Biased mutations and microsatellite variation

Mutation bias is one of the forces that may constrain the variation at microsatellite loci. Here, we study the dynamics of population statistics and the genetic distance between two populations under multiple stepwise mutations with linear bias and random drift. Expressions are derived for these statistics as functions of time, as well as at mutation-drift equilibrium. Applying these expressions to published data on humans and chimpanzees, the regression coefficient of mutation bias on allele size was estimated to be at least between - 0.0064 and -0.013. The assumption of mutational bias produces larger estimates of divergence times than are obtained in its absence; in particular, the time of split between African and non-African human populations is estimated to be between 183,000 and 222,000 years, assuming one-step mutations and no selection. With multistep mutations, the divergence time is estimated to be lower.      

Frequency-dependent selection, metrical characters and molecular evolution

Computer models of selection acting on a quantitative character show that a combination of frequency-dependent and stabilizing selection can maintain many polymorphisms among the genes that determine the character. The models also show that the random order of mutations can give rise to selectively driven stochastic effects that are sometimes more important than random genetic drift. They suggest simple explanations for patterns of divergence between populations and species, and for apparent discrepancies between the rates of morphological and molecular evolution. They point towards a selective theory of 'molecular clocks'.     

Estimating selection on nonsynonymous mutations

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.     

MUTATION AND EXTINCTION: THE ROLE OF VARIABLE MUTATIONAL EFFECTS,SYNERGISTIC EPISTASIS,BENEFICIAL MUTATIONS,AND DEGREE OF OUTCROSSING

Recent theoretical studies have illustrated the potential role of spontaneous deleterious mutation as a cause of extinction in small populations. However, these studies have not addressed several genetic issues, which can in principle have a substantial influence on the risk of extinction. These include the presence of synergistic epistasis, which can reduce the rate of mutation accumulation by progressively magnifying the selective effects of mutations, and the occurrence of beneficial mutations, which can offset the effects of previous deleterious mutations. In stochastic simulations of small populations (effective sizes on the order of 100 or less), we show that both synergistic epistasis and the rate of beneficial mutation must be unrealistically high to substantially reduce the risk of extinction due to random fixation of deleterious mutations. However, in analytical calculations based on diffusion theory, we show that in large, outcrossing populations (effective sizes greater than a few hundred), very low levels of beneficial mutation are sufficient to prevent mutational decay. Further simulation results indicate that in populations small enough to be highly vulnerable to mutational decay, variance in deleterious mutational effects reduces the risk of extinction, assuming that the mean deleterious mutational effect is on the order of a few percent or less. We also examine the magnitude of outcrossing that is necessary to liberate a predominantly selfing population from the threat of long-term mutational deterioration. The critical amount of outcrossing appears to be greater than is common in near-obligately selfing plant species, supporting the contention that such species are generally doomed to extinction via random drift of new mutations. Our results support the hypothesis that a long-term effective population size in the neighborhood of a few hundred individuals defines an approximate threshold, below which outcrossing populations are vulnerable to extinction via fixation of deleterious mutations, and above which immunity is acquired.     

Statistical methods for detecting natural selection from genomic data

In the study of molecular and phenotypic evolution, understanding the relative importance of random genetic drift and positive selection as the mechanisms for driving divergences between populations and maintaining polymorphisms within populations has been a central issue. A variety of statistical methods has been developed for detecting natural selection operating at the amino acid and nucleotide sequence levels. These methods may be largely classified into those aimed at detecting recurrent and/or recent/ongoing natural selection by utilizing the divergence and/or polymorphism data. Using these methods, pervasive positive selection has been identified for protein-coding and non-coding sequences in the genomic analysis of some organisms. However, many of these methods have been criticized by using computer simulation and real data analysis to produce excessive false-positives and to be sensitive to various disturbing factors. Importantly, some of these methods have been invalidated experimentally. These facts indicate that many of the statistical methods for detecting natural selection are unreliable. In addition, the signals that have been believed as the evidence for fixations of advantageous mutations due to positive selection may also be interpreted as the evidence for fixations of deleterious mutations due to random genetic drift. The genomic diversity data are rapidly accumulating in various organisms, and detection of natural selection may play a critical role for clarifying the relative role of random genetic drift and positive selection in molecular and phenotypic evolution. It is therefore important to develop reliable statistical methods that are unbiased as well as robust against various disturbing factors, for inferring natural selection.     

