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Clonal Interference and the Periodic Selection of New Beneficial Mutations in Escherichia coli

de Visser, J. Arjan G. M.; Rozen, Daniel E.
Fonte: Copyright © 2006 by the Genetics Society of America Publicador: Copyright © 2006 by the Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em /04/2006 EN
Relevância na Pesquisa
46.58%
The conventional model of adaptation in asexual populations implies sequential fixation of new beneficial mutations via rare selective sweeps that purge all variation and preserve the clonal genotype. However, in large populations multiple beneficial mutations may co-occur, causing competition among them, a phenomenon called “clonal interference.” Clonal interference is thus expected to lead to longer fixation times and larger fitness effects of mutations that ultimately become fixed, as well as to a genetically more diverse population. Here, we study the significance of clonal interference in populations consisting of mixtures of differently marked wild-type and mutator strains of Escherichia coli that adapt to a minimal-glucose environment for 400 generations. We monitored marker frequencies during evolution and measured the competitive fitness of random clones from each marker state after evolution. The results demonstrate the presence of multiple beneficial mutations in these populations and slower and more erratic invasion of mutants than expected by the conventional model, showing the signature of clonal interference. We found that a consequence of clonal interference is that fitness estimates derived from invasion trajectories were less than half the magnitude of direct estimates from competition experiments...

Clonal interference in large populations

Park, Su-Chan; Krug, Joachim
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.26%
Clonal interference, the competition between lineages arising from different beneficial mutations in an asexually reproducing population, is an important factor determining the tempo and mode of microbial adaptation. The standard theory of this phenomenon neglects the occurrence of multiple mutations as well as the correlation between loss by genetic drift and clonal competition, which is questionable in large populations. Working within the Wright–Fisher model with multiplicative fitness (no epistasis), we determine the rate of adaptation asymptotically for very large population sizes and show that the standard theory fails in this regime. Our study also explains the success of the standard theory in predicting the rate of adaptation for moderately large populations. Furthermore, we show that the nature of the substitution process changes qualitatively when multiple mutations are allowed for, because several mutations can be fixed in a single fixation event. As a consequence, the index of dispersion for counts of the fixation process displays a minimum as a function of population size, whereas the origination process of fixed mutations becomes completely regular for very large populations. We find that the number of mutations fixed in a single event is geometrically distributed as in the neutral case. These conclusions are based on extensive simulations combined with analytic results for the limit of infinite population size.

Clonal Interference, Multiple Mutations and Adaptation in Large Asexual Populations

Fogle, Craig A.; Nagle, James L.; Desai, Michael M.
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em /12/2008 EN
Relevância na Pesquisa
46.34%
Two important problems affect the ability of asexual populations to accumulate beneficial mutations and hence to adapt. First, clonal interference causes some beneficial mutations to be outcompeted by more-fit mutations that occur in the same genetic background. Second, multiple mutations occur in some individuals, so even mutations of large effect can be outcompeted unless they occur in a good genetic background that contains other beneficial mutations. In this article, we use a Monte Carlo simulation to study how these two factors influence the adaptation of asexual populations. We find that the results depend qualitatively on the shape of the distribution of the fitness effects of possible beneficial mutations. When this distribution falls off slower than exponentially, clonal interference alone reasonably describes which mutations dominate the adaptation, although it gives a misleading picture of the evolutionary dynamics. When the distribution falls off faster than exponentially, an analysis based on multiple mutations is more appropriate. Using our simulations, we are able to explore the limits of validity of both of these approaches, and we explore the complex dynamics in the regimes where neither one is fully applicable.

The two-mutant problem: clonal interference in evolutionary graph theory

Paley, Chris; Taraskin, Sergei; Elliott, Stephen
Fonte: Springer-Verlag Publicador: Springer-Verlag
Tipo: Artigo de Revista Científica
Publicado em 18/06/2010 EN
Relevância na Pesquisa
46.34%
In large asexual populations, clonal interference, whereby different beneficial mutations compete to fix in the population simultaneously, may be the norm. Results extrapolated from the spread of individual mutations in homogeneous backgrounds are found to be misleading in such situations: clonal interference severely inhibits the spread of beneficial mutations. In contrast with results gained in systems with just one mutation striving for fixation at any one time, the spatial structure of the population is found to be an important factor in determining the fixation probability when there are two beneficial mutations.

