Evolution of mutation rates in hypermutable populations of Escherichia coli propagated at very small effective population size.
ABSTRACT: Mutation is the ultimate source of the genetic variation-including variation for mutation rate itself-that fuels evolution. Natural selection can raise or lower the genomic mutation rate of a population by changing the frequencies of mutation rate modifier alleles associated with beneficial and deleterious mutations. Existing theory and observations suggest that where selection is minimized, rapid systematic evolution of mutation rate either up or down is unlikely. Here, we report systematic evolution of higher and lower mutation rates in replicate hypermutable Escherichia coli populations experimentally propagated at very small effective size-a circumstance under which selection is greatly reduced. Several populations went extinct during this experiment, and these populations tended to evolve elevated mutation rates. In contrast, populations that survived to the end of the experiment tended to evolve decreased mutation rates. We discuss the relevance of our results to current ideas about the evolution, maintenance and consequences of high mutation rates.
Project description:All organisms encode enzymes that replicate, maintain, pack, recombine, and repair their genetic material. For this reason, mutation rates and biases also evolve by mutation, variation, and natural selection. By examining metagenomic time series of the Lenski long-term evolution experiment (LTEE) with Escherichia coli (Good, et al. 2017), we find that local mutation rate variation has evolved during the LTEE. Each LTEE population has evolved idiosyncratic differences in their rates of point mutations, indels, and mobile element insertions, due to the fixation of various hypermutator and antimutator alleles. One LTEE population, called Ara+3, shows a strong, symmetric wave pattern in its density of point mutations, radiating from the origin of replication. This pattern is largely missing from the other LTEE populations, most of which evolved missense, indel, or structural mutations in topA, fis, and dusB- loci that all affect DNA topology. The distribution of mutations in those genes over time suggests epistasis and historical contingency in the evolution of DNA topology, which may have in turn affected local mutation rates. Overall, the replicate populations of the LTEE have largely diverged in their mutation rates and biases, even though they have adapted to identical abiotic conditions.
Project description:Mutation rates can evolve through genetic drift, indirect selection due to genetic hitchhiking, or direct selection on the physicochemical cost of high fidelity. However, for many systems, it has been difficult to disentangle the relative impact of these forces empirically. In RNA viruses, an observed correlation between mutation rate and virulence has led many to argue that their extremely high mutation rates are advantageous because they may allow for increased adaptability. This argument has profound implications because it suggests that pathogenesis in many viral infections depends on rare or de novo mutations. Here, we present data for an alternative model whereby RNA viruses evolve high mutation rates as a byproduct of selection for increased replicative speed. We find that a poliovirus antimutator, 3DG64S, has a significant replication defect and that wild-type (WT) and 3DG64S populations have similar adaptability in 2 distinct cellular environments. Experimental evolution of 3DG64S under selection for replicative speed led to reversion and compensation of the fidelity phenotype. Mice infected with 3DG64S exhibited delayed morbidity at doses well above the lethal level, consistent with attenuation by slower growth as opposed to reduced mutational supply. Furthermore, compensation of the 3DG64S growth defect restored virulence, while compensation of the fidelity phenotype did not. Our data are consistent with the kinetic proofreading model for biosynthetic reactions and suggest that speed is more important than accuracy. In contrast with what has been suggested for many RNA viruses, we find that within-host spread is associated with viral replicative speed and not standing genetic diversity.
Project description:Mutations are the ultimate source of heritable variation for evolution. Understanding how mutation rates themselves evolve is thus essential for quantitatively understanding many evolutionary processes. According to theory, mutation rates should be minimized for well-adapted populations living in stable environments, whereas hypermutators may evolve if conditions change. However, the long-term fate of hypermutators is unknown. Using a phylogenomic approach, we found that an adapting Escherichia coli population that first evolved a mutT hypermutator phenotype was later invaded by two independent lineages with mutY mutations that reduced genome-wide mutation rates. Applying neutral theory to synonymous substitutions, we dated the emergence of these mutations and inferred that the mutT mutation increased the point-mutation rate by ∼150-fold, whereas the mutY mutations reduced the rate by ∼40-60%, with a corresponding decrease in the genetic load. Thus, the long-term fate of the hypermutators was governed by the selective advantage arising from a reduced mutation rate as the potential for further adaptation declined.
