Evolution of the human immunodeficiency virus envelope gene is dominated by purifying selection

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.     

The interaction among evolutionary forces in the pathogenic fungus Mycosphaerella graminicola

The population genetic dynamic of a species is driven by interactions among mutation, migration, drift, mating system, and selection, but it is rare to have sufficient empirical data to estimate values for all of these forces and to allow comparison of the relative magnitudes of these evolutionary forces. We combined data from a mark-release-recapture experiment, extensive population surveys, and computer simulations to evaluate interactions among these evolutionary forces in the pathogenic fungus Mycosphaerella graminicola. The results from these studies showed that, on average, the immigration rate was 0.027, the fraction of outcrossing individuals was 0.035, and the selection coefficient associated with immigrants was 0.106 each generation. We also estimated that effective population sizes for this fungus were larger than 24,000 and the mutation rate for the RFLP markers used in surveys and field experiments was approximately 4 x 10(-5). Computer simulations based on these estimates indicate that, on average, the global population of M. graminicola has reached equilibrium. Population genetic parameters including number of alleles, gene diversity, and population subdivision estimated from the computer simulations were surprisingly close to empirical estimates. Simulations also revealed that random drift is the major evolutionary force decreasing genetic variation in this fungus, followed by natural selection. The major force adding to genetic variation was mutation, followed by gene flow and sexual recombination. Gene flow played the leading role in decreasing population subdivision while natural selection was the major factor increasing population subdivision.     

Environmental variance in male mating success modulates the positive versus negative impacts of sexual selection on genetic load

Sexual selection on males is predicted to increase population fitness, and delay population extinction, when mating success negatively covaries with genetic load across individuals. However, such benefits of sexual selection could be counteracted by simultaneous increases in genome-wide drift resulting from reduced effective population size caused by increased variance in fitness. Resulting fixation of deleterious mutations could be greatest in small populations, and when environmental variation in mating traits partially decouples sexual selection from underlying genetic variation. The net consequences of sexual selection for genetic load and population persistence are therefore likely to be context dependent, but such variation has not been examined. We use a genetically explicit individual-based model to show that weak sexual selection can increase population persistence time compared to random mating. However, for stronger sexual selection such positive effects can be overturned by the detrimental effects of increased genome-wide drift. Furthermore, the relative strengths of mutation-purging and drift critically depend on the environmental variance in the male mating trait. Specifically, increasing environmental variance caused stronger sexual selection to elevate deleterious mutation fixation rate and mean selection coefficient, driving rapid accumulation of drift load and decreasing population persistence times. These results highlight an intricate balance between conflicting positive and negative consequences of sexual selection on genetic load, even in the absence of sexually antagonistic selection. They imply that environmental variances in key mating traits, and intrinsic genetic drift, should be properly factored into future theoretical and empirical studies of the evolution of population fitness under sexual selection.     

Estimating the strength of selective sweeps from deep population diversity data

Selective sweeps are typically associated with a local reduction of genetic diversity around the adaptive site. However, selective sweeps can also quickly carry neutral mutations to observable population frequencies if they arise early in a sweep and hitchhike with the adaptive allele. We show that the interplay between mutation and exponential amplification through hitchhiking results in a characteristic frequency spectrum of the resulting novel haplotype variation that depends only on the ratio of the mutation rate and the selection coefficient of the sweep. On the basis of this result, we develop an estimator for the selection coefficient driving a sweep. Since this estimator utilizes the novel variation arising from mutations during a sweep, it does not rely on preexisting variation and can also be applied to loci that lack recombination. Compared with standard approaches that infer selection coefficients from the size of dips in genetic diversity around the adaptive site, our estimator requires much shorter sequences but sampled at high population depth to capture low-frequency variants; given such data, it consistently outperforms standard approaches. We investigate analytically and numerically how the accuracy of our estimator is affected by the decay of the sweep pattern over time as a consequence of random genetic drift and discuss potential effects of recombination, soft sweeps, and demography. As an example for its use, we apply our estimator to deep sequencing data from human immunodeficiency virus populations.     

The interaction of genetic drift and mutation with selection in a fluctuating environment

The interaction of genetic drift, mutation, and selection in a random environment is investigated using an asymptotic analysis based on assumptions of weak mutation and strong selection. It is shown that genetic drift can be a potent force for removing variation from the population when the random environment tends to occasionally push alleles down to low frequencies.     

