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1.
The proportion of amino acid substitutions driven by adaptive evolution can potentially be estimated from polymorphism and divergence data by an extension of the McDonald-Kreitman test. We have developed a maximum-likelihood method to do this and have applied our method to several data sets from three Drosophila species: D. melanogaster, D. simulans, and D. yakuba. The estimated number of adaptive substitutions per codon is not uniformly distributed among genes, but follows a leptokurtic distribution. However, the proportion of amino acid substitutions fixed by adaptive evolution seems to be remarkably constant across the genome (i.e., the proportion of amino acid substitutions that are adaptive appears to be the same in fast-evolving and slow-evolving genes; fast-evolving genes have higher numbers of both adaptive and neutral substitutions). Our estimates do not seem to be significantly biased by selection on synonymous codon use or by the assumption of independence among sites. Nevertheless, an accurate estimate is hampered by the existence of slightly deleterious mutations and variations in effective population size. The analysis of several Drosophila data sets suggests that approximately 25% +/- 20% of amino acid substitutions were driven by positive selection in the divergence between D. simulans and D. yakuba. 相似文献
2.
We investigate the extent by which the estimates of the rate of adaptive molecular evolution obtained by extending the McDonald-Kreitman test are biased if the species, subjected to analysis, diverged recently. We show that estimates can be biased if the nucleotide divergence between the species is low relative to within species variation, and that the magnitude of the bias depends on the rate of adaptive evolution and the distribution of fitness effects of new mutations. Bias appears to be because of three factors: (1) misattribution of polymorphism to divergence; (2) the contribution of ancestral polymorphism to divergence; and (3) different rates of fixation of neutral and advantageous mutations. If there is little adaptive molecular evolution, then slightly deleterious mutations inflate estimates of the rate of adaptive evolution, because these contribute proportionately more to polymorphism than to nucleotide divergence than neutral mutations. However, if there is substantial adaptive evolution, polymorphism contributing to apparent divergence may downwardly bias estimates. We propose a simple method for correcting the different contributions of slightly deleterious and neutral mutations to polymorphism and divergence, and apply it to datasets from several species. We find that estimates of the rate of adaptive molecular evolution from closely related species may be underestimates by ~10% or more. However, after the contribution of polymorphism to divergence is removed, the rate of adaptive evolution may still be overestimated as a consequence of ancestral polymorphism and time for fixation effects. This bias may be substantial if branch lengths are less than 10N (e) generations. 相似文献
3.
Eyre-Walker A 《Genetics》2002,162(4):2017-2024
Artifactual evidence of adaptive amino acid substitution can be generated within a McDonald-Kreitman test if some amino acid mutations are slightly deleterious and there has been an increase in effective population size. Here I investigate the conditions under which this occurs. I show that fairly small increases in effective population size can generate artifactual evidence of positive selection if there is no selection upon synonymous codon use. This problem is exacerbated by the removal of low-frequency polymorphisms. However, selection on synonymous codon use restricts the conditions under which artifactual evidence of adaptive evolution is produced. 相似文献
4.
Positive and negative selection on the human genome. 总被引:42,自引:0,他引:42
The distinction between deleterious, neutral, and adaptive mutations is a fundamental problem in the study of molecular evolution. Two significant quantities are the fraction of DNA variation in natural populations that is deleterious and destined to be eliminated and the fraction of fixed differences between species driven by positive Darwinian selection. We estimate these quantities using the large number of human genes for which there are polymorphism and divergence data. The fraction of amino acid mutations that is neutral is estimated to be 0.20 from the ratio of common amino acid (A) to synonymous (S) single nucleotide polymorphisms (SNPs) at frequencies of > or =15%. Among the 80% of amino acid mutations that are deleterious at least 20% of them are only slightly deleterious and often attain frequencies of 1-10%. We estimate that these slightly deleterious mutations comprise at least 3% of amino acid SNPs in the average individual or at least 300 per diploid genome. This estimate is not sensitive to human population history. The A/S ratio of fixed differences is greater than that of common SNPs and suggests that a large fraction of protein divergence is adaptive and driven by positive Darwinian selection. 相似文献
5.