Project description:The advent of high-throughput sequencing techniques has made it possible to follow the genomic evolution of pathogenic bacteria by comparing longitudinally collected bacteria sampled from human hosts. Such studies in the context of chronic airway infections by Pseudomonas aeruginosa in cystic fibrosis (CF) patients have indicated high bacterial population diversity. Such diversity may be driven by hypermutability resulting from DNA mismatch repair system (MRS) deficiency, a common trait evolved by P. aeruginosa strains in CF infections. No studies to date have utilized whole-genome sequencing to investigate within-host population diversity or long-term evolution of mutators in CF airways. We sequenced the genomes of 13 and 14 isolates of P. aeruginosa mutator populations from an Argentinian and a Danish CF patient, respectively. Our collection of isolates spanned 6 and 20 years of patient infection history, respectively. We sequenced 11 isolates from a single sample from each patient to allow in-depth analysis of population diversity. Each patient was infected by clonal populations of bacteria that were dominated by mutators. The in vivo mutation rate of the populations was ?100 SNPs/year-?40-fold higher than rates in normo-mutable populations. Comparison of the genomes of 11 isolates from the same sample showed extensive within-patient genomic diversification; the populations were composed of different sub-lineages that had coexisted for many years since the initial colonization of the patient. Analysis of the mutations identified genes that underwent convergent evolution across lineages and sub-lineages, suggesting that the genes were targeted by mutation to optimize pathogenic fitness. Parallel evolution was observed in reduction of overall catabolic capacity of the populations. These findings are useful for understanding the evolution of pathogen populations and identifying new targets for control of chronic infections.
Project description:The production and maintenance of genetic and phenotypic diversity under temporally fluctuating selection and the signatures of environmental changes in the patterns of this variation have been important areas of focus in population genetics. On one hand, periods of constant selection pull the genetic makeup of populations toward local fitness optima. On the other, to cope with changes in the selection regime, populations may evolve mechanisms that create a diversity of genotypes. By tuning the rates at which variability is produced--such as the rates of recombination, mutation, or migration--populations may increase their long-term adaptability. Here we use theoretical models to gain insight into how the rates of these three evolutionary forces are shaped by fluctuating selection. We compare and contrast the evolution of recombination, mutation, and migration under similar patterns of environmental change and show that these three sources of phenotypic variation are surprisingly similar in their response to changing selection. We show that the shape, size, variance, and asymmetry of environmental fluctuation have different but predictable effects on evolutionary dynamics.
Project description:BACKGROUND: An important question is whether evolution favors properties such as mutational robustness or evolvability that do not directly benefit any individual but can influence the course of future evolution. Functionally similar proteins can differ substantially in their robustness to mutations and capacity to evolve new functions, but it has remained unclear whether any of these differences might be due to evolutionary selection for these properties. RESULTS: Here, we use laboratory experiments to demonstrate that evolution favors protein mutational robustness if the evolving population is sufficiently large. We neutrally evolve cytochrome P450 proteins under identical selection pressures and mutation rates in populations of different sizes, and show that proteins from the larger and thus more polymorphic population tend towards higher mutational robustness. Proteins from the larger population also evolve greater stability, a biophysical property that is known to enhance both mutational robustness and evolvability. The excess mutational robustness and stability is well described by mathematical theory, and can be quantitatively related to the way that the proteins occupy their neutral network. CONCLUSION: Our work is the first experimental demonstration of the general tendency of evolution to favor mutational robustness and protein stability in highly polymorphic populations. We suggest that this phenomenon could contribute to the mutational robustness and evolvability of viruses and bacteria that exist in large populations.
Project description:Evolution at high mutation rates is minimally affected by six processes: mutation-selection balance, error catastrophes, Muller's Ratchet, robustness and compensatory evolution, and clonal interference. Including all of these processes in a tractable, analytical model is difficult, but they can be captured in simulations that utilize realistic genotype-phenotype-fitness maps, as done here by modeling RNA folding. Subjecting finite, asexual populations to a range of mutation rates revealed simple criteria that predict when particular evolutionary processes are important. Populations were initiated with a genotype encoding the most fit phenotype. When purifying selection was strong relative to mutation, the initial genotype was replaced by one more mutationally robust, and the maximally fit phenotype was maintained in a mutation-selection balance where the deleterious mutation rate determined mean fitness. With weaker purifying selection, the most fit genotypes were lost. Although loss of the best genotype was ongoing and might have led to a progressive fitness decline, continual compensatory evolution led to an approximate fitness equilibration. Per total genomic mutation rate, mean fitness was similar for strong and weak purifying selection. These results represent a first step at separating interactions between evolutionary processes at high mutation rate, but additional theory is needed to interpret some outcomes.
