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1.
Keightley PD  Eyre-Walker A 《Genetics》2007,177(4):2251-2261
The distribution of fitness effects of new mutations (DFE) is important for addressing several questions in genetics, including the nature of quantitative variation and the evolutionary fate of small populations. Properties of the DFE can be inferred by comparing the distributions of the frequencies of segregating nucleotide polymorphisms at selected and neutral sites in a population sample, but demographic changes alter the spectrum of allele frequencies at both neutral and selected sites, so can bias estimates of the DFE if not accounted for. We have developed a maximum-likelihood approach, based on the expected allele-frequency distribution generated by transition matrix methods, to estimate parameters of the DFE while simultaneously estimating parameters of a demographic model that allows a population size change at some time in the past. We tested the method using simulations and found that it accurately recovers simulated parameter values, even if the simulated demography differs substantially from that assumed in our analysis. We use our method to estimate parameters of the DFE for amino acid-changing mutations in humans and Drosophila melanogaster. For a model of unconditionally deleterious mutations, with effects sampled from a gamma distribution, the mean estimate for the distribution shape parameter is approximately 0.2 for human populations, which implies that the DFE is strongly leptokurtic. For Drosophila populations, we estimate that the shape parameter is approximately 0.35. Differences in the shape of the distribution and the mean selection coefficient between humans and Drosophila result in significantly more strongly deleterious mutations in Drosophila than in humans, and, conversely, nearly neutral mutations are significantly less frequent.  相似文献   

2.
The bimodal distribution of fitness effects of new mutations and standing genetic variation, due to early‐acting strongly deleterious recessive mutations and late‐acting mildly deleterious mutations, is analyzed using the Kondrashov model for lethals (K), with either the infinitesimal model for selfing (IMS) or the Gaussian allele model (GAM) for quantitative genetic variance under stabilizing selection. In the combined models (KIMS and KGAM) high genomic mutation rates to lethals and weak stabilizing selection on many characters create strong interactions between early and late inbreeding depression, by changing the distribution of lineages selfed consecutively for different numbers of generations. Alternative stable equilibria can exist at intermediate selfing rates for a given set of parameters. Evolution of quantitative genetic variance under multivariate stabilizing selection can strongly influence the purging of nearly recessive lethals, and sometimes vice versa. If the selfing rate at the purging threshold for quantitative genetic variance in IMS or GAM alone exceeds that for nearly recessive lethals in K alone, then in KIMS and KGAM stabilizing selection causes selective interference with purging of lethals, increasing the mean number of lethals compared to K; otherwise, stabilizing selection causes selective facilitation in purging of lethals, decreasing the mean number of lethals.  相似文献   

3.
The distribution of fitness effects (DFE) of new mutations is of fundamental importance in evolutionary genetics. Recently, methods have been developed for inferring the DFE that use information from the allele frequency distributions of putatively neutral and selected nucleotide polymorphic variants in a population sample. Here, we extend an existing maximum-likelihood method that estimates the DFE under the assumption that mutational effects are unconditionally deleterious, by including a fraction of positively selected mutations. We allow one or more classes of positive selection coefficients in the model and estimate both the fraction of mutations that are advantageous and the strength of selection acting on them. We show by simulations that the method is capable of recovering the parameters of the DFE under a range of conditions. We apply the method to two data sets on multiple protein-coding genes from African populations of Drosophila melanogaster. We use a probabilistic reconstruction of the ancestral states of the polymorphic sites to distinguish between derived and ancestral states at polymorphic nucleotide sites. In both data sets, we see a significant improvement in the fit when a category of positively selected amino acid mutations is included, but no further improvement if additional categories are added. We estimate that between 1% and 2% of new nonsynonymous mutations in D. melanogaster are positively selected, with a scaled selection coefficient representing the product of the effective population size, N(e), and the strength of selection on heterozygous carriers of ~2.5.  相似文献   