Deleterious mutations present a significant obstacle to adaptive evolution. Deleterious mutations can inhibit the spread of linked adaptive mutations through a population; conversely, adaptive substitutions can increase the frequency of linked deleterious mutations and even result in their fixation. To assess the impact of adaptive mutations on linked deleterious mutations, we examined the distribution of deleterious and neutral amino acid polymorphism in the human genome. Within genomic regions that show evidence of recent hitchhiking, we find fewer neutral but a similar number of deleterious SNPs compared to other genomic regions. The higher ratio of deleterious to neutral SNPs is consistent with simulated hitchhiking events and implies that positive selection eliminates some deleterious alleles and increases the frequency of others. The distribution of disease-associated alleles is also altered in hitchhiking regions. Disease alleles within hitchhiking regions have been associated with auto-immune disorders, metabolic diseases, cancers, and mental disorders. Our results suggest that positive selection has had a significant impact on deleterious polymorphism and may be partly responsible for the high frequency of certain human disease alleles. 相似文献
6.
We present a survey of nucleotide polymorphism of three novel, rapidly evolving genes in populations of Drosophila melanogaster and D. simulans. Levels of silent polymorphism are comparable to other loci, but the number of replacement polymorphisms is higher than that in most other genes surveyed in D. melanogaster and D. simulans. Tests of neutrality fail to reject neutral evolution with one exception. This concerns a gene located in a region of high recombination rate in D. simulans and in a region of low recombination rate in D. melanogaster, due to an inversion. In the latter case it shows a very low number of polymorphisms, presumably due to selective sweeps in the region. Patterns of nucleotide polymorphism suggest that most substitutions are neutral or nearly neutral and that weak (positive and purifying) selection plays a significant role in the evolution of these genes. At all three loci, purifying selection of slightly deleterious replacement mutations appears to be more efficient in D. simulans than in D. melanogaster, presumably due to different effective population sizes. Our analysis suggests that current knowledge about genome-wide patterns of nucleotide polymorphism is far from complete with respect to the types and range of nucleotide substitutions and that further analysis of differences between local populations will be required to understand the forces more completely. We note that rapidly diverging and nearly neutrally evolving genes cannot be expected only in the genome of Drosophila, but are likely to occur in large numbers also in other organisms and that their function and evolution are little understood so far. 相似文献
7.
Changes in effective population size impinge on patterns of molecular evolution. Notably, slightly deleterious mutations are more likely to drift to fixation in smaller populations, which should typically also lead to an overall acceleration in the rates of evolution. This prediction has been validated empirically for several endosymbiont and island taxa. Here, we first show that rate accelerations are also evident in bacterial pathogens whose recent shifts in virulence make them prime candidates for reduced effective population size: Bacillus anthracis, Bordetella parapertussis, Mycobacterium leprae, Salmonella enterica typhi, Shigella spp., and Yersinia pestis. Using closely related genomes to analyze substitution rate dynamics across six phylogenetically independent bacterial clades, we demonstrate that relative rates of coding sequence evolution are biased according to gene functional category. Notably, genes that buffer against slightly deleterious mutations, such as chaperones, experience stronger rate accelerations than other functional classes at both nonsynonymous and synonymous sites. Although theory predicts altered evolutionary dynamics for buffer loci in the face of accumulating deleterious mutations, to observe even stronger rate accelerations is surprising. We suggest that buffer loci experience elevated substitution rates because the accumulation of deleterious mutations in the remainder of the genome favors compensatory substitutions in trans. Critically, the hyper-acceleration is evident across phylogenetically independent clades, supporting the hypothesis that reductions in effective population size predictably induce epistatic responses in genes that buffer against slightly deleterious mutations. 相似文献
8.