Pervasive genomic recombination of HIV-1 in vivo

Recombinants of preexisting human immunodeficiency virus type 1 (HIV-1) strains are now circulating globally. To increase our understanding of the importance of these recombinants, we assessed recombination within an individual infected from a single source by studying the linkage patterns of the auxiliary genes of HIV-1 subtype B. Maximum-likelihood phylogenetic techniques revealed evidence for recombination from topological incongruence among adjacent genes. Coalescent methods were then used to estimate the in vivo recombination rate. The estimated mean rate of 1.38 x 10(-4) recombination events/adjacent sites/generation is approximately 5.5-fold greater than the reported point mutation rate of 2.5 x 10(-5)/site/generation. Recombination was found to be frequent enough to mask evidence for purifying selection by Tajima's D test. Thus, recombination is a major evolutionary force affecting genetic variation within an HIV-1-infected individual, of the same order of magnitude as point mutational change.     

Random genetic drift during cyclical ameiotic parthenogenesis

The classical models of population genetics assume sexual reproduction and do not apply to organisms in which parthenogenetic reproduction is alternated with sexual recombination. Under cyclic parthenogenesis, variation in rates or frequencies of parthenogenetic reproduction among clones produces selection that is independent of processes occurring in the sexual phases.In this paper I examine how selection during cyclic parthenogenesis influences random genetic drift and leads to a loss of variance among clones. To illustrate these effects, computer simulations are presented demonstrating the response of effective clone number and equilibrium clone diversity to selection and mutation.     

Drift increases the advantage of sex in RNA bacteriophage Phi6

The pervasiveness of sex and recombination remains one of the most enigmatic problems in evolutionary biology. According to many theoretical models, recombination can increase the rate of adaptation by restoring genetic variation. However, the potential for genetic drift to generate conditions that produce this outcome has yet to be studied experimentally. We have designed and performed an experiment that reveals the effects of drift on existing genetic variation by minimizing the influence of variation on beneficial mutation rate. Our experiment was conducted in populations of RNA bacteriophage Phi6 initiated from a common source population at varying bottleneck sizes. The segmented genome of this virus results in genetic exchange between viruses that co-infect the same host cell. In response to selection for growth in a high-temperature environment, sexual lines outperformed their asexual counterparts on average. The advantage of sex attenuated with increasing effective population size, implying that the rate of adaptation was limited by clonal interference among segments caused by drift. This is the first empirical evidence that the advantage of sex during adaptation increases with the intensity of drift.     

Why is the genome variable? Insights from Drosophila.

The analysis of variation in DNA restriction maps and DNA sequence in natural populations of Drosophila melanogaster and related species has revealed a remarkable richness of diversity. This review describes some of the results of population genetic studies of this variation that are beginning to reveal how interactions between natural selection, genetic drift, mutation rate, recombination rate and population size have contributed to the observed patterns.     

Evolution of intrahost HIV-1 genetic diversity during chronic infection

HIV-1 is one of the fastest evolving entities known. Given that census population sizes of HIV-1 within individuals are much greater than the inverse mutation rate, every possible single point mutation in the viral genome occurs each generation. This enormous capability to generate genetic variation allows for escape from immune surveillance and antiviral therapy. However, compared to this potential, populations of HIV-1 within individuals exhibit little genetic variation. This discrepancy between the known mutation rate of HIV-1 and the average level of genetic variation in the env gene observed in vivo is reflected in comparisons of the actual numbers of productively infected cells, estimated as 10(7), and the effective population size, estimated as 10(3). Using approximate Bayesian computation, we evaluated several hypotheses based on a variety of selective and demographic processes to explain the low effective population size of HIV-1. Of the models we examined, the metapopulation model, in which HIV-1 evolves within an individual as a large collection of small subpopulations subject to frequent migration, extinction, and recolonization, was most consistent with the observed levels of genetic variation and the average frequencies of those variants. The metapopulation model links previous studies of viral dynamics and population genetics.     

Diversifying selection drives parallel evolution of gill raker number and body size along the speciation continuum of European whitefish

Adaptive radiation is the evolution of ecological and phenotypical diversity. It arises via ecological opportunity that promotes the exploration of underutilized or novel niches mediating specialization and reproductive isolation. The assumed precondition for rapid local adaptation is diversifying natural selection, but random genetic drift could also be a major driver of this process. We used 27 populations of European whitefish (Coregonus lavaretus) from nine lakes distributed in three neighboring subarctic watercourses in northern Fennoscandia as a model to test the importance of random drift versus diversifying natural selection for parallel evolution of adaptive phenotypic traits. We contrasted variation for two key adaptive phenotypic traits correlated with resource utilization of polymorphic fish; the number of gill rakers and the total length of fish, with the posterior distribution of neutral genetic differentiation from 13 microsatellite loci, to test whether the observed phenotypic divergence could be achieved by random genetic drift alone. Our results show that both traits have been under diversifying selection and that the evolution of these morphs has been driven by isolation through habitat adaptations. We conclude that diversifying selection acting on gill raker number and body size has played a significant role in the ongoing adaptive radiation of European whitefish morphs in this region.     