4.
Loewe L  Charlesworth B  Bartolomé C  Nöel V 《Genetics》2006,172(2):1079-1092
The distribution of mutational effects on fitness is of fundamental importance for many aspects of evolution. We develop two methods for characterizing the fitness effects of deleterious, nonsynonymous mutations, using polymorphism data from two related species. These methods also provide estimates of the proportion of amino acid substitutions that are selectively favorable, when combined with data on between-species sequence divergence. The methods are applicable to species with different effective population sizes, but that share the same distribution of mutational effects. The first, simpler, method assumes that diversity for all nonneutral mutations is given by the value under mutation-selection balance, while the second method allows for stronger effects of genetic drift and yields estimates of the parameters of the probability distribution of mutational effects. We apply these methods to data on populations of Drosophila miranda and D. pseudoobscura and find evidence for the presence of deleterious nonsynonymous mutations, mostly with small heterozygous selection coefficients (a mean of the order of 10(-5) for segregating variants). A leptokurtic gamma distribution of mutational effects with a shape parameter between 0.1 and 1 can explain observed diversities, in the absence of a separate class of completely neutral nonsynonymous mutations. We also describe a simple approximate method for estimating the harmonic mean selection coefficient from diversity data on a single species.  相似文献   

5.
Contrasting the efficacy of selection on the X and autosomes in Drosophila   总被引:1,自引:0,他引:1  
To investigate the relative efficacy of both positive and purifying natural selection on the X chromosome and the autosomes in Drosophila, we compared rates and patterns of molecular evolution between these chromosome sets using the newly available alignments of orthologous genes from 12 species. Parameters that may influence the relative X versus autosomal substitution rates include the relative effective population sizes, the male and female germline mutation rates, the distribution of allelic effects on fitness, and the degree of dominance of novel mutations. Our analysis reveals that codon usage bias is consistently greater for X-linked genes, suggesting that purifying selection consistently has greater efficacy on the X chromosome than on the autosomes across the Drosophila phylogeny. However, our results are less consistent with respect to the efficacy of positive selection, with only some lineages showing a higher substitution rate on the X chromosome. This suggests that either the distribution of selective effects of mutations or other relevant parameters are sufficiently variable across species to tip the balance in different ways in individual lineages. These data suggest that rates of substitution are not solely governed by adaptive evolution. This genome-wide analysis provides a clear picture that the efficacy of selection varies intragenomically and that this effect is markedly more consistent across the phylogeny in the case of purifying selection. Our results also suggest that simple models that predict systematic differences in rates of evolution between the X and the autosomes can only be made to be compatible with these Drosophila data if the relevant population genetic parameters that drive substitution rates differ among species and chromosomal contexts.  相似文献   

6.
Cowperthwaite MC  Bull JJ  Meyers LA 《Genetics》2005,170(4):1449-1457
Beneficial mutations are the driving force of evolution by natural selection. Yet, relatively little is known about the distribution of the fitness effects of beneficial mutations in populations. Recent work of Gillespie and Orr suggested some of the first generalizations for the distributions of beneficial fitness effects and, surprisingly, they depend only weakly on biological details. In particular, the theory suggests that beneficial mutations obey an exponential distribution of fitness effects, with the same exponential parameter across different regions of genotype space, provided only that few possible beneficial mutations are available to that genotype. Here we tested this hypothesis with a quasi-empirical model of RNA evolution in which fitness is based on the secondary structures of molecules and their thermodynamic stabilities. The fitnesses of randomly selected genotypes appeared to follow a Gumbel-type distribution and thus conform to a basic assumption of adaptation theory. However, the observed distributions of beneficial fitness effects conflict with specific predictions of the theory. In particular, the distributions of beneficial fitness effects appeared exponential only when the vast majority of small-effect beneficial mutations were ignored. Additionally, the distribution of beneficial fitness effects varied with the fitness of the parent genotype. We believe that correlation of the fitness values among similar genotypes is likely the cause of the departure from the predictions of recent adaptation theory. Although in conflict with the current theory, these results suggest that more complex statistical generalizations about beneficial mutations may be possible.  相似文献   