The Role of Clonal Interference in the Evolutionary Dynamics of Plasmid-Host Adaptation

Hughes, Julie M.; Lohman, Brian K.; Deckert, Gail E.; Nichols, Eric P.; Settles, Matt; Abdo, Zaid; Top, Eva M.
Fonte: American Society of Microbiology Publicador: American Society of Microbiology
Tipo: Artigo de Revista Científica
Publicado em 03/07/2012 EN
Relevância na Pesquisa
46.17%
Promiscuous plasmids replicate in a wide range of bacteria and therefore play a key role in the dissemination of various host-beneficial traits, including antibiotic resistance. Despite the medical relevance, little is known about the evolutionary dynamics through which drug resistance plasmids adapt to new hosts and thereby persist in the absence of antibiotics. We previously showed that the incompatibility group P-1 (IncP-1) minireplicon pMS0506 drastically improved its stability in novel host Shewanella oneidensis MR-1 after 1,000 generations under antibiotic selection for the plasmid. The only mutations found were those affecting the N terminus of the plasmid replication initiation protein TrfA1. Our aim in this study was to gain insight into the dynamics of plasmid evolution. Changes in stability and genotype frequencies of pMS0506 were monitored in evolving populations of MR-1 (pMS0506). Genotypes were determined by sequencing trfA1 amplicons from individual clones and by 454 pyrosequencing of whole plasmids from entire populations. Stability of pMS0506 drastically improved by generation 200. Many evolved plasmid genotypes with point mutations as well as in-frame and frameshift deletions and duplications in trfA1 were observed in all lineages with both sequencing methods. Strikingly...

Clonal Interference in the Evolution of Influenza

Strelkowa, Natalja; Lässig, Michael
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em /10/2012 EN
Relevância na Pesquisa
46.51%
The seasonal influenza A virus undergoes rapid evolution to escape human immune response. Adaptive changes occur primarily in antigenic epitopes, the antibody-binding domains of the viral hemagglutinin. This process involves recurrent selective sweeps, in which clusters of simultaneous nucleotide fixations in the hemagglutinin coding sequence are observed about every 4 years. Here, we show that influenza A (H3N2) evolves by strong clonal interference. This mode of evolution is a red queen race between viral strains with different beneficial mutations. Clonal interference explains and quantifies the observed sweep pattern: we find an average of at least one strongly beneficial amino acid substitution per year, and a given selective sweep has three to four driving mutations on average. The inference of selection and clonal interference is based on frequency time series of single-nucleotide polymorphisms, which are obtained from a sample of influenza genome sequences over 39 years. Our results imply that mode and speed of influenza evolution are governed not only by positive selection within, but also by background selection outside antigenic epitopes: immune adaptation and conservation of other viral functions interfere with each other. Hence...

Synchronous Waves of Failed Soft Sweeps in the Laboratory: Remarkably Rampant Clonal Interference of Alleles at a Single Locus

Lee, Ming-Chun; Marx, Christopher J.
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em /03/2013 EN
Relevância na Pesquisa
46.44%
It has increasingly been recognized that adapting populations of microbes contain not one, but many lineages continually arising and competing at once. This process, termed “clonal interference,” alters the rate and dynamics of adaptation and biases winning mutations toward those with the largest selective effect. Here we uncovered a dramatic example of clonal interference between multiple similar mutations occurring at the same locus within replicate populations of Methylobacterium extorquens AM1. Because these mutational events involved the transposition of an insertion sequence into a narrow window of a single gene, they were both readily detectable at low frequencies and could be distinguished due to differences in insertion sites. This allowed us to detect up to 17 beneficial alleles of this type coexisting in a single population. Despite conferring a large selective benefit, the majority of these alleles rose and then fell in frequency due to other lineages emerging that were more fit. By comparing allele-frequency dynamics to the trajectories of fitness gains by these populations, we estimated the fitness values of the genotypes that contained these mutations. Collectively across all populations, these alleles arose upon backgrounds with a wide range of fitness values. Within any single population...

Non-cell autonomous tumor-growth driving supports sub-clonal heterogeneity

Marusyk, Andriy; Tabassum, Doris P.; Altrock, Philipp M.; Almendro, Vanessa; Michor, Franziska; Polyak, Kornelia
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
36.26%
Cancers arise through a process of somatic evolution that can result in substantial sub-clonal heterogeneity within tumors. The mechanisms responsible for the coexistence of distinct sub-clones and the biological consequences of this coexistence remain poorly understood. Here we used a mouse xenograft model to investigate the impact of sub-clonal heterogeneity on tumor phenotypes and the competitive expansion of individual clones. We found that tumor growth can be driven by a minor cell subpopulation, which enhances the proliferation of all cells within a tumor by overcoming environmental constraints and yet can be outcompeted by faster proliferating competitors, resulting in tumor collapse. We then developed a mathematical modeling framework to identify the rules underlying the generation of intratumor clonal heterogeneity. We found that non-cell autonomous driving, together with clonal interference, stabilizes sub-clonal heterogeneity, thereby enabling inter-clonal interactions that can lead to new phenotypic traits.

