Distribution of fixed beneficial mutations and the rate of adaptation in asexual populations

When large asexual populations adapt, competition between simultaneously segregating mutations slows the rate of adaptation and restricts the set of mutations that eventually fix. This phenomenon of interference arises from competition between mutations of different strengths as well as competition between mutations that arise on different fitness backgrounds. Previous work has explored each of these effects in isolation, but the way they combine to influence the dynamics of adaptation remains largely unknown. Here, we describe a theoretical model to treat both aspects of interference in large populations. We calculate the rate of adaptation and the distribution of fixed mutational effects accumulated by the population. We focus particular attention on the case when the effects of beneficial mutations are exponentially distributed, as well as on a more general class of exponential-like distributions. In both cases, we show that the rate of adaptation and the influence of genetic background on the fixation of new mutants is equivalent to an effective model with a single selection coefficient and rescaled mutation rate, and we explicitly calculate these effective parameters. We find that the effective selection coefficient exactly coincides with the most common fixed mutational effect. This equivalence leads to an intuitive picture of the relative importance of different types of interference effects, which can shift dramatically as a function of the population size, mutation rate, and the underlying distribution of fitness effects.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Fitness maps to a large-effect locus in introduced stickleback populations

Mutations of small effect underlie most adaptation to new environments, but beneficial variants with large fitness effects are expected to contribute under certain conditions. Genes and genomic regions having large effects on phenotypic differences between populations are known from numerous taxa, but fitness effect sizes have rarely been estimated. We mapped fitness over a generation in an F2 intercross between a marine and a lake stickleback population introduced to a freshwater pond. A quantitative trait locus map of the number of surviving offspring per F2 female detected a single, large-effect locus near Ectodysplasin (Eda), a gene having an ancient freshwater allele causing reduced bony armor and other changes. F2 females homozygous for the freshwater allele had twice the number of surviving offspring as homozygotes for the marine allele, producing a large selection coefficient, s = 0.50 ± 0.09 SE. Correspondingly, the frequency of the freshwater allele increased from 0.50 in F2 mothers to 0.58 in surviving offspring. We