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1.
Many bacterial populations harbour substantial numbers of hypermutable bacteria, in spite of hypermutation being associated with deleterious mutations. One reason for the persistence of hypermutators is the provision of novel mutations, enabling rapid adaptation to continually changing environments, for example coevolving virulent parasites. However, hypermutation also increases the rate at which intraspecific parasites (social cheats) are generated. Interspecific and intraspecific parasitism are therefore likely to impose conflicting selection pressure on mutation rate. Here, we combine theory and experiments to investigate how simultaneous selection from inter- and intraspecific parasitism affects the evolution of bacterial mutation rates in the plant-colonizing bacterium Pseudomonas fluorescens. Both our theoretical and experimental results suggest that phage presence increases and selection for public goods cooperation (the production of iron-scavenging siderophores) decreases selection for mutator bacteria. Moreover, phages imposed a much greater growth cost than social cheating, and when both selection pressures were imposed simultaneously, selection for cooperation did not affect mutation rate evolution. Given the ubiquity of infectious phages in the natural environment and clinical infections, our results suggest that phages are likely to be more important than social interactions in determining mutation rate evolution.  相似文献   

2.
3.
To study the role of mutator bacteria in the evolution of bacterial populations, we followed the impact of the mutation rate of Escherichia coli strains in the colonisation of the gut of axenic mice and the evolution of the mutation rate of bacterial populations living in the gut. We show that mutator bacteria have an advantage during the colonization. This adaptive advantage comes from their ability to generate adaptive mutations faster than wild type strains, mutations that allow their maintenance in the ecosystem. However, while mutator bacteria are becoming specialised to the environment they are living in, they accumulate mutations that may be deleterious or lethal in secondary environments. By following the evolution of the mutation rate of bacterial populations living in the gut of mice receiving antibiotics, we show that this therapy selects not only for antibiotic resistant mutants but also for mutator alleles that enhance mutation rates and are responsible for the appearance of the resistance. The costs of a high mutation rate, due to the accumulation of mutations, is seen in environments where changes are recurrent. In an ever-changing situation where every change is new, mutator bacteria might help the evolution of bacterial populations.  相似文献   

4.
The appearance of new mutations within a population provides the raw material for evolution. The consistent decline in fitness observed in classical mutation accumulation studies has provided support for the long-held view that deleterious mutations are more common than beneficial mutations. Here we present results of a study using a mutation accumulation design with the bacterium Streptococcus pneumoniae in which the fitness of the derived populations increased. This rise in fitness was associated specifically with adaptation to survival during brief stationary phase periods between single-colony population bottlenecks. To understand better the population dynamics behind this unanticipated adaptation, we developed a maximum likelihood model describing the processes of mutation and stationary-phase selection in the context of frequent population bottlenecks. Using this model, we estimate that the rate of beneficial mutations may be as high as 4.8×10(-4) events per genome for each time interval corresponding to the pneumococcal generation time. This rate is several orders of magnitude higher than earlier estimates of beneficial mutation rates in bacteria but supports recent results obtained through the propagation of small populations of Escherichia coli. Our findings indicate that beneficial mutations may be relatively frequent in bacteria and suggest that in S. pneumoniae, which develops natural competence for transformation, a steady supply of such mutations may be available for sampling by recombination.  相似文献   

5.
The dominant paradigm for the evolution of mutator alleles in bacterial populations is that they spread by indirect selection for linked beneficial mutations when bacteria are poorly adapted. In this paper, we challenge the ubiquity of this paradigm by demonstrating that a clinically important stressor, hydrogen peroxide, generates direct selection for an elevated mutation rate in the pathogenic bacterium Pseudomonas aeruginosa as a consequence of a trade-off between the fidelity of DNA repair and hydrogen peroxide resistance. We demonstrate that the biochemical mechanism underlying this trade-off in the case of mutS is the elevated secretion of catalase by the mutator strain. Our results provide, to our knowledge, the first experimental evidence that direct selection can favour mutator alleles in bacterial populations, and pave the way for future studies to understand how mutation and DNA repair are linked to stress responses and how this affects the evolution of bacterial mutation rates.  相似文献   