Contribution of Selection for Protein Folding Stability in Shaping the Patterns of Polymorphisms in Coding Regions

Serohijos, Adrian W.R.; Shakhnovich, Eugene I.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
46.17%
The patterns of polymorphisms in genomes are imprints of the evolutionary forces at play in nature. In particular, polymorphisms have been extensively used to infer the fitness effects of mutations and their dynamics of fixation. However, the role and contribution of molecular biophysics to these observations remain unclear. Here, we couple robust findings from protein biophysics, enzymatic flux theory, the selection against the cytotoxic effects of protein misfolding, and explicit population dynamics simulations in the polyclonal regime. First, we recapitulate results on the dynamics of clonal interference and on the shape of the DFE, thus providing them with a molecular and mechanistic foundation. Second, we predict that if evolution is indeed under the dynamic equilibrium of mutation–selection balance, the fraction of stabilizing and destabilizing mutations is almost equal among single-nucleotide polymorphisms segregating at high allele frequencies. This prediction is proven true for polymorphisms in the human coding region. Overall, our results show how selection for protein folding stability predominantly shapes the patterns of polymorphisms in coding regions.

Genetic Diversity and the Structure of Genealogies in Rapidly Adapting Populations

Desai, Michael Manish; Walczak, Aleksandra M.; Fisher, Daniel S.
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
46.39%
Positive selection distorts the structure of genealogies and hence alters patterns of genetic variation within a population. Most analyses of these distortions focus on the signatures of hitchhiking due to hard or soft selective sweeps at a single genetic locus. However, in linked regions of rapidly adapting genomes, multiple beneficial mutations at different loci can segregate simultaneously within the population, an effect known as clonal interference. This leads to a subtle interplay between hitchhiking and interference effects, which leads to a unique signature of rapid adaptation on genetic variation both at the selected sites and at linked neutral loci. Here, we introduce an effective coalescent theory (a “fitness-class coalescent”) that describes how positive selection at many perfectly linked sites alters the structure of genealogies. We use this theory to calculate several simple statistics describing genetic variation within a rapidly adapting population and to implement efficient backward-time coalescent simulations, which can be used to predict how clonal interference alters the expected patterns of molecular evolution.; Organismic and Evolutionary Biology; Physics

The Dynamics of Genetic Draft in Rapidly Adapting Populations

Kosheleva, Katya; Desai, Michael Manish
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
46.17%
The accumulation of beneficial mutations on competing genetic backgrounds in rapidly adapting populations has a striking impact on evolutionary dynamics. This effect, known as clonal interference, causes erratic fluctuations in the frequencies of observed mutations, randomizes the fixation times of successful mutations, and leaves distinct signatures on patterns of genetic variation. Here, we show how this form of “genetic draft” affects the forward-time dynamics of site frequencies in rapidly adapting asexual populations. We calculate the probability that mutations at individual sites shift in frequency over a characteristic timescale, extending Gillespie’s original model of draft to the case where many strongly selected beneficial mutations segregate simultaneously. We then derive the sojourn time of mutant alleles, the expected fixation time of successful mutants, and the site frequency spectrum of beneficial and neutral mutations. Finally, we show how this form of draft affects inferences in the McDonald–Kreitman test and how it relates to recent observations that some aspects of genetic diversity are described by the Bolthausen–Sznitman coalescent in the limit of very rapid adaptation.; Organismic and Evolutionary Biology; Physics

Non-cell autonomous tumor-growth driving supports sub-clonal heterogeneity

Marusyk, Andriy; Tabassum, Doris P.; Altrock, Philipp M.; Almendro, Vanessa; Michor, Franziska; Polyak, Kornelia
Fonte: Harvard University Publicador: Harvard University
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
36.26%
SUMMARY Cancers arise through a process of somatic evolution that can result in substantial sub-clonal heterogeneity within tumors. The mechanisms responsible for the coexistence of distinct sub-clones and the biological consequences of this coexistence remain poorly understood. Here we used a mouse xenograft model to investigate the impact of sub-clonal heterogeneity on tumor phenotypes and the competitive expansion of individual clones. We found that tumor growth can be driven by a minor cell subpopulation, which enhances the proliferation of all cells within a tumor by overcoming environmental constraints and yet can be outcompeted by faster proliferating competitors, resulting in tumor collapse. We then developed a mathematical modeling framework to identify the rules underlying the generation of intratumor clonal heterogeneity. We found that non-cell autonomous driving, together with clonal interference, stabilizes sub-clonal heterogeneity, thereby enabling inter-clonal interactions that can lead to new phenotypic traits.