Transposable elements, mutational correlations, and population divergence in Caenorhabditis elegans

Transposable element activity is thought to be responsible for a large portion of all mutations, but its influence on the evolution of populations has not been well studied. Using mutation accumulation experiments with the nematode Caenorhabditis elegans, we investigated the impact of transposable element activity on the production of mutational variances and covariances. The experiments involved the use of two mutator strains (RNAi-deficient mutants) that are characterized by high levels of germline transposition, as well as the Bristol N2 strain, which lacks germline transposition. We found that transposition led to an increase in mutational heritabilities, as well as to the intensification of correlation patterns observed in the absence of transposition. No mutational trade-offs were detected and mutations generally had a deleterious effect on components of fitness. We also tested whether the pattern of mutational covariation could be used to predict observed patterns of population divergence in this species. Using 15 natural populations, we found that population divergence of C. elegans in multivariate phenotypic space occurred in directions only partially concordant with mutation, and thus other evolutionary factors, such as natural selection and genetic drift, must be acting to produce divergence within this species. Our results suggest that mutations induced by mobile elements in C. elegans are similar to other spontaneous mutations with respect to their contribution to the microevolution of quantitative traits.     

The genetics of adaptation: the roles of pleiotropy, stabilizing selection and drift in shaping the distribution of bidirectional fixed mutational effects

Pleiotropy allows for the deterministic fixation of bidirectional mutations: mutations with effects both in the direction of selection and opposite to selection for the same character. Mutations with deleterious effects on some characters can fix because of beneficial effects on other characters. This study analytically quantifies the expected frequency of mutations that fix with negative and positive effects on a character and the average size of a fixed effect on a character when a mutation pleiotropically affects from very few to many characters. The analysis allows for mutational distributions that vary in shape and provides a framework that would allow for varying the frequency at which mutations arise with deleterious and positive effects on characters. The results show that a large fraction of fixed mutations will have deleterious pleiotropic effects even when mutation affects as little as two characters and only directional selection is occurring, and, not surprisingly, as the degree of pleiotropy increases the frequency of fixed deleterious effects increases. As a point of comparison, we show how stabilizing selection and random genetic drift affect the bidirectional distribution of fixed mutational effects. The results are then applied to QTL studies that seek to find loci that contribute to phenotypic differences between populations or species. It is shown that QTL studies are biased against detecting chromosome regions that have deleterious pleiotropic effects on characters.     

Selection in Finite Populations with Multiple Alleles. III. Genetic Divergence with Centripetal Selection and Mutation

Natural selection for an intermediate level of gene or enzyme activity has been shown to lead to a high frequency of heterotic polymorphisms in populations subject to mutation and random genetic drift. The model assumes a symmetrical spectrum of mutational variation, with the majority of variants having only minor effects on the probability of survival. Each mutational event produces a variant which is novel to the population. Allelic effects are assumed to be additive on the scale of enzyme activity, heterosis arising whenever a heterozygote has a mean level of activity closer to optimal than that of other genotypes in the population.-A new measure of genetic divergence between populations is proposed, which is readily interpreted genetically, and increases approximately linearly with time under centripetal selection, drift and mutation. The parameter is closely related to the rate of accumulation of mutational changes in a cistron over an evolutionary time span.-A survey of published data concerning polymorphic loci in man and Drosophila suggests than an alternative model, based on the superiority of hybrid molecules, is not of general importance. Thirteen loci giving rise to hybrid zones on electrophoresis have a mean heterozygote frequency of 0.22 +/-.06, compared with a value of 0.23 +/-.04 for 16 loci classified as producing no hybrid enzyme.     