An important goal of evolutionary biology is to understand the constraints that shape the dynamics and outcomes of evolution. Here, we address the extent to which the structure of the standard genetic code constrains evolution by analyzing adaptive mutations of the antibiotic resistance gene TEM-1 β-lactamase and the fitness distribution of codon substitutions in two influenza hemagglutinin inhibitor genes. We find that the architecture of the genetic code significantly constrains the adaptive exploration of sequence space. However, the constraints endow the code with two advantages: the ability to restrict access to amino acid mutations with a strong negative effect and, most remarkably, the ability to enrich for adaptive mutations. Our findings support the hypothesis that the standard genetic code was shaped by selective pressure to minimize the deleterious effects of mutation yet facilitate the evolution of proteins through imposing an adaptive mutation bias. 相似文献
9.
Estimation of the distribution of selection coefficients of mutations is a long-standing issue in molecular evolution. In addition to population-based methods, the distribution can be estimated from DNA sequence data by phylogenetic-based models. Previous models have generally found unimodal distributions where the probability mass is concentrated between mildly deleterious and nearly neutral mutations. Here we use a sitewise mutation-selection phylogenetic model to estimate the distribution of selection coefficients among novel and fixed mutations (substitutions) in a data set of 244 mammalian mitochondrial genomes and a set of 401 PB2 proteins from influenza. We find a bimodal distribution of selection coefficients for novel mutations in both the mitochondrial data set and for the influenza protein evolving in its natural reservoir, birds. Most of the mutations are strongly deleterious with the rest of the probability mass concentrated around mildly deleterious to neutral mutations. The distribution of the coefficients among substitutions is unimodal and symmetrical around nearly neutral substitutions for both data sets at adaptive equilibrium. About 0.5% of the nonsynonymous mutations and 14% of the nonsynonymous substitutions in the mitochondrial proteins are advantageous, with 0.5% and 24% observed for the influenza protein. Following a host shift of influenza from birds to humans, however, we find among novel mutations in PB2 a trimodal distribution with a small mode of advantageous mutations. 相似文献
10.
Evolution of the human immunodeficiency virus envelope gene is dominated by purifying selection
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Edwards CT Holmes EC Pybus OG Wilson DJ Viscidi RP Abrams EJ Phillips RE Drummond AJ 《Genetics》2006,174(3):1441-1453
The evolution of the human immunodeficiency virus (HIV-1) during chronic infection involves the rapid, continuous turnover of genetic diversity. However, the role of natural selection, relative to random genetic drift, in governing this process is unclear. We tested a stochastic model of genetic drift using partial envelope sequences sampled longitudinally in 28 infected children. In each case the Bayesian posterior (empirical) distribution of coalescent genealogies was estimated using Markov chain Monte Carlo methods. Posterior predictive simulation was then used to generate a null distribution of genealogies assuming neutrality, with the null and empirical distributions compared using four genealogy-based summary statistics sensitive to nonneutral evolution. Because both null and empirical distributions were generated within a coalescent framework, we were able to explicitly account for the confounding influence of demography. From the distribution of corrected P-values across patients, we conclude that empirical genealogies are more asymmetric than expected if evolution is driven by mutation and genetic drift only, with an excess of low-frequency polymorphisms in the population. This indicates that although drift may still play an important role, natural selection has a strong influence on the evolution of HIV-1 envelope. A negative relationship between effective population size and substitution rate indicates that as the efficacy of selection increases, a smaller proportion of mutations approach fixation in the population. This suggests the presence of deleterious mutations. We therefore conclude that intrahost HIV-1 evolution in envelope is dominated by purifying selection against low-frequency deleterious mutations that do not reach fixation. 相似文献
11.