Scaling, genetic drift and clonal interference in the extinction pattern of asexual populations

Rosa, A.; Gordo, I.; Campos, P.R.A.
Fonte: American Physical Society Publicador: American Physical Society
Tipo: Artigo de Revista Científica
Publicado em 05/07/2005 ENG
Relevância na Pesquisa
46.17%
We investigate the dynamics of loss of favorable mutations in an asexual haploid population. In the current work, we consider homogeneous as well as spatially structured population models. We focus our analysis on statistical measurements of the probability distribution of the maximum population size N(sb) achieved by those mutations that have not reached fixation. Our results show a crossover behavior which demonstrates the occurrence of two evolutionary regimes. In the first regime, which takes place for small N(sb) , the probability distribution is described by a power law with characteristic exponent theta(d) =1.8 +/- 0.01. This power law is not influenced by the rate of beneficial mutations. The second regime, which occurs for intermediate to large values of N(sb), has a characteristic exponent theta(c) which increases as the rate of beneficial mutations grows. These results establish where genetic drift and clonal interference become the main underlying mechanism in the extinction of advantageous mutations.

Molecular Characterization of Clonal Interference during Adaptive Evolution in Asexual Populations of Saccharomyces cerevisiae

Kao, Katy C.; Sherlock, Gavin
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/2008 EN
Relevância na Pesquisa
46.34%
The classical model of adaptive evolution in an asexual population postulates that each adaptive clone is derived from the one preceding it1. However, experimental evidence suggests more complex dynamics2-5 with theory predicting the fixation probability of a beneficial mutation as dependent on the mutation rate, population size, and the mutation's selection coefficient6. Clonal interference has been demonstrated in viruses7 and bacteria8, but has not been demonstrated in a eukaryote and a detailed molecular characterization is lacking. Here we use different fluorescent markers to visualize the dynamics of asexually evolving yeast populations. For each adaptive clone within one of our evolving populations, we have identified the underlying mutations, monitored their population frequencies and used microarrays to characterize changes in the transcriptome. These data provide the most detailed molecular characterization of an experimental evolution to date, and provide direct experimental evidence supporting both the clonal interference and the multiple mutation models.

Ex Uno Plures: Clonal Reinforcement Drives Evolution of a Simple Microbial Community

Kinnersley, Margie; Wenger, Jared; Kroll, Evgueny; Adams, Julian; Sherlock, Gavin; Rosenzweig, Frank
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 26/06/2014 EN
Relevância na Pesquisa
36.18%
A major goal of genetics is to define the relationship between phenotype and genotype, while a major goal of ecology is to identify the rules that govern community assembly. Achieving these goals by analyzing natural systems can be difficult, as selective pressures create dynamic fitness landscapes that vary in both space and time. Laboratory experimental evolution offers the benefit of controlling variables that shape fitness landscapes, helping to achieve both goals. We previously showed that a clonal population of E. coli experimentally evolved under continuous glucose limitation gives rise to a genetically diverse community consisting of one clone, CV103, that best scavenges but incompletely utilizes the limiting resource, and others, CV101 and CV116, that consume its overflow metabolites. Because this community can be disassembled and reassembled, and involves cooperative interactions that are stable over time, its genetic diversity is sustained by clonal reinforcement rather than by clonal interference. To understand the genetic factors that produce this outcome, and to illuminate the community's underlying physiology, we sequenced the genomes of ancestral and evolved clones. We identified ancestral mutations in intermediary metabolism that may have predisposed the evolution of metabolic interdependence. Phylogenetic reconstruction indicates that the lineages that gave rise to this community diverged early...

Adaptation in Sexuals vs. Asexuals: Clonal Interference and the Fisher-Muller Model

Kim, Yuseob; Orr, H. Allen
Fonte: Copyright © 2005 by the Genetics Society of America Publicador: Copyright © 2005 by the Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em /11/2005 EN
Relevância na Pesquisa
46.17%
Fisher and Muller's theory that recombination speeds adaptation by eliminating competition among beneficial mutations has proved a popular explanation for the advantage of sex. Recent theoretical studies have attempted to quantify the speed of adaptation under the Fisher-Muller model, partly in an attempt to understand the role of “clonal interference” in microbial experimental evolution. We reexamine adaptation in sexuals vs. asexuals, using a model of DNA sequence evolution. In this model, a modest number of sites can mutate to beneficial alleles and the fitness effects of these mutations are unequal. We study (1) transition probabilities to different beneficial mutations; (2) waiting times to the first and the last substitutions of beneficial mutations; and (3) trajectories of mean fitness through time. We find that some of these statistics are surprisingly similar between sexuals and asexuals. These results highlight the importance of the choice of substitution model in assessing the Fisher-Muller advantage of sex.