6.
Codon bias and plasticity in immunoglobulins   总被引:6,自引:1,他引:5  
Immunoglobulin genes experience Darwinian evolution twice. In addition to the germline evolution all genes experience, immunoglobulins are subjected, upon exposure to antigen, to somatic hypermutation. This is accompanied by selection for high affinity to the eliciting antigen and frequently results in a significant increase in the specificity of the responding population. The hypermutation mechanism displays a strong sequence specificity. Thus arises the opportunity to manipulate codon bias in a site-specific manner so as to direct hypermutation to those parts of the gene that encode the antigen-binding portions of the molecule and away from those that encode the structurally conserved regions. This segregation of mutability would clearly be advantageous; it would enhance the generation of potentially useful variants while keeping mutational loss to acceptably low levels. But it is not clear that the advantage gained would be large enough to produce a measurable effect within the background stochasticity of the evolutionary process. I have performed a pair of statistical tests to determine whether site- specific codon bias in human immunoglobulin genes is correlated with the sequence specificity of the somatic mutation mechanism. The sequence specificity of the mutator was determined by analysis of a database of published immunoglobulin intron sequences that had experienced somatic mutation but not selection. The site-specific codon bias was determined by analysis of published sequences of human germline immunoglobulin V genes. Both tests strongly suggest that evolution has acted to enhance the plasticity of immunoglobulin genes under somatic hypermutation.   相似文献   

7.
朱林江  李崎 《遗传》2014,36(4):327-335
细胞具有普遍的突变和进化能力, 如病原菌的抗药性、工业菌株的适应性和人体细胞的癌变等, 但是细胞的适应性突变是如何产生的呢?通过非致死性突变分析模型的建立与应用, 产生了新的适应性进化观点, 即环境胁迫诱导细胞适应性突变。这种环境诱导的细胞突变过程涉及多方面的生理调控, 包括细胞内毒性物质(如氧活性物质)积累并造成DNA损伤、DNA错配修复的活性受到抑制、胞内RpoS反应和SOS反应被激活等。这些反应使胞内高保真的DNA复制状态转变为低保真的DNA修复状态, 提高胞内突变率和重组活性。此外, 基因转录影响基因组的不稳定, 容易产生DNA损伤, 并造成局部的高突变率, 即形成了转录偶联的DNA修复与突变为基础的适应性突变观点。文章围绕环境胁迫诱导细胞突变率增加和转录偶联的DNA修复与突变这两种适应性突变分子机制, 阐述其相关的研究进展, 以期更好地理解环境条件诱导细胞发生适应性突变的过程。  相似文献   

8.
Evolutionary genetics: The economics of mutation.   总被引:1,自引:0,他引:1  
The presence of mutator genotypes in populations of bacteria may be favoured by selection because they produce rare beneficial mutations and thereby increase the rate of adaptive evolution. Recent work, however, shows that the relationship between mutation rates and adaptive evolution is more complicated.  相似文献   

9.
Stationary-phase mutation in microbes can produce selected (''adaptive'') mutants preferentially. In one system, this occurs via a distinct, recombination-dependent mechanism. Two points of controversy have surrounded these adaptive reversions of an Escherichia coli lac mutation. First, are the mutations directed preferentially to the selected gene in a Lamarckian manner? Second, is the adaptive mutation mechanism specific to the F plasmid replicon carrying lac? We report that lac adaptive mutations are associated with hypermutation in unselected genes, in all replicons in the cell. The associated mutations have a similar sequence spectrum to the adaptive reversions. Thus, the adaptive mutagenesis mechanism is not directed to the lac genes, in a Lamarckian manner, nor to the F'' replicon carrying lac. Hypermutation was not found in non-revertants exposed to selection. Therefore, the genome-wide hypermutation underlying adaptive mutation occurs in a differentiated subpopulation. The existence of mutable subpopulations in non-growing cells is important in bacterial evolution and could be relevant to the somatic mutations that give rise to cancers in multicellular organisms.  相似文献   

10.
Beneficial mutations can become costly following an environmental change. Compensatory mutations can relieve these costs, while not affecting the selected function, so that the benefits are retained if the environment shifts back to be similar to the one in which the beneficial mutation was originally selected. Compensatory mutations have been extensively studied in the context of antibiotic resistance, responses to specific genetic perturbations, and in the determination of interacting gene network components. Few studies have focused on the role of compensatory mutations during more general adaptation, especially as the result of selection in fluctuating environments where adaptations to different environment components may often involve trade‐offs. We examine whether costs of a mutation in lacI, which deregulated the expression of the lac operon in evolving populations of Escherichia coli bacteria, were compensated. This mutation occurred in multiple replicate populations selected in environments that fluctuated between growth on lactose, where the mutation was beneficial, and on glucose, where it was deleterious. We found that compensation for the cost of the lacI mutation was rare, but, when it did occur, it did not negatively affect the selected benefit. Compensation was not more likely to occur in a particular evolution environment. Compensation has the potential to remove pleiotropic costs of adaptation, but its rarity indicates that the circumstances to bring about the phenomenon may be peculiar to each individual or impeded by other selected mutations.  相似文献   