Fujimoto A Kado T Yoshimaru H Tsumura Y Tachida H 《Journal of molecular evolution》2008,67(2):201-210
In order to evaluate effects of the population structure and natural selection on organisms having long generation times, we surveyed DNA polymorphisms at five loci encoding 9-cis-epoxycarotenoid dioxygenase (NCED), ammonium transporter, calmodulin, aquaporin, and the second major allergen with polymethylgalacturonase enzyme activity in the pollen (Cryj2) in a conifer, Cryptomeria japonica. The average nucleotide diversity at silent sites across 12 loci including the previously analyzed seven loci was 0.0044. The population recombination rate (4Nr, where N and r are the effective population size and recombination rate per base per generation, respectively) was estimated as 0.00046 and a slow reduction in the population size was indicated, according to the maximum likelihood method implemented in LAMARC. At NCED, the McDonald-Kreitman (MK) test revealed an excess of replacement polymorphisms, suggesting contributions of slightly deleterious mutations. In contrast, the MK test revealed an excess of replacement divergence at Cryj2 and a maximum likelihood approach using the PAML package revealed that certain amino acid sites had a nonsynonymous/synonymous substitution rate ratio (omega) > 4.0, indicating adaptive evolution at this locus. The overall analysis of the 12 loci suggested that adaptive, neutral, and slightly deleterious evolution played important roles in the evolution of C. japonica. 相似文献
12.
Comparison of the ratio of nonsynonymous to synonymous polymorphisms within species with the ratio of nonsynonymous to synonymous substitutions between species has been widely used as a supposed indicator of positive Darwinian selection, with the ratio of these 2 ratios being designated as a neutrality index (NI). Comparison of genome-wide polymorphism within 12 species of bacteria with divergence from an outgroup species showed substantial differences in NI among taxa. A low level of nonsynonymous polymorphism at a locus was the best predictor of NI < 1, rather than a high level of nonsynonymous substitution between species. Moreover, genes with NI < 1 showed a strong tendency toward the occurrence of rare nonsynonymous polymorphisms, as expected under the action of ongoing purifying selection. Thus, our results are more consistent with the hypothesis that a high relative rate of between-species nonsynonymous substitution reflects mainly the action of purifying selection within species to eliminate slightly deleterious mutations rather than positive selection between species. This conclusion is consistent with previous results highlighting an important role of slightly deleterious variants in bacterial evolution and suggests caution in the use of the McDonald-Kreitman test and related statistics as tests of positive selection. 相似文献
13.
Bachtrog D 《Genetics》2003,165(3):1221-1232
The neo-sex chromosomes of Drosophila miranda constitute an ideal system to study the effects of recombination on patterns of genome evolution. Due to a fusion of an autosome with the Y chromosome, one homolog is transmitted clonally. Here, I compare patterns of molecular evolution of 18 protein-coding genes located on the recombining neo-X and their homologs on the nonrecombining neo-Y chromosome. The rate of protein evolution has significantly increased on the neo-Y lineage since its formation. Amino acid substitutions are accumulating uniformly among neo-Y-linked genes, as expected if all loci on the neo-Y chromosome suffer from a reduced effectiveness of natural selection. In contrast, there is significant heterogeneity in the rate of protein evolution among neo-X-linked genes, with most loci being under strong purifying selection and two genes showing evidence for adaptive evolution. This observation agrees with theory predicting that linkage limits adaptive protein evolution. Both the neo-X and the neo-Y chromosome show an excess of unpreferred codon substitutions over preferred ones and no difference in this pattern was observed between the chromosomes. This suggests that there has been little or no selection maintaining codon bias in the D. miranda lineage. A change in mutational bias toward AT substitutions also contributes to the decline in codon bias. The contrast in patterns of molecular evolution between amino acid mutations and synonymous mutations on the neo-sex-linked genes can be understood in terms of chromosome-specific differences in effective population size and the distribution of selective effects of mutations. 相似文献
14.
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
15.