Project description:The rates and selective effects of beneficial mutations, together with population genetic factors such as population size and recombination rate, determine the outcomes of adaptation and the signatures this process leaves in patterns of genetic diversity. Previous experimental studies of microbial evolution have focused primarily on initially clonal populations, finding that adaptation is characterized by new strongly selected beneficial mutations that sweep rapidly to fixation. Here, we study evolution in diverse outcrossed yeast populations, tracking the rate and genetic basis of adaptation over time. We combine time-serial measurements of fitness and allele frequency changes in 18 populations of budding yeast evolved at different outcrossing rates to infer the drivers of adaptation on standing genetic variation. In contrast to initially clonal populations, we find that adaptation is driven by a large number of weakly selected, linked variants. Populations undergoing different rates of outcrossing make use of this selected variation differently: whereas asexual populations evolve via rapid, inefficient, and highly variable fixation of clones, sexual populations adapt continuously by gradually breaking down linkage disequilibrium between selected variants. Our results demonstrate how recombination can sustain adaptation over long timescales by inducing a transition from selection on genotypes to selection on individual alleles, and show how pervasive linked selection can affect evolutionary dynamics.
Project description:Parallel evolution, defined as identical changes arising in independent populations, is often attributed to similar selective pressures favoring the fixation of identical genetic changes. However, some level of parallel evolution is also expected if mutation rates are heterogeneous across regions of the genome. Theory suggests that mutation and selection can have equal impacts on patterns of parallel evolution; however, empirical studies have yet to jointly quantify the importance of these two processes. Here, we introduce several statistical models to examine the contributions of mutation and selection heterogeneity to shaping parallel evolutionary changes at the gene-level. Using this framework, we analyze published data from forty experimentally evolved Saccharomyces cerevisiae populations. We can partition the effects of a number of genomic variables into those affecting patterns of parallel evolution via effects on the rate of arising mutations, and those affecting the retention versus loss of the arising mutations (i.e., selection). Our results suggest that gene-to-gene heterogeneity in both mutation and selection, associated with gene length, recombination rate, and number of protein domains drive parallel evolution at both synonymous and nonsynonymous sites. While there are still a number of parallel changes that are not well described, we show that allowing for heterogeneous rates of mutation and selection can provide improved predictions of the prevalence and degree of parallel evolution.
Project description:Many species are shifting their ranges in response to global climate change. Range expansions are known to have profound effects on the genetic composition of populations. The evolution of dispersal during range expansion increases invasion speed, provided that a species can adapt sufficiently fast to novel local conditions. Genetic diversity at the expanding range border is however depleted due to iterated founder effects. The surprising ability of colonizing species to adapt to novel conditions while being subjected to genetic bottlenecks is termed 'the genetic paradox of invasive species'. Mutational processes have been argued to provide an explanation for this paradox. Mutation rates can evolve, under conditions that favor an increased rate of adaptation, by hitchhiking on beneficial mutations through induced linkage disequilibrium. Here we argue that spatial sorting, iterated founder events, and population structure benefit the build-up and maintenance of such linkage disequilibrium. We investigate if the evolution of mutation rates could play a role in explaining the 'genetic paradox of invasive species' for a sexually reproducing species colonizing a landscape of gradually changing conditions.We use an individual-based model to show the evolutionary increase of mutation rates in sexual populations during range expansion, in coevolution with the dispersal probability. The observed evolution of mutation rate is adaptive and clearly advances invasion speed both through its effect on the evolution of dispersal probability, and the evolution of local adaptation. This also occurs under a variable temperature gradient, and under the assumption of 90% lethal mutations.In this study we show novel consequences of the particular genetic properties of populations under spatial disequilibrium, i.e. the coevolution of dispersal probability and mutation rate, even in a sexual species and under realistic spatial gradients, resulting in faster invasions. The evolution of mutation rates can therefore be added to the list of possible explanations for the 'genetic paradox of invasive species'. We conclude that range expansions and the evolution of mutation rates are in a positive feedback loop, with possibly far-reaching ecological consequences concerning invasiveness and the adaptability of species to novel environmental conditions.