonymous and nonsense mutations. In addition, we found surprisingly high costs for mutations that lead to drastic amino acid changes, mutations that create new CpG sites (possibly because they trigger the host’s immune system), and G→A and C→T mutations. Our results demonstrate the power of analyzing mutant frequencies fromin vivoviral populations to study costs of mutations. A better understanding of fitness costs will help to predict the evolution of HIV.

scholarly journals The role of synonymous mutations in the evolution of TEM β-lactamase genes

2021 ◽  
Author(s):  
Mohammad Faheem ◽  
Charles J. Zhang ◽  
Monica N. Morris ◽  
Juergen Pleiss ◽  
Peter Oelschlaeger
Keyword(s):  
Escherichia Coli ◽  
Amino Acid ◽  
Disc Diffusion ◽  
Nucleotide Change ◽  
Nonsynonymous Mutation ◽  
Synonymous Mutations ◽  
Extended Spectrum ◽  
Genes Encoding ◽  
Variant Genes

Nonsynonymous mutations are well documented in TEM β-lactamases. The resulting amino acid changes often alter the conferred phenotype from broad spectrum (2b) conferred by TEM-1 to extended spectrum (2be), inhibitor resistant (2br), or both extended spectrum and inhibitor resistant (2ber). The encoding blaTEM genes also deviate in numerous synonymous mutations, which are not well understood. blaTEM-3 (2be), blaTEM-33 (2br), and blaTEM-109 (2ber) were studied in comparison to blaTEM-1. blaTEM-33 was chosen for more detailed studies, because it deviates from blaTEM-1 by a single nonsynonymous mutation and three additional, synonymous mutations. Genes encoding the enzymes with only nonsynonymous or all, including synonymous, mutations plus all permutations between blaTEM-1 and blaTEM-33 were expressed in Escherichia coli cells. In disc diffusion assays, genes encoding TEM-3, TEM-33, and TEM-109 with all synonymous mutations resulted in higher resistance levels than genes without synonymous mutations. Disc diffusion assays with the 16 genes carrying all possible nucleotide change combinations between blaTEM-1 and blaTEM-33 indicated different susceptibilities for different variants. Nucleotide BLAST searches did not identify genes without synonymous mutations but some without nonsynonymous mutations. Energies of possible secondary mRNA structures calculated with mfold are generally higher with synonymous mutations, suggesting that their role could be to destabilize the mRNA and facilitate its unfolding for efficient translation. In summary, our data indicate that transitions from blaTEM-1 to other variant genes by simply acquiring the nonsynonymous mutations is not favored. Instead, synonymous mutations seem to support the transition to other variant genes with nonsynonymous mutations leading to different phenotypes.

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