Molecular correlates of reproductive isolation

Evolution of reproductive isolation as a byproduct of genetic divergence in isolated populations is the dominant (albeit not exclusive) mode of speciation in sexual animals. But little is known about the factors linking speciation to general divergence. Several authors have argued that allopatric speciation should proceed more rapidly if isolated populations also experience divergent selection. Reproductive isolation between allopatric populations is not subject to direct selection; it can accumulate only by random drift or as a fortuitous byproduct of selection on other traits. Here I present a novel analysis of published data, demonstrating that pre- and postmating isolation of Drosophila species are more tightly correlated with allozyme divergence than with silent DNA divergence. Inasmuch as proteins are more subject to the action of natural selection than are silent DNA polymorphisms, this result provides broad support for a model of selection-mediated allopatric speciation.     

MUTATION LOAD AND THE SURVIVAL OF SMALL POPULATIONS

Previous attempts to model the joint action of selection and mutation in finite populations have treated population size as being independent of the mutation load. However, the accumulation of deleterious mutations is expected to cause a gradual reduction in population size. Consequently, in small populations random genetic drift will progressively overpower selection making it easier to fix future mutations. This synergistic interaction, which we refer to as a mutational melt-down, ultimately leads to population extinction. For many conditions, the coefficient of variation of extinction time is less than 0.1, and for species that reproduce by binary fission, the expected extinction time is quite insensitive to population carrying capacity. These results are consistent with observations that many cultures of ciliated protozoans and vertebrate fibroblasts have characteristic extinction times. The model also predicts that clonal lineages are unlikely to survive more than 10⁴ to 10⁵ generations, which is consistent with existing data on parthenogenetic animals. Contrary to the usual view that Muller's ratchet does more damage when selection is weak, we show that the mean extinction time declines as mutations become more deleterious. Although very small sexual populations, such as self-fertilized lines, are subject to mutational meltdowns, recombination effectively eliminates the process when the effective population size exceeds a dozen or so. The concept of the effective mutation load is developed, and several procedures for estimating it are described. It is shown that this load can be reduced substantially when mutational effects are highly variable.     

Microevolution in island forms: the roles of drift and directional selection in morphological divergence of a passerine bird

Abstract.— Theory predicts that in small isolated populations random genetic drift can lead to phenotypic divergence; however this prediction has rarely been tested quantitatively in natural populations. Here we utilize natural repeated island colonization events by members of the avian species complex, Zosterops lateralis , to assess whether or not genetic drift alone is an adequate explanation for the observed patterns of microevolutionary divergence in morphology. Morphological and molecular genetic characteristics of island and mainland populations are compared to test three predictions of drift theory: (1) that the pattern of morphological change is idiosyncratic to each island; (2) that there is concordance between morphological and neutral genetic shifts across island populations; and (3) for populations whose time of colonization is known, that the rate of morphological change is sufficiently slow to be accounted for solely by genetic drift. Our results are not consistent with these predictions. First, the direction of size shifts was consistently towards larger size, suggesting the action of a nonrandom process. Second, patterns of morphological divergence among recently colonized populations showed little concordance with divergence in neutral genetic characters. Third, rate tests of morphological change showed that effective population sizes were not small enough for random processes alone to account for the magnitude of microevolutionary change. Altogether, these three lines of evidence suggest that drift alone is not an adequate explanation of morphological differentiation in recently colonized island Zosterops and therefore we suggest that the observed microevolutionary changes are largely a result of directional natural selection.     

Dynamics of inbreeding depression due to deleterious mutations in small populations: mutation parameters and inbreeding rate

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.     

FURTHER SIMULATION STUDIES ON EVOLUTION BY GENE DUPLICATION

In order to understand the origin of multigene families, Monte Carlo simulations were performed to see how a genetic system evolves under unequal crossing-over, mutation, random genetic drift and natural selection, starting from a single gene copy. Both haploid and diploid models were examined. Beneficial, neutral, and detrimental mutations were incorporated, and “positive” selection favors those chromosomes (haploid) or individuals (diploid) with more beneficial mutations than others. The same model for haploids was previously investigated with special reference to the evolution of gene organization, and the ratio of the numbers of beneficial genes to pseudogenes was found to be a rough indicator of the relative strengths of positive and negative (against deleterious alleles) natural selection (Ohta, 1987b). In the present paper, the evolution of gene organization and of sequence divergence among genes in the multigene family is examined. It is shown that positive selection accelerates the accumulation of arrays containing different beneficial mutations, but that total divergence including both neutral and beneficial mutations is not very sensitive to positive selection, under this model. The proportion of beneficial mutations in the total mutations accumulated is a better indicator of positive selection than is the total divergence. It is pointed out that various observed examples in which amino-acid substitutions are accelerated, as compared with synonymous substitutions in duplicated genes (Li, 1985), may reflect the effect of selection similar to the present scheme. The diploid model is shown to be more efficient for accumulating beneficial mutations in duplicated genes than the haploid one, and the relevance of this finding to the advantage of sexual reproduction is discussed.     