7.
For a quantitative understanding of the process of adaptation, we need to understand its "raw material," that is, the frequency and fitness effects of beneficial mutations. At present, most empirical evidence suggests an exponential distribution of fitness effects of beneficial mutations, as predicted for Gumbel-domain distributions by extreme value theory. Here, we study the distribution of mutation effects on cefotaxime (Ctx) resistance and fitness of 48 unique beneficial mutations in the bacterial enzyme TEM-1 β-lactamase, which were obtained by screening the products of random mutagenesis for increased Ctx resistance. Our contributions are threefold. First, based on the frequency of unique mutations among more than 300 sequenced isolates and correcting for mutation bias, we conservatively estimate that the total number of first-step mutations that increase Ctx resistance in this enzyme is 87 [95% CI 75-189], or 3.4% of all 2,583 possible base-pair substitutions. Of the 48 mutations, 10 are synonymous and the majority of the 38 non-synonymous mutations occur in the pocket surrounding the catalytic site. Second, we estimate the effects of the mutations on Ctx resistance by determining survival at various Ctx concentrations, and we derive their fitness effects by modeling reproduction and survival as a branching process. Third, we find that the distribution of both measures follows a Fréchet-type distribution characterized by a broad tail of a few exceptionally fit mutants. Such distributions have fundamental evolutionary implications, including an increased predictability of evolution, and may provide a partial explanation for recent observations of striking parallel evolution of antibiotic resistance.  相似文献   

8.
MacLellan K  Kwan L  Whitlock MC  Rundle HD 《Heredity》2012,108(3):203-210
Stress is generally thought to increase the strength of selection, although empirical results are mixed and general conclusions are difficult because data are limited. Here we compare the fitness effects of nine independent recessive mutations in Drosophila melanogaster in a high- and low-dietary-stress environment, estimating the strength of selection on these mutations arising from both a competitive measure of male reproductive success and productivity (female fecundity and the subsequent survival to adulthood of her offspring). The effect of stress on male reproductive success has not been addressed previously for individual loci and is of particular interest with respect to the alignment of natural and sexual selection. Our results do not support the hypothesis that stress increases the efficacy of selection arising from either fitness component. Results concerning the alignment of natural and sexual selection were mixed, although data are limited. In the low-stress environment, selection on mating success and productivity were concordant for five of nine mutations (four out of four when restricted to those with significant or near-significant productivity effects), whereas in the high-stress environment, selection aligned for seven of nine mutations (two out of two when restricted to those having significant productivity effects). General conclusions as to the effects of stress on the strength of selection and the alignment of natural and sexual selection await data from additional mutations, fitness components and stressors.  相似文献   

9.
P. D. Keightley 《Genetics》1996,144(4):1993-1999
Much population genetics and evolution theory depends on knowledge of genomic mutation rates and distributions of mutation effects for fitness, but most information comes from a few mutation accumulation experiments in Drosophila in which replicated chromosomes are sheltered from natural selection by a balancer chromosome. I show here that data from these experiments imply the existence of a large class of minor viability mutations with approximately equivalent effects. However, analysis of the distribution of viabilities of chromosomes exposed to EMS mutagenesis reveals a qualitatively different distribution of effects lacking such a minor effects class. A possible explanation for this difference is that transposable element insertions, a common class of spontaneous mutation event in Drosophila, frequently generate minor viability effects. This explanation would imply that current estimates of deleterious mutation rates are not generally applicable in evolutionary models, as transposition rates vary widely. Alternatively, much of the apparent decline in viability under spontaneous mutation accumulation could have been nonmutational, perhaps due to selective improvement of balancer chromosomes. This explanation accords well with the data and implies a spontaneous mutation rate for viability two orders of magnitude lower than previously assumed, with most mutation load attributable to major effects.  相似文献   