Few loci have been measured for DNA polymorphism and divergence in several species. Here we report such data from the protein-coding region of xanthine dehydrogenase (Xdh) in 22 species of Drosophila. Many of our samples were from closely related species, allowing us to confidently assign substitutions to individual lineages. Surprisingly, Xdh appears to be fixing more A/T mutations than G/C mutations in most lineages, leading to evolution of higher A/T content in the recent past. We found no compelling evidence for selection on protein variation, though some aspects of the data support the notion that a significant fraction of amino acid polymorphisms are slightly deleterious. Finally, we found no convincing evidence that levels of silent heterozygosity are associated with rates of protein evolution. 相似文献
16.
Andrew J. Eckert Andrew D. Bower Kathleen D. Jermstad Jill L. Wegrzyn Brian J. Knaus John V. Syring David B. Neale 《Molecular ecology》2013,22(22):5635-5650
Estimates from molecular data for the fraction of new nonsynonymous mutations that are adaptive vary strongly across plant species. Much of this variation is due to differences in life history strategies as they influence the effective population size (Ne). Ample variation for these estimates, however, remains even when comparisons are made across species with similar values of Ne. An open question thus remains as to why the large disparity for estimates of adaptive evolution exists among plant species. Here, we have estimated the distribution of deleterious fitness effects (DFE) and the fraction of adaptive nonsynonymous substitutions (α) for 11 species of soft pines (subgenus Strobus) using DNA sequence data from 167 orthologous nuclear gene fragments. Most newly arising nonsynonymous mutations were inferred to be so strongly deleterious that they would rarely become fixed. Little evidence for long‐term adaptive evolution was detected, as all 11 estimates for α were not significantly different from zero. Nucleotide diversity at synonymous sites, moreover, was strongly correlated with attributes of the DFE across species, thus illustrating a strong consistency with the expectations from the Nearly Neutral Theory of molecular evolution. Application of these patterns to genome‐wide expectations for these species, however, was difficult as the loci chosen for the analysis were a biased set of conserved loci, which greatly influenced the estimates of the DFE and α. This implies that genome‐wide parameter estimates will need truly genome‐wide data, so that many of the existing patterns documented previously for forest trees (e.g. little evidence for signature of selection) may need revision. 相似文献
17.
Most rare missense alleles are deleterious in humans: implications for complex disease and association studies
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The accumulation of mildly deleterious missense mutations in individual human genomes has been proposed to be a genetic basis for complex diseases. The plausibility of this hypothesis depends on quantitative estimates of the prevalence of mildly deleterious de novo mutations and polymorphic variants in humans and on the intensity of selective pressure against them. We combined analysis of mutations causing human Mendelian diseases, of human-chimpanzee divergence, and of systematic data on human genetic variation and found that ~20% of new missense mutations in humans result in a loss of function, whereas ~27% are effectively neutral. Thus, the remaining 53% of new missense mutations have mildly deleterious effects. These mutations give rise to many low-frequency deleterious allelic variants in the human population, as is evident from a new data set of 37 genes sequenced in >1,500 individual human chromosomes. Surprisingly, up to 70% of low-frequency missense alleles are mildly deleterious and are associated with a heterozygous fitness loss in the range 0.001-0.003. Thus, the low allele frequency of an amino acid variant can, by itself, serve as a predictor of its functional significance. Several recent studies have reported a significant excess of rare missense variants in candidate genes or pathways in individuals with extreme values of quantitative phenotypes. These studies would be unlikely to yield results if most rare variants were neutral or if rare variants were not a significant contributor to the genetic component of phenotypic inheritance. Our results provide a justification for these types of candidate-gene (pathway) association studies and imply that mutation-selection balance may be a feasible evolutionary mechanism underlying some common diseases. 相似文献
18.