Modeling stochastic clonal interference

Campos, Paulo R. A.; Adami, Christoph; Wilke, Claus O.
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Publicado em 30/04/2003
Relevância na Pesquisa
46.17%
We study the competition between several advantageous mutants in an asexual population (clonal interference) as a function of the time between the appearance of the mutants, their selective advantages, and the rate of deleterious mutations. We find that the overall probability of fixation (the probability that at least one of the mutants becomes the ancestor of the entire population) does not depend on the time interval between the appearance of these mutants, and equals the probability that a genotype bearing all of these mutations reaches fixation. This result holds also in the presence of deleterious mutations, and for an arbitrary number of competing mutants. We also show that if mutations interfere, an increase in the mean number of fixation events is associated with a decrease in the expected fitness gain of the population.; Comment: 18 pages and 6 figures, requires svmult.cls. To appear in "Modeling in Molecular Biology" (Springer Series in Natural Computing), G. Ciobanu ed

Clonal Interference, Multiple Mutations, and Adaptation in Large Asexual Populations

Fogle, Craig A.; Nagle, James L.; Desai, Michael M.
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Publicado em 07/04/2008
Relevância na Pesquisa
46.34%
Two important problems affect the ability of asexual populations to accumulate beneficial mutations, and hence to adapt. First, clonal interference causes some beneficial mutations to be outcompeted by more-fit mutations which occur in the same genetic background. Second, multiple mutations occur in some individuals, so even mutations of large effect can be outcompeted unless they occur in a good genetic background which contains other beneficial mutations. In this paper, we use a Monte Carlo simulation to study how these two factors influence the adaptation of asexual populations. We find that the results depend qualitatively on the shape of the distribution of the effects of possible beneficial mutations. When this distribution falls off slower than exponentially, clonal interference alone reasonably describes which mutations dominate the adaptation, although it gives a misleading picture of the evolutionary dynamics. When the distribution falls off faster than exponentially, an analysis based on multiple mutations is more appropriate. Using our simulations, we are able to explore the limits of validity of both of these approaches, and we explore the complex dynamics in the regimes where neither are fully applicable.; Comment: 24 pages...

The interplay of two mutations in a population of varying size: a stochastic eco-evolutionary model for clonal interference

Billiard, Sylvain; Smadi, Charline
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Publicado em 18/05/2015
Relevância na Pesquisa
46.34%
Clonal interference, competition between multiple co-occurring beneficial mutations, has a major role in adaptation of asexual populations. We provide a simple individual based stochastic model of clonal interference taking into account a wide variety of competitive interactions which can be found in nature. In particular, we relax the classical assumption of transitivity between the different mutations. It allows us to predict genetic patterns, such as coexistence of several mutants or emergence of Rock-Paper-Scissors cycles, which were not explained by existing models. In addition, we call into questions some classical preconceived ideas about fixation time and fixation probability of competing mutations.

Reliable reconstruction of HIV-1 whole genome haplotypes reveals clonal interference and genetic hitchhiking among immune escape variants

Pandit, Aridaman; de Boer, Rob J
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Publicado em 26/09/2013
Relevância na Pesquisa
46.17%
Following transmission, HIV-1 evolves into a diverse population, and next generation sequencing enables us to detect variants occurring at low frequencies. Studying viral evolution at the level of whole genomes was hitherto not possible because next generation sequencing delivers relatively short reads. We here provide a proof of principle that whole HIV-1 genomes can be reliably reconstructed from short reads, and use this to study the selection of immune escape mutations at the level of whole genome haplotypes. Using realistically simulated HIV-1 populations, we demonstrate that reconstruction of complete genome haplotypes is feasible with high fidelity. We do not reconstruct all genetically distinct genomes, but each reconstructed haplotype represents one or more of the quasispecies in the HIV-1 population. We then reconstruct 30 whole genome haplotypes from published short sequence reads sampled longitudinally from a single HIV-1 infected patient. We confirm the reliability of the reconstruction by validating our predicted haplotype genes with single genome amplification sequences, and by comparing haplotype frequencies with observed epitope escape frequencies. Phylogenetic analysis shows that the HIV-1 population undergoes selection driven evolution...