QUANTITATIVE GENETICS OF MORPHOLOGICAL DIFFERENTIATION IN PEROMYSCUS. II. ANALYSIS OF SELECTION AND DRIFT

The hypothesis that the morphological divergence of local populations of Peromyscus is due to random genetic drift was evaluated by testing the proportionality of the among-locality covariance matrix, L, and the additive genetic covariance matrix, G. Overall, significant proportionality of L? and ? was not observed, indicating the evolutionary divergence of local populations does not result from random genetic drift. The forces of selection needed to differentiate three taxa of Peromyscus were reconstructed to examine the divergence of species and subspecies. The selection gradients obtained illustrate the inadequacy of univariate analyses of selection by finding that some characters evolve in the direction opposite to the force of selection acting directly on them. A retrospective selection index was constructed using the estimated selection gradients, and truncation selection on this index was used to estimate the minimum selective mortality per generation required to produce the observed change. On any of the time scales used, the proportion of the population that would need to be culled was quite low, the greatest being of the same order of magnitude as the selective intensities observed in extant natural populations. Thus, entirely plausible intensities of directional natural selection can produce species-level differences in a period of time too short to be resolved in the fossil record.     

The hypothesis of immune testing of partners—coordinated adaptations and changes in mating preferences

Reproductive isolation plays the key role in speciation. According to the prevailing ideas, the main speciation mechanism is gradual accumulation of genetic differences in isolated populations (allopatric phase of speciation) based on mutations, selection, and genetic drift. In this case, reproductive isolation emerges as an occasional byproduct of adaptation to different conditions (ecological speciation) or accumulation of random changes in the gene pool resulting from long-term isolation. Pure sympatric speciation assumes isolation as a direct product of selection (divergent or disruptive selection) that favors individuals selectively mating with their likes. A third possibility is substantiated below. We believe that isolation can be a regular and determined product rather than occasional byproduct of divergence. It can rely on the friend/foe discrimination mechanisms, some of which can be “immune-based” and compare the partner’s and own properties (signaling molecules, pheromones, and other antigens in a broad sense). Antigens of the major histocompatibility complex (MHC) can play a substantial role in such testing of potential mates.     

Contrasting patterns of body shape and neutral genetic divergence in marine and lake populations of threespine sticklebacks

Comparisons of neutral marker and quantitative trait divergence can provide important insights into the relative roles of natural selection and neutral genetic drift in population differentiation. We investigated phenotypic and genetic differentiation among Fennoscandian threespine stickleback (Gasterosteus aculeatus) populations, and found that the highest degree of differentiation occurred between sea and freshwater habitats. Within habitats, morphological divergence was highest among the different freshwater populations. Pairwise phenotypic and neutral genetic distances among populations were positively correlated, suggesting that genetic drift may have contributed to the morphological differentiation among habitats. On the other hand, the degree of phenotypic differentiation (PST) clearly surpassed the neutral expectation set by FST, suggesting a predominant role for natural selection over genetic drift as an explanation for the observed differentiation. However, separate PST/FST comparisons by habitats revealed that body shape divergence between lake and marine populations, and even among marine populations, can be strongly influenced by natural selection. On the other hand, genetic drift can play an important role in the differentiation among lake populations.     