11.
Protein evolution by hypermutation and selection in the B cell line DT40   总被引:1,自引:0,他引:1  
Genome-wide mutations and selection within a population are the basis of natural evolution. A similar process occurs during antibody affinity maturation when immunoglobulin genes are hypermutated and only those B cells which express antibodies of improved antigen-binding specificity are expanded. Protein evolution might be simulated in cell culture, if transgene-specific hypermutation can be combined with the selection of cells carrying beneficial mutations. Here, we describe the optimization of a GFP transgene in the B cell line DT40 by hypermutation and iterative fluorescence activated cell sorting. Artificial evolution in DT40 offers unique advantages and may be easily adapted to other transgenes, if the selection for desirable mutations is feasible.  相似文献   

12.
The influence of structural variation, previously observed in a panel of V186.2 VH/V lambda 1-expressing anti-NP antibodies from the secondary response, on the affinity of these antibodies was examined by site-specific mutagenesis and recombinant antibody construction. A tryptophan----leucine exchange at position 33 in the VH segment of all but one of the high-affinity antibodies is the most frequently observed somatic mutation and by itself leads to a 10-fold higher affinity; all other somatic exchanges are irrelevant for affinity selection. In the single case of a high-affinity antibody without this common exchange, high affinity is mediated by a combination of mutations (including a one-codon deletion) in VH and the particular D-JH rearrangement carried by this antibody. The data indicate that the pattern of somatic diversification through hypermutation is shaped by affinity selection, but that only a single point mutation is available in the VH and the VL gene of lambda 1 chain-bearing anti-NP antibodies which by itself leads to an increase of hapten-binding affinity. Based on the analysis of two secondary response antibodies from which somatic mutations in VH and VL have been eliminated, it is also concluded that the recruitment of B cell clones into the pathway of hypermutation involves a mechanism which is not based upon affinity differences towards the antigen.  相似文献   

13.
Compensatory mutations are individually deleterious but harmless in appropriate combinations either at more than two sites within a gene or on separate genes. Considering that dominance effects of selection and heterodimer formation of gene products may affect the rate of compensatory evolution, we investigate compensatory neutral mutation models for diploid populations. Our theoretical analysis on the average time until fixation of compensatory mutations shows that these factors play an important role in reducing the fixation time of compensatory mutations if mutation rates are not low. Compensatory evolution of heterodimers is shown to occur more easily if the deleterious effects of single mutants are recessive.  相似文献   

14.
Evolutionary theory assumed that mutations occur constantly, gradually, and randomly over time. This formulation from the "modern synthesis" of the 1930s was embraced decades before molecular understanding of genes or mutations. Since then, our labs and others have elucidated mutation mechanisms activated by stress responses. Stress-induced mutation mechanisms produce mutations, potentially accelerating evolution, specifically when cells are maladapted to their environment, that is, when they are stressed. The mechanisms of stress-induced mutation that are being revealed experimentally in laboratory settings provide compelling models for mutagenesis that propels pathogen-host adaptation, antibiotic resistance, cancer progression and resistance, and perhaps much of evolution generally. We discuss double-strand-break-dependent stress-induced mutation in Escherichia coli. Recent results illustrate how a stress response activates mutagenesis and demonstrate this mechanism's generality and importance to spontaneous mutation. New data also suggest a possible harmony between previous, apparently opposed, models for the molecular mechanism. They additionally strengthen the case for anti-evolvability therapeutics for infectious disease and cancer.  相似文献   

15.
The evolution of mutation rates: separating causes from consequences   总被引:21,自引:0,他引:21  
Natural selection can adjust the rate of mutation in a population by acting on allelic variation affecting processes of DNA replication and repair. Because mutation is the ultimate source of the genetic variation required for adaptation, it can be appealing to suppose that the genomic mutation rate is adjusted to a level that best promotes adaptation. Most mutations with phenotypic effects are harmful, however, and thus there is relentless selection within populations for lower genomic mutation rates. Selection on beneficial mutations can counter this effect by favoring alleles that raise the mutation rate, but the effect of beneficial mutations on the genomic mutation rate is extremely sensitive to recombination and is unlikely to be important in sexual populations. In contrast, high genomic mutation rates can evolve in asexual populations under the influence of beneficial mutations, but this phenomenon is probably of limited adaptive significance and represents, at best, a temporary reprieve from the continual selection pressure to reduce mutation. The physiological cost of reducing mutation below the low level observed in most populations may be the most important factor in setting the genomic mutation rate in sexual and asexual systems, regardless of the benefits of mutation in producing new adaptive variation. Maintenance of mutation rates higher than the minimum set by this "cost of fidelity" is likely only under special circumstances.  相似文献   

