Recessive Beneficial Mutations Research Articles

Evidence that genetic drift not adaptation drives fast-Z and large-Z effects in Ficedula flycatchers.

The sex chromosomes have been hypothesized to play a key role in driving adaptation and speciation across many taxa. The reason for this is thought to be the hemizygosity of the heteromorphic part of sex chromosomes in the heterogametic sex, which exposes recessive mutations to natural and sexual selection. The exposure of recessive beneficial mutations increases their rate of fixation on the sex chromosomes, which results in a faster rate of evolution. In addition, genetic incompatibilities between sex-linked loci are exposed faster in the genomic background of hybrids of divergent lineages, which makes sex chromosomes contribute disproportionately to reproductive isolation. However, in birds, which show a Z/W sex determination system, the role of adaptation versus genetic drift as the driving force of the faster differentiation of the Z chromosome (fast-Z effect) and the disproportionate role of the Z chromosome in reproductive isolation (large-Z effect) are still debated. Here, we address this debate in the bird genus Ficedula flycatchers based on population-level whole-genome sequencing data of six species. Our analysis provides evidence for both faster lineage sorting and reduced gene flow on the Z chromosome than the autosomes. However, these patterns appear to be driven primarily by the increased role of genetic drift on the Z chromosome, rather than an increased rate of adaptive evolution. Genomic scans of selective sweeps and fixed differences in fact suggest a reduced action of positive selection on the Z chromosome.

Multiple Stochastic Parameters Influence Genome Dynamics in a Heterozygous Diploid Eukaryotic Model.

The heterozygous diploid genome of Candida albicans displays frequent genomic rearrangements, in particular loss-of-heterozygosity (LOH) events, which can be seen on all eight chromosomes and affect both laboratory and clinical strains. LOHs, which are often the consequence of DNA damage repair, can be observed upon stresses reminiscent of the host environment, and result in homozygous regions of various sizes depending on the molecular mechanisms at their origins. Recent studies have shed light on the biological importance of these frequent and ubiquitous LOH events in C. albicans. In diploid Saccharomyces cerevisiae, LOH facilitates the passage of recessive beneficial mutations through Haldane’s sieve, allowing rapid evolutionary adaptation. This also appears to be true in C. albicans, where the full potential of an adaptive mutation is often only observed upon LOH, as illustrated in the case of antifungal resistance and niche adaptation. To understand the genome-wide dynamics of LOH events in C. albicans, we constructed a collection of 15 strains, each one carrying a LOH reporter system on a different chromosome arm. This system involves the insertion of two fluorescent marker genes in a neutral genomic region on both homologs, allowing spontaneous LOH events to be detected by monitoring the loss of one of the fluorescent markers using flow cytometry. Using this collection, we observed significant LOH frequency differences between genomic loci in standard laboratory growth conditions; however, we further demonstrated that comparable heterogeneity was also observed for a given genomic locus between independent strains. Additionally, upon exposure to stress, three outcomes could be observed in C. albicans, where individual strains displayed increases, decreases, or no effect of stress in terms of LOH frequency. Our results argue against a general stress response triggering overall genome instability. Indeed, we showed that the heterogeneity of LOH frequency in C. albicans is present at various levels, inter-strain, intra-strain, and inter-chromosomes, suggesting that LOH events may occur stochastically within a cell, though the genetic background potentially impacts genome stability in terms of LOH throughout the genome in both basal and stress conditions. This heterogeneity in terms of genome stability may serve as an important adaptive strategy for the predominantly clonal human opportunistic pathogen C. albicans, by quickly generating a wide spectrum of genetic variation combinations potentially permitting subsistence in a rapidly evolving environment.

Absence of a Faster-X Effect in Beetles (Tribolium, Coleoptera).

The faster-X effect, namely the rapid evolution of protein-coding genes on the X chromosome, has been widely reported in metazoans. However, the prevalence of this phenomenon across diverse systems and its potential causes remain largely unresolved. Analysis of sex-biased genes may elucidate its possible mechanisms: for example, in systems with X/Y males a more pronounced faster-X effect in male-biased genes than in female-biased or unbiased genes may suggest fixation of recessive beneficial mutations rather than genetic drift. Further, theory predicts that the faster-X effect should be promoted by X chromosome dosage compensation. Here, we asked whether we could detect a faster-X effect in genes of the beetle Tribolium castaneum (and T. freemani orthologs), which has X/Y sex-determination and heterogametic males. Our comparison of protein sequence divergence (dN/dS) on the X chromosome vs. autosomes indicated a rarely observed absence of a faster-X effect in this organism. Further, analyses of sex-biased gene expression revealed that the X chromosome was particularly highly enriched for ovary-biased genes, which evolved slowly. In addition, an evaluation of male X chromosome dosage compensation in the gonads and in non-gonadal somatic tissues indicated a striking lack of compensation in the testis. This under-expression in testis may limit fixation of recessive beneficial X-linked mutations in genes transcribed in these male sex organs. Taken together, these beetles provide an example of the absence of a faster-X effect on protein evolution in a metazoan, that may result from two plausible factors, strong constraint on abundant X-linked ovary-biased genes and a lack of gonadal dosage compensation.