We have evaluated the molecular evolution of the chemokine receptor CCR5 in primates. The chemokine receptor CCR5 serves as a major co-receptor for human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) infection. Knowledge of evolution of the CCR5 molecule and selection on the CCR5 gene may shed light on its functional role. The comparison of differences between intraspecific polymorphisms and interspecific fixed substitutions provides useful information regarding modes of selection during the course of evolution. There is marked polymorphism in the CCR5 gene sequence within different primate species, whereas sequence divergence between different species is small. By using contingency tests, we compared synonymous (SS) and nonsynonymous (NS) CCR5 mutations occurring within and between a broad range of primates. Our results demonstrate that CCR5 evolution did not follow expectations of strict neutrality at the level of the whole gene. The proportion of NS to SS at the intraspecific level was significantly higher than that observed at the interspecific level. These results suggest that most CCR5 NS polymorphisms are slightly deleterious. However, at domains more closely correlated with its known biological functions, there was no obvious evidence to support deviation from neutrality. 相似文献
19.
Adaptive protein evolution of X-linked and autosomal genes in Drosophila: implications for faster-X hypotheses 总被引:1,自引:0,他引:1
Connallon T 《Molecular biology and evolution》2007,24(11):2566-2572
Patterns of sex chromosome and autosome evolution can be used to elucidate the underlying genetic basis of adaptative change. Evolutionary theory predicts that X-linked genes will adapt more rapidly than autosomes if adaptation is limited by the availability of beneficial mutations and if such mutations are recessive. In Drosophila, rates of molecular divergence between species appear to be equivalent between autosomes and the X chromosome. However, molecular divergence contrasts are difficult to interpret because they reflect a composite of adaptive and nonadaptive substitutions between species. Predictions based on faster-X theory also assume that selection is equally effective on the X and autosomes; this might not be true because the effective population sizes of X-linked and autosomal genes systematically differ. Here, population genetic and divergence data from Drosophila melanogaster, Drosophila simulans, and Drosophila yakuba are used to estimate the proportion of adaptive amino acid substitutions occurring in the D. melanogaster lineage. After gene composition and effective population size differences between chromosomes are controlled, X-linked and autosomal genes are shown to have equivalent rates of adaptive divergence with approximately 30% of amino acid substitutions driven by positive selection. The results suggest that adaptation is either unconstrained by a lack of beneficial genetic variation or that beneficial mutations are not recessive and are thus highly visible to natural selection whether on sex chromosomes or on autosomes. 相似文献
20.
Carneiro M Albert FW Melo-Ferreira J Galtier N Gayral P Blanco-Aguiar JA Villafuerte R Nachman MW Ferrand N 《Molecular biology and evolution》2012,29(7):1837-1849
The nearly neutral theory of molecular evolution predicts that the efficacy of both positive and purifying selection is a function of the long-term effective population size (N(e)) of a species. Under this theory, the efficacy of natural selection should increase with N(e). Here, we tested this simple prediction by surveying ~1.5 to 1.8 Mb of protein coding sequence in the two subspecies of the European rabbit (Oryctolagus cuniculus algirus and O. c. cuniculus), a mammal species characterized by high levels of nucleotide diversity and N(e) estimates for each subspecies on the order of 1 × 10(6). When the segregation of slightly deleterious mutations and demographic effects were taken into account, we inferred that >60% of amino acid substitutions on the autosomes were driven to fixation by positive selection. Moreover, we inferred that a small fraction of new amino acid mutations (<4%) are effectively neutral (defined as 0 < N(e)s < 1) and that this fraction was negatively correlated with a gene's expression level. Consistent with models of recurrent adaptive evolution, we detected a negative correlation between levels of synonymous site polymorphism and the rate of protein evolution, although the correlation was weak and nonsignificant. No systematic X chromosome-autosome difference was found in the efficacy of selection. For example, the proportion of adaptive substitutions was significantly higher on the X chromosome compared with the autosomes in O. c. algirus but not in O. c. cuniculus. Our findings support widespread positive and purifying selection in rabbits and add to a growing list of examples suggesting that differences in N(e) among taxa play a substantial role in determining rates and patterns of protein evolution. 相似文献