10.
We investigate the impact of antagonistic pleiotropy on the most widely used methods of estimation of the average coefficient of dominance of deleterious mutations from segregating populations. A proportion of the deleterious mutations affecting a given studied fitness component are assumed to have an advantageous effect on another one, generating overdominance on global fitness. Using diffusion approximations and transition matrix methods, we obtain the distribution of gene frequencies for nonpleiotropic and pleiotropic mutations in populations at the mutation-selection-drift balance. From these distributions we build homozygous and heterozygous chromosomes and assess the behavior of the estimators of dominance. A very small number of deleterious mutations with antagonistic pleiotropy produces substantial increases on the estimate of the average degree of dominance of mutations affecting the fitness component under study. For example, estimates are increased three- to fivefold when 2% of segregating loci are over-dominant for fitness. In contrast, strengthening pleiotropy, where pleiotropic effects are assumed to be also deleterious, has little effect on the estimates of the average degree of dominance, supporting previous results. The antagonistic pleiotropy model considered, applied under mutational parameters described in the literature, produces patterns for the distribution of chromosomal viabilities, levels of genetic variance, and homozygous mutation load generally consistent with those observed empirically for viability in Drosophila melanogaster.  相似文献   

11.
Mosaic Analysis of Lethal Mutations in Drosophila   总被引:4,自引:4,他引:0       下载免费PDF全文
The effects of various lethal mutations were studied when they were present in the hemizygous state as sectors in genetic mosaics (gynandromorphs) of Drosophila melanogaster. Sixty percent of the lethals studied can survive to adulthood in combination with normal tissue in mosaics, whereas the remainder cause the death of such mosaic animals. Some of the gynandromorph-viable lethals appeared to be locally active, in that they allowed the survival of only those mosaics in which the male tissue was present in the abdomen. The regions affected by these lethals were identified more precisely by analysis of the tissue distributions in the surviving gynandromorphs.  相似文献   

12.
A multilocus stochastic model is developed to simulate the dynamics of mutational load in small populations of various sizes. Old mutations sampled from a large ancestral population at mutation-selection balance and new mutations arising each generation are considered jointly, using biologically plausible lethal and deleterious mutation parameters. The results show that inbreeding depression and the number of lethal equivalents due to partially recessive mutations can be partly purged from the population by inbreeding, and that this purging mainly involves lethals or detrimentals of large effect. However, fitness decreases continuously with inbreeding, due to increased fixation and homozygosity of mildly deleterious mutants, resulting in extinctions of very small populations with low reproductive rates. No optimum inbreeding rate or population size exists for purging with respect to fitness (viability) changes, but there is an optimum inbreeding rate at a given final level of inbreeding for reducing inbreeding depression or the number of lethal equivalents. The interaction between selection against partially recessive mutations and genetic drift in small populations also influences the rate of decay of neutral variation. Weak selection against mutants relative to genetic drift results in apparent overdominance and thus an increase in effective size (Ne) at neutral loci, and strong selection relative to drift leads to a decrease in Ne due to the increased variance in family size. The simulation results and their implications are discussed in the context of biological conservation and tests for purging.  相似文献   

13.
Charlesworth B 《Genetics》2012,191(1):233-246
In the putatively ancestral population of Drosophila melanogaster, the ratio of silent DNA sequence diversity for X-linked loci to that for autosomal loci is approximately one, instead of the expected "null" value of 3/4. One possible explanation is that background selection (the hitchhiking effect of deleterious mutations) is more effective on the autosomes than on the X chromosome, because of the lack of crossing over in male Drosophila. The expected effects of background selection on neutral variability at sites in the middle of an X chromosome or an autosomal arm were calculated for different models of chromosome organization and methods of approximation, using current estimates of the deleterious mutation rate and distributions of the fitness effects of deleterious mutations. The robustness of the results to different distributions of fitness effects, dominance coefficients, mutation rates, mapping functions, and chromosome size was investigated. The predicted ratio of X-linked to autosomal variability is relatively insensitive to these variables, except for the mutation rate and map length. Provided that the deleterious mutation rate per genome is sufficiently large, it seems likely that background selection can account for the observed X to autosome ratio of variability in the ancestral population of D. melanogaster. The fact that this ratio is much less than one in D. pseudoobscura is also consistent with the model's predictions, since this species has a high rate of crossing over. The results suggest that background selection may play a major role in shaping patterns of molecular evolution and variation.  相似文献   