Altered access to beneficial mutations slows adaptation and biases fixed mutations in diploids.

Ploidy varies considerably in nature. However, our understanding of the impact of ploidy on adaptation is incomplete. Many microbial evolution experiments characterize adaptation in haploid organisms, but few focus on diploid organisms. Here, we perform a 4,000-generation evolution experiment using diploid strains of the yeast Saccharomyces cerevisiae. We show that the rate of adaptation and spectrum of beneficial mutations are influenced by ploidy. Haldane's sieve effectively alters access to recessive beneficial mutations in diploid populations, leading to a slower rate of adaptation and a spectrum of beneficial mutations that is shifted towards dominant mutations. Genomic position also has an important role, as the prevalence of homozygous mutations is largely dependent on their proximity to a recombination hotspot. Our results demonstrate key aspects of diploid adaptation that have previously been understudied and provide support for several proposed theories.

Sex chromosomes and speciation in birds and other ZW systems.

Theory and empirical patterns suggest a disproportionate role for sex chromosomes in evolution and speciation. Focusing on ZW sex determination (females ZW, males ZZ; the system in birds, many snakes, and lepidopterans), I review how evolutionary dynamics are expected to differ between the Z, W and the autosomes, discuss how these differences may lead to a greater role of the sex chromosomes in speciation and use data from birds to compare relative evolutionary rates of sex chromosomes and autosomes. Neutral mutations, partially or completely recessive beneficial mutations, and deleterious mutations under many conditions are expected to accumulate faster on the Z than on autosomes. Sexually antagonistic polymorphisms are expected to arise on the Z, raising the possibility of the spread of preference alleles. The faster accumulation of many types of mutations and the potential for complex evolutionary dynamics of sexually antagonistic traits and preferences contribute to a role for the Z chromosome in speciation. A quantitative comparison among a wide variety of bird species shows that the Z tends to have less within-population diversity and greater between-species differentiation than the autosomes, likely due to both adaptive evolution and a greater rate of fixation of deleterious alleles. The W chromosome also shows strong potential to be involved in speciation, in part because of its co-inheritance with the mitochondrial genome. While theory and empirical evidence suggest a disproportionate role for sex chromosomes in speciation, the importance of sex chromosomes is moderated by their small size compared to the whole genome.

Positive selection drives faster-Z evolution in silkmoths.

Genes linked to X or Z chromosomes, which are hemizygous in the heterogametic sex, are predicted to evolve at different rates than those on autosomes. This "faster-X effect" can arise either as a consequence of hemizygosity, which leads to more efficient selection for recessive beneficial mutations in the heterogametic sex, or as a consequence of reduced effective population size of the hemizygous chromosome, which leads to increased fixation of weakly deleterious mutations due to genetic drift. Empirical results to date suggest that, while the overall pattern across taxa is complicated, systems with male heterogamy show a faster-X effect attributable to more efficient selection, whereas the faster-Z effect in female-heterogametic taxa is attributable to increased drift. To test the generality of the faster-Z pattern seen in birds and snakes, we sequenced the genome of the lepidopteran silkmoth Bombyx huttoni. We show that silkmoths experience faster-Z evolution, but unlike in birds and snakes, the faster-Z effect appears to be attributable to more efficient positive selection. These results suggest that female heterogamy alone is unlikely to explain the reduced efficacy of selection on vertebrate Z chromosomes. It is likely that many factors, including differences in overall effective population size, influence Z chromosome evolution.

Loss-of-heterozygosity facilitates passage through Haldane's sieve for Saccharomyces cerevisiae undergoing adaptation.

Haldane's sieve posits that the majority of beneficial mutations that contribute to adaptation should be dominant, as these are the mutations most likely to establish and spread when rare. It has been argued, however, that if the dominance of mutations in their current and previous environments are correlated, Haldane's sieve could be eliminated. We constructed heterozygous lines of Saccharomyces cerevisiae containing single adaptive mutations obtained during exposure to the fungicide nystatin. Here we show that no clear dominance relationship exists across environments: mutations exhibited a range of dominance levels in a rich medium, yet were exclusively recessive under nystatin stress. Surprisingly, heterozygous replicates exhibited variable-onset rapid growth when exposed to nystatin. Targeted Sanger sequencing demonstrated that loss-of-heterozygosity (LOH) accounted for these growth patterns. Our experiments demonstrate that recessive beneficial mutations can avoid Haldane's sieve in clonal organisms through rapid LOH and thus contribute to rapid evolutionary adaptation.

Hitchhiking of Deleterious Alleles and the Cost of Adaptation in Partially Selfing Species

Self-fertilization is generally seen to be disadvantageous in the long term. It increases genetic drift, which subsequently reduces polymorphism and the efficiency of selection, which also challenges adaptation. However, high selfing rates can increase the fixation probability of recessive beneficial mutations, but existing theory has generally not accounted for the effect of linked sites. Here, we analyze a model for the fixation probability of deleterious mutants that hitchhike with selective sweeps in diploid, partially selfing populations. Approximate analytical solutions show that, conditional on the sweep not being lost by drift, higher inbreeding rates increase the fixation probability of the deleterious allele, due to the resulting reduction in polymorphism and effective recombination. When extending the analysis to consider a distribution of deleterious alleles, as well as the average fitness increase after a sweep, we find that beneficial alleles generally need to be more recessive than the previously assumed dominance threshold (h < 1/2) for selfing to be beneficial from one-locus theory. Our results highlight that recombination aiding the efficiency of selection on multiple loci amplifies the fitness benefits of outcrossing over selfing, compared to results obtained from one-locus theory. This effect additionally increases the parameter range under which obligate outcrossing is beneficial over partial selfing.

Pollen-Specific, but Not Sperm-Specific, Genes Show Stronger Purifying Selection and Higher Rates of Positive Selection Than Sporophytic Genes in Capsella grandiflora

Selection on the gametophyte can be a major force shaping plant genomes as 7-11% of genes are expressed only in that phase and 60% of genes are expressed in both the gametophytic and sporophytic phases. The efficacy of selection on gametophytic tissues is likely to be influenced by sexual selection acting on male and female functions of hermaphroditic plants. Moreover, the haploid nature of the gametophytic phase allows selection to be efficient in removing recessive deleterious mutations and fixing recessive beneficial mutations. To assess the importance of gametophytic selection, we compared the strength of purifying selection and extent of positive selection on gametophyte- and sporophyte-specific genes in the highly outcrossing plant Capsella grandiflora. We found that pollen-exclusive genes had a larger fraction of sites under strong purifying selection, a greater proportion of adaptive substitutions, and faster protein evolution compared with seedling-exclusive genes. In contrast, sperm cell-exclusive genes had a smaller fraction of sites under strong purifying selection, a lower proportion of adaptive substitutions, and slower protein evolution compared with seedling-exclusive genes. Observations of strong selection acting on pollen-expressed genes are likely explained by sexual selection resulting from pollen competition aided by the haploid nature of that tissue. The relaxation of selection in sperm might be due to the reduced influence of intrasexual competition, but reduced gene expression may also be playing an important role.

An excess of gene expression divergence on the X chromosome in Drosophila embryos: implications for the faster-X hypothesis.

The X chromosome is present as a single copy in the heterogametic sex, and this hemizygosity is expected to drive unusual patterns of evolution on the X relative to the autosomes. For example, the hemizgosity of the X may lead to a lower chromosomal effective population size compared to the autosomes, suggesting that the X might be more strongly affected by genetic drift. However, the X may also experience stronger positive selection than the autosomes, because recessive beneficial mutations will be more visible to selection on the X where they will spend less time being masked by the dominant, less beneficial allele—a proposal known as the faster-X hypothesis. Thus, empirical studies demonstrating increased genetic divergence on the X chromosome could be indicative of either adaptive or non-adaptive evolution. We measured gene expression in Drosophila species and in D. melanogaster inbred strains for both embryos and adults. In the embryos we found that expression divergence is on average more than 20% higher for genes on the X chromosome relative to the autosomes; but in contrast, in the inbred strains, gene expression variation is significantly lower on the X chromosome. Furthermore, expression divergence of genes on Muller's D element is significantly greater along the branch leading to the obscura sub-group, in which this element segregates as a neo-X chromosome. In the adults, divergence is greatest on the X chromosome for males, but not for females, yet in both sexes inbred strains harbour the lowest level of gene expression variation on the X chromosome. We consider different explanations for our results and conclude that they are most consistent within the framework of the faster-X hypothesis.