16.
BACKGROUND: The rate at which beneficial mutations accumulate determines how fast asexual populations evolve, but this is only partially understood. Some recent clonal-interference models suggest that evolution in large asexual populations is limited because smaller beneficial mutations are outcompeted by larger beneficial mutations that occur in different lineages within the same population. This analysis assumes that the important mutations fix one at a time; it ignores multiple beneficial mutations that occur in the lineage of an earlier beneficial mutation, before the first mutation in the series can fix. We focus on the effects of such multiple mutations. RESULTS: Our analysis predicts that the variation in fitness maintained by a continuously evolving population increases as the logarithm of the population size and logarithm of the mutation rate and thus yields a similar logarithmic increase in the speed of evolution. To test these predictions, we evolved asexual budding yeast in glucose-limited media at a range of population sizes and mutation rates. CONCLUSIONS: We find that their evolution is dominated by the accumulation of multiple mutations of moderate effect. Our results agree with our theoretical predictions and are inconsistent with the one-by-one fixation of mutants assumed by recent clonal-interference analysis.  相似文献   

17.

Background  

It is commonly thought that large asexual populations evolve more rapidly than smaller ones, due to their increased rate of beneficial mutations. Less clear is how population size influences the level of fitness an asexual population can attain. Here, we simulate the evolution of bacteria in repeated serial passage experiments to explore how features such as fitness landscape ruggedness, the size of the mutational target under selection, and the mutation supply rate, interact to affect the evolution of microbial populations of different sizes.  相似文献   

18.
Mutagenesis is often increased in bacterial populations as a consequence of stress-induced genetic pathways. Analysis of the molecular mechanisms involved suggests that mutagenesis might be increased as a by-product of the stress response of the organism. By contrast, computer simulations and analyses of stress-inducible phenotypes among natural isolates of Escherichia coli suggest that stress-induced mutagenesis (SIM) could be the result of selection because of the beneficial mutations that such a process can potentially generate. Regardless of the nature of the selective pressure acting on SIM, it is possible that the resulting increased genetic variability plays an important role in bacterial evolution.  相似文献   

19.
The population dynamics theory of B cells in a typical germinal center could play an important role in revealing how affinity maturation is achieved. However, the existing models encountered some conflicts with experiments. To resolve these conflicts, we present a coarse-grained model to calculate the B cell population development in affinity maturation, which allows a comprehensive analysis of its parameter space to look for optimal values of mutation rate, selection strength, and initial antibody-antigen binding level that maximize the affinity improvement. With these optimized parameters, the model is compatible with the experimental observations such as the ∼100-fold affinity improvements, the number of mutations, the hypermutation rate, and the “all or none” phenomenon. Moreover, we study the reasons behind the optimal parameters. The optimal mutation rate, in agreement with the hypermutation rate in vivo, results from a tradeoff between accumulating enough beneficial mutations and avoiding too many deleterious or lethal mutations. The optimal selection strength evolves as a balance between the need for affinity improvement and the requirement to pass the population bottleneck. These findings point to the conclusion that germinal centers have been optimized by evolution to generate strong affinity antibodies effectively and rapidly. In addition, we study the enhancement of affinity improvement due to B cell migration between germinal centers. These results could enhance our understanding of the functions of germinal centers.  相似文献   

20.
Glémin S  Ronfort J  Bataillon T 《Genetics》2003,165(4):2193-2212
Inbreeding depression is a general phenomenon that is due mainly to recessive deleterious mutations, the so-called mutation load. It has been much studied theoretically. However, until very recently, population structure has not been taken into account, even though it can be an important factor in the evolution of populations. Population subdivision modifies the dynamics of deleterious mutations because the outcome of selection depends on processes both within populations (selection and drift) and between populations (migration). Here, we present a general model that permits us to gain insight into patterns of inbreeding depression, heterosis, and the load in subdivided populations. We show that they can be interpreted with reference to single-population theory, using an appropriate local effective population size that integrates the effects of drift, selection, and migration. We term this the "effective population size of selection" (NS(e)). For the infinite island model, for example, it is equal to NS(e) = N1 + m/hs, where N is the local population size, m the migration rate, and h and s the dominance and selection coefficients of deleterious mutation. Our results have implications for the estimation and interpretation of inbreeding depression in subdivided populations, especially regarding conservation issues. We also discuss the possible effects of migration and subdivision on the evolution of mating systems.  相似文献   

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