14.
P. D. Keightley 《Genetics》1994,138(4):1315-1322
Parameters of continuous distributions of effects and rates of spontaneous mutation for relative viability in Drosophila are estimated by maximum likelihood from data of two published experiments on accumulation of mutations on protected second chromosomes. A model of equal mutant effects gives a poor fit to the data of the two experiments; higher likelihoods are obtained with leptokurtic distributions or for models in which there is more than one class of mutation effect. Minimum estimates of mutation rates (events per generation) at polygenes affecting viability on chromosome 2 are 0.14 and 0.068, but estimates are strongly confounded with other parameters in the model. Separate information on rates of molecular divergence between Drosophila species and from rates of movement of transposable elements is used to infer the overall genomic mutation rate in Drosophila, and the viability data are analyzed with mutation rate as a known parameter. If, for example, a mutation rate for chromosome 2 of 0.4 is assumed, maximum likelihood estimates of mean mutant effect on relative viability are 0.4% and 1%, but the majority of mutations have very much smaller effects than these values as distributions are highly leptokurtic. The methodology is applied to estimate viability effects of single P element insertional mutations. The mean effect per insertion is found to be higher, and their distribution is found to be less leptokurtic than for spontaneous mutations. The equilibrium genetic variance of viability predicted by a mutation-selection balance model with parameters estimated from the mutation accumulation experiments is similar to laboratory estimates of genetic variance of viability from natural populations of Drosophila.  相似文献   

15.
Martin G  Lenormand T 《Genetics》2008,179(2):907-916
The distribution of the selection coefficients of beneficial mutations is pivotal to the study of the adaptive process, both at the organismal level (theories of adaptation) and at the gene level (molecular evolution). A now famous result of extreme value theory states that this distribution is an exponential, at least when considering a well-adapted wild type. However, this prediction could be inaccurate under selection for an optimum (because fitness effect distributions have a finite right tail in this case). In this article, we derive the distribution of beneficial mutation effects under a general model of stabilizing selection, with arbitrary selective and mutational covariance between a finite set of traits. We assume a well-adapted wild type, thus taking advantage of the robustness of tail behaviors, as in extreme value theory. We show that, under these general conditions, both beneficial mutation effects and fixed effects (mutations escaping drift loss) are beta distributed. In both cases, the parameters have explicit biological meaning and are empirically measurable; their variation through time can also be predicted. We retrieve the classic exponential distribution as a subcase of the beta when there are a moderate to large number of weakly correlated traits under selection. In this case too, we provide an explicit biological interpretation of the parameters of the distribution. We show by simulations that these conclusions are fairly robust to a lower adaptation of the wild type and discuss the relevance of our findings in the context of adaptation theories and experimental evolution.  相似文献   

16.
Loewe L  Charlesworth B 《Genetics》2007,175(3):1381-1393
Background selection involves the reduction in effective population size caused by the removal of recurrent deleterious mutations from a population. Previous work has examined this process for large genomic regions. Here we focus on the level of a single gene or small group of genes and investigate how the effects of background selection caused by nonsynonymous mutations are influenced by the lengths of coding sequences, the number and length of introns, intergenic distances, neighboring genes, mutation rate, and recombination rate. We generate our predictions from estimates of the distribution of the fitness effects of nonsynonymous mutations, obtained from DNA sequence diversity data in Drosophila. Results for genes in regions with typical frequencies of crossing over in Drosophila melanogaster suggest that background selection may influence the effective population sizes of different regions of the same gene, consistent with observed differences in codon usage bias along genes. It may also help to cause the observed effects of gene length and introns on codon usage. Gene conversion plays a crucial role in determining the sizes of these effects. The model overpredicts the effects of background selection with large groups of nonrecombining genes, because it ignores Hill-Robertson interference among the mutations involved.  相似文献   