The adaptive value of epigenetic mutation: Limited in large but high in small peripheral populations

The fate of populations during range expansions, invasions and environmental changes is largely influenced by their ability to adapt to peripheral habitats. Recent models demonstrate that stable epigenetic modifications of gene expression that occur more frequently than genetic mutations can both help and hinder adaptation in panmictic populations. However, these models do not consider interactions between epimutations and evolutionary forces in peripheral populations. Here, we use mainland–island mathematical models and simulations to explore how the faster rate of epigenetic mutation compared to genetic mutations interacts with migration, selection and genetic drift to affect adaptation in peripheral populations. Our model focuses on cases where epigenetic marks are stably inherited. In a large peripheral population, where the effect of genetic drift is negligible, our analyses suggest that epimutations with random fitness impacts that occur at rates as high as 10^–3 increase local adaptation when migration is strong enough to overwhelm divergent selection. When migration is weak relative to selection and epimutations with random fitness impacts decrease adaptation, we find epigenetic modifications must be highly adaptively biased to enhance adaptation. Finally, in small peripheral populations, where genetic drift is strong, epimutations contribute to adaptation under a wider range of evolutionary conditions. Overall, our results suggest that epimutations can change outcomes of adaptation in peripheral populations, which has implications for understanding conservation and range expansions and contractions, especially of small populations.     

Divergence at neutral and non-neutral loci in Drosophila buzzatii populations and their hybrids

The impact of intraspecific hybridisation on fitness and morphological traits depends on the history of natural selection and genetic drift, which may have led to differently coadapted gene-complexes in the parental populations. The divergence at neutral and non-neutral loci between populations can be evaluated by estimating F_ST and Q_ST respectively, and hence give an estimate of drift and selection in the populations. Here we investigate (1) whether divergence between populations in quantitative traits (wing size and shape) can be attributed to selection or drift alone, (2) The impact of intraspecific hybridisation on estimators for divergence at neutral (F_ST) and non-neutral loci (Q_ST) in hybrids, (3) If measurement of shape is more informative than size in order to detect divergence in quantitative traits between populations. The aims were addressed by performing two hybridisations between three populations of Drosophila buzzatii, one between populations from Argentina and the Canary Islands (separated for 200 years), and the other between populations from Argentina and Australia (separated for 80 years). We observed the highest divergence at neutral loci between the Argentinean and Canary Island populations, but highest morphological divergence between the Argentinean and Australian populations, indicating that natural selection is acting on the wings. Divergence based on Q_ST measures in the hybrids was sensitive towards increased phenotypic variance (σ²p) within groups and should be used with care when σ²p of populations differ. Our results indicate that measures of shape give a better estimate of divergence at the underlying quantitative traits loci than measures of size.     

Fisherian and Wrightian theories of speciation

Fisher's theory of sexual selection, Wright's shifting-balance theory, and recent models based on them are reviewed as mechanisms of animal speciation. The joint evolution of mating preferences and secondary sexual characters can cause rapid nonadaptive phenotypic divergence and premating isolation between geographically separated populations, or along a cline. Extensive comparative data on Drosophila species support the suggestion of R. A. Fisher and T. Dobzhansky that the evolution of mating preferences can reinforce partial postmating isolation between sympatric populations. The interaction of natural selection and random genetic drift in local populations with a small effective size can produce a rapid transition between relatively stable phenotypes separated by an adaptive valley, or between chromosomal rearrangements with a heterozygote disadvantage. Large demographic fluctuations, such as frequent random local extinction and colonization, are required for the rapid spread of new adaptations (or karyotypes) when intermediate phenotypes (or rearrangement heterozygotes) are selected against.     

GENETIC MODELS OF ADAPTATION AND GENE FLOW IN PERIPHERAL POPULATIONS

We investigate the interplay between gene flow and adaptation in peripheral populations of a widespread species. Models are developed for the evolution of a quantitative trait under clinally varying selection in a species whose density decreases from the center of the range to its periphery. Two major results emerge. First, gene flow from populations at the range center can be a strong force that inhibits peripheral populations from evolving to their local ecological optima. As a result, peripheral populations experience persistent directional selection. Second, response to local selection pressures can cause rapid and substantial evolution when a peripheral population is isolated from gene flow. The amount of evolutionary change depends on gene flow, selection, the ecological gradient, and the trait's heritability. Rapid divergence can also occur between the two halves of a formerly continuous population that is divided by a vicariant event. A general conclusion is that disruption of gene flow can cause evolutionary divergence, perhaps leading to speciation, in the absence of contributions from random genetic drift.