A second-generation assembly of the Drosophila simulans genome provides new insights into patterns of lineage-specific divergence

We create a new assembly of the Drosophila simulans genome using 142 million paired short-read sequences and previously published data for strain w501. Our assembly represents a higher-quality genomic sequence with greater coverage, fewer misassemblies, and, by several indexes, fewer sequence errors. Evolutionary analysis of this genome reference sequence reveals interesting patterns of lineage-specific divergence that are different from those previously reported. Specifically, we find that Drosophila melanogaster evolves faster than D. simulans at all annotated classes of sites, including putatively neutrally evolving sites found in minimal introns. While this may be partly explained by a higher mutation rate in D. melanogaster, we also find significant heterogeneity in rates of evolution across classes of sites, consistent with historical differences in the effective population size for the two species. Also contrary to previous findings, we find that the X chromosome is evolving significantly faster than autosomes for nonsynonymous and most noncoding DNA sites and significantly slower for synonymous sites. The absence of a X/A difference for putatively neutral sites and the robustness of the pattern to Gene Ontology and sex-biased expression suggest that partly recessive beneficial mutations may comprise a substantial fraction of noncoding DNA divergence observed between species. Our results have more general implications for the interpretation of evolutionary analyses of genomes of different quality.

Faster-Z Evolution Is Predominantly Due to Genetic Drift

Genes linked to sex chromosomes may show different levels of functional change than autosomal genes due to different evolutionary pressures. We used whole-genome data from zebra finch-chicken orthologs to test for Faster-Z evolution, finding that Z-linked genes evolve up to 50% more rapidly than autosomal genes. We combined these divergence data with information about sex-specific expression patterns in order to determine whether the Faster-Z Effect that we observe was predominantly the result of positive selection of recessive beneficial mutations in the heterogametic sex or primarily due to genetic drift attributable to the lower effective population size of the Z chromosome compared with an autosome. The Faster-Z Effect was no more prevalent for genes expressed predominantly in females; therefore, our data indicate that the largest source of Faster-Z Evolution is the increased levels of genetic drift on the Z chromosome. This is likely a product of sexual selection acting on males, which reduces the effective population size of the Z relative to that of the autosomes. Additionally, this latter result suggests that the relative evolutionary pressures underlying Faster-Z Evolution are different from those in analogous Faster-X Evolution.

Effects of X-Linkage and Sex-Biased Gene Expression on the Rate of Adaptive Protein Evolution in Drosophila

Patterns of polymorphism and divergence in Drosophila protein-coding genes suggest that a considerable fraction of amino acid differences between species can be attributed to positive selection and that genes with sex-biased expression, that is, those expressed predominantly in one sex, have especially high rates of adaptive evolution. Previous studies, however, have been restricted to autosomal sex-biased genes and, thus, do not provide a complete picture of the evolutionary forces acting on sex-biased genes across the genome. To determine the effects of X-linkage on sex-biased gene evolution, we surveyed DNA sequence polymorphism and divergence in 45 X-linked genes, including 17 with male-biased expression, 13 with female-biased expression, and 15 with equal expression in the 2 sexes. Using both single- and multilocus tests for selection, we found evidence for adaptive evolution in both groups of sex-biased genes. The signal of adaptive evolution was particularly strong for X-linked male-biased genes. A comparison with data from 91 autosomal genes revealed a "fast-X" effect, in which the rate of adaptive evolution was greater for X-linked than for autosomal genes. This effect was strongest for male-biased genes but could be seen in the other groups as well. A genome-wide analysis of coding sequence divergence that accounted for sex-biased expression also uncovered a fast-X effect for male-biased and unbiased genes, suggesting that recessive beneficial mutations play an important role in adaptation.

Haldane's sieve and adaptation from the standing genetic variation.

We consider populations that adapt to a sudden environmental change by fixing alleles found at mutation-selection balance. In particular, we calculate probabilities of fixation for previously deleterious alleles, ignoring the input of new mutations. We find that "Haldane's sieve"--the bias against the establishment of recessive beneficial mutations--does not hold under these conditions. Instead probabilities of fixation are generally independent of dominance. We show that this result is robust to patterns of sex expression for both X-linked and autosomal loci. We further show that adaptive evolution is invariably slower at X-linked than autosomal loci when evolution begins from mutation-selection balance. This result differs from that obtained when adaptation uses new mutations, a finding that may have some bearing on recent attempts to distinguish between hitchhiking and background selection by contrasting the molecular population genetics of X-linked vs. autosomal loci. Last, we suggest a test to determine whether adaptation used new mutations or previously deleterious alleles from the standing genetic variation.