17.
The fitness effects of mutations are central to evolution, yet have begun to be characterized in detail only recently. Site-directed mutagenesis is a powerful tool for achieving this goal, which is particularly suited for viruses because of their small genomes. Here, I discuss the evolutionary relevance of mutational fitness effects and critically review previous site-directed mutagenesis studies. The effects of single-nucleotide substitutions are standardized and compared for five RNA or single-stranded DNA viruses infecting bacteria, plants or animals. All viruses examined show very low tolerance to mutation when compared with cellular organisms. Moreover, for non-lethal mutations, the mean fitness reduction caused by single mutations is remarkably constant (0.10–0.13), whereas the fraction of lethals varies only modestly (0.20–0.41). Other summary statistics are provided. These generalizations about the distribution of mutational fitness effects can help us to better understand the evolution of RNA and single-stranded DNA viruses.  相似文献   

18.
Beneficial fitness effects are not exponential for two viruses   总被引:1,自引:0,他引:1  
The distribution of fitness effects for beneficial mutations is of paramount importance in determining the outcome of adaptation. It is generally assumed that fitness effects of beneficial mutations follow an exponential distribution, for example, in theoretical treatments of quantitative genetics, clonal interference, experimental evolution, and the adaptation of DNA sequences. This assumption has been justified by the statistical theory of extreme values, because the fitnesses conferred by beneficial mutations should represent samples from the extreme right tail of the fitness distribution. Yet in extreme value theory, there are three different limiting forms for right tails of distributions, and the exponential describes only those of distributions in the Gumbel domain of attraction. Using beneficial mutations from two viruses, we show for the first time that the Gumbel domain can be rejected in favor of a distribution with a right-truncated tail, thus providing evidence for an upper bound on fitness effects. Our data also violate the common assumption that small-effect beneficial mutations greatly outnumber those of large effect, as they are consistent with a uniform distribution of beneficial effects.  相似文献   

19.
Recent mutation accumulation results from invertebrate species suggest that mild deleterious mutation is far less frequent than previously thought, implying smaller expressed mutational loads. Although the rate (lambda) and effect (s) of very slight deleterious mutation remain unknown, most mutational fitness decline would come from moderately deleterious mutation (s approximately 0.2, lambda approximately 0.03), and this situation would not qualitatively change in harsh environments. Estimates of the average coefficient of dominance (h) of non-severe deleterious mutations are controversial. The typical value of h = 0.4 can be questioned, and a lower estimate (about 0.1) is suggested. Estimated mutational parameters are remarkably alike for morphological and fitness component traits (excluding lethals), indicating low mutation rates and moderate mutational effects, with a distribution generally showing strong negative asymmetry and little leptokurtosis. New mutations showed considerable genotype-environment interaction. However, the mutational variance of fitness-component traits due to non-severe detrimental mutations did not increase with environmental harshness. For morphological traits, a class of predominantly additive mutations with no detectable effect on fitness and relatively small effect on the trait was identified. This should be close to that responsible for standing variation in natural populations.  相似文献   

20.
In the ‘doubling-dose’ method currently used in genetic risk evaluation, two principle assumptions are made and these are: (1) there is proportionality between spontaneous and induced mutations and (2) the lesions that lead to spontaneous and induced mutations are essentially similar. The studies reported in this paper were directed at examining the validity of these two assumptions in Drosophila. An analysis was made of the distribution of sex-linked recessive lethals induced by MR, one of the well-studied mutator systems in Drosophila.

Appropriate genetic complementation tests with 15 defined X-chromosome duplications showed that MR-induced lethals occurred at many sites along the X-chromosome (in contrast to the known locus specificity of MR-induced visible-mutations); some, but not all these sites at which recessive lethals arose in the MR-system are the same as those known to be hot-spots for X-ray-induced lethals. With in situ hybridization we were able to demonstrate that a majority of MR-induced lethals is associated with a particular mobile DNA sequence, the P-element, i.e. they arose as a result of transposition.

The differences between the profiles of MR-induced and X-ray-induced recessive lethals, and the nature of MR-induced and X-ray-induced mutations, thus raise questions about the validity of the assumptions involved in the use of the ‘doubling-dose’ method.  相似文献   


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