植物病原物的群体遗传学

品种单一化、生产密集型和一年多茬的现代农业特点导致病原物呈现出进化速度加快、致病力增强及流行风险增大趋势。深入研究病原物群体遗传学对认识病害的流行、有效选育和使用抗性品种乃至控制病害具有重要意义。文章阐述了植物病原物群体遗传学的研究目标和内容、突变、基因迁移、基因重组、随机遗传漂变和自然选择5大遗传机制在植物病原物进化过程中的作用,以及目前植物病原物群体遗传学研究的现状。     

植物病原物的群体遗传学

品种单一化、生产密集型和一年多茬的现代农业特点导致病原物呈现出进化速度加快、致病力增强及流行风险增大趋势。深入研究病原物群体遗传学对认识病害的流行、有效选育和使用抗性品种乃至控制病害具有重要意义。文章阐述了植物病原物群体遗传学的研究目标和内容、突变、基因迁移、基因重组、随机遗传漂变和自然选择5大遗传机制在植物病原物进化过程中的作用, 以及目前植物病原物群体遗传学研究的现状。     

SEXUAL SELECTION CAN INCREASE THE EFFECT OF RANDOM GENETIC DRIFT—A QUANTITATIVE GENETIC MODEL OF POLYMORPHISM IN OOPHAGA PUMILIO,THE STRAWBERRY POISON‐DART FROG

The variation in color pattern between populations of the poison‐dart frog Oophaga pumilio across the Bocas del Toro archipelago in Panama is suggested to be due to sexual selection, as two other nonsexually selecting Dendrobatid species found in the same habitat and range do not exhibit this variation. We theoretically test this assertion using a quantitative genetic sexual selection model incorporating aposematic coloration and random drift. We find that sexual selection could cause the observed variation via a novel process we call “coupled drift.” Within our model, for certain parameter values, sexual selection forces frog color to closely follow the evolution of female preference. Any between‐population variation in preference due to genetic drift is passed on to color. If female preference in O. pumilio is strongly affected by drift, whereas color in the nonsexually selecting Dendrobatid species is not, coupled drift will cause increased between‐population phenotypic variation. However, with different parameter values, coupled drift will result in between‐population variation in color being suppressed compared to its neutral value, or in little or no effect. We suggest that coupled drift is a novel theoretical process that could have a role linking sexual selection with speciation both in O. pumilio, and perhaps more generally.     

Daily sampling of an HIV-1 patient with slowly progressing disease displays persistence of multiple env subpopulations consistent with neutrality

The molecular evolution of HIV-1 is characterized by frequent substitutions, indels and recombination events. In addition, a HIV-1 population may adapt through frequency changes of its variants. To reveal such population dynamics we analyzed HIV-1 subpopulation frequencies in an untreated patient with stable, low plasma HIV-1 RNA levels and close to normal CD4+ T-cell levels. The patient was intensively sampled during a 32-day period as well as approximately 1.5 years before and after this period (days -664, 1, 2, 3, 11, 18, 25, 32 and 522). 77 sequences of HIV-1 env (approximately 3100 nucleotides) were obtained from plasma by limiting dilution with 7-11 sequences per time point, except day -664. Phylogenetic analysis using maximum likelihood methods showed that the sequences clustered in six distinct subpopulations. We devised a method that took into account the relatively coarse sampling of the population. Data from days 1 through 32 were consistent with constant within-patient subpopulation frequencies. However, over longer time periods, i.e. between days 1...32 and 522, there were significant changes in subpopulation frequencies, which were consistent with evolutionarily neutral fluctuations. We found no clear signal of natural selection within the subpopulations over the study period, but positive selection was evident on the long branches that connected the subpopulations, which corresponds to >3 years as the subpopulations already were established when we started the study. Thus, selective forces may have been involved when the subpopulations were established. Genetic drift within subpopulations caused by de novo substitutions could be resolved after approximately one month. Overall, we conclude that subpopulation frequencies within this patient changed significantly over a time period of 1.5 years, but that this does not imply directional or balancing selection. We show that the short-term evolution we study here is likely representative for many patients of slow and normal disease progression.     

Recombination disequilibrium in ideal and natural populations

Following Hardy-Weinberg disequilibrium (HWD) occurring at a single locus and linkage disequilibrium (LD) between two loci in generations, we here proposed the third genetic disequilibrium in a population: recombination disequilibrium (RD). RD is a measurement of crossover interference among multiple loci in a random mating population. In natural populations besides recombination interference, RD may also be due to selection, mutation, gene conversion, drift and/or migration. Therefore, similarly to LD, RD will also reflect the history of natural selection and mutation. In breeding populations, RD purely results from recombination interference and hence can be used to build or evaluate and correct a linkage map. Practical examples from F₂, testcross and human populations indeed demonstrate that RD is useful for measuring recombination interference between two short intervals and evaluating linkage maps. As with LD, RD will be important for studying genetic mapping, association of haplotypes with disease, plant breading and population history.     

The coalescent process in models with selection, recombination and geographic subdivision

A population genetic model with a single locus at which balancing selection acts and many linked loci at which neutral mutations can occur is analysed using the coalescent approach. The model incorporates geographic subdivision with migration, as well as mutation, recombination, and genetic drift of neutral variation. It is found that geographic subdivision can affect genetic variation even with high rates of migration, providing that selection is strong enough to maintain different allele frequencies at the selected locus. Published sequence data from the alcohol dehydrogenase locus of Drosophila melanogaster are found to fit the proposed model slightly better than a similar model without subdivision.     

Genetic Drift of HIV Populations in Culture

Populations of Human Immunodeficiency Virus type 1 (HIV-1) undergo a surprisingly large amount of genetic drift in infected patients despite very large population sizes, which are predicted to be mostly deterministic. Several models have been proposed to explain this phenomenon, but all of them implicitly assume that the process of virus replication itself does not contribute to genetic drift. We developed an assay to measure the amount of genetic drift for HIV populations replicating in cell culture. The assay relies on creation of HIV populations of known size and measurements of variation in frequency of a neutral allele. Using this assay, we show that HIV undergoes approximately ten times more genetic drift than would be expected from its population size, which we defined as the number of infected cells in the culture. We showed that a large portion of the increase in genetic drift is due to non-synchronous infection of target cells. When infections are synchronized, genetic drift for the virus is only 3-fold higher than expected from its population size. Thus, the stochastic nature of biological processes involved in viral replication contributes to increased genetic drift in HIV populations. We propose that appreciation of these effects will allow better understanding of the evolutionary forces acting on HIV in infected patients.     

Sex: differences in mutation, recombination, selection, gene flow, and genetic drift

In many instances, there are large sex differences in mutation rates, recombination rates, selection, rates of gene flow, and genetic drift. Mutation rates are often higher in males, a difference that has been estimated both directly and indirectly. The higher male mutation rate appears related to the larger number of cell divisions in male lineages but mutation rates also appear gene- and organism-specific. When there is recombination in only one sex, it is always the homogametic sex. When there is recombination in both sexes, females often have higher recombination but there are many exceptions. There are a number of hypotheses to explain the sex differences in recombination. Sex-specific differences in selection may result in stable polymorphisms or for sex chromosomes, faster evolutionary change. In addition, sex-dependent selection may result in antagonistic pleiotropy or sexually antagonistic genes. There are many examples of sex-specific differences in gene flow (dispersal) and a number of adaptive explanations for these differences. The overall effective population size (genetic drift) is dominated by the lower sex-specific effective population size. The mean of the mutation, recombination, and gene flow rates over the two sexes can be used in a population genetics context unless there are sex-specific differences in selection or genetic drift. Sex-specific differences in these evolutionary factors appear to be unrelated to each other. The evolutionary explanations for sex-specific differences for each factor are multifaceted and, in addition, explanations may include chance, nonadaptive differences, or mechanistic, nonevolutionary factors.     

Demographic processes affect HIV-1 evolution in primary infection before the onset of selective processes

HIV-1 transmission and viral evolution in the first year of infection were studied in 11 individuals representing four transmitter-recipient pairs and three independent seroconverters. Nine of these individuals were enrolled during acute infection; all were men who have sex with men (MSM) infected with HIV-1 subtype B. A total of 475 nearly full-length HIV-1 genome sequences were generated, representing on average 10 genomes per specimen at 2 to 12 visits over the first year of infection. Single founding variants with nearly homogeneous viral populations were detected in eight of the nine individuals who were enrolled during acute HIV-1 infection. Restriction to a single founder variant was not due to a lack of diversity in the transmitter as homogeneous populations were found in recipients from transmitters with chronic infection. Mutational patterns indicative of rapid viral population growth dominated during the first 5 weeks of infection and included a slight contraction of viral genetic diversity over the first 20 to 40 days. Subsequently, selection dominated, most markedly in env and nef. Mutants were detected in the first week and became consensus as early as day 21 after the onset of symptoms of primary HIV infection. We found multiple indications of cytotoxic T lymphocyte (CTL) escape mutations while reversions appeared limited. Putative escape mutations were often rapidly replaced with mutually exclusive mutations nearby, indicating the existence of a maturational escape process, possibly in adaptation to viral fitness constraints or to immune responses against new variants. We showed that establishment of HIV-1 infection is likely due to a biological mechanism that restricts transmission rather than to early adaptive evolution during acute infection. Furthermore, the diversity of HIV strains coupled with complex and individual-specific patterns of CTL escape did not reveal shared sequence characteristics of acute infection that could be harnessed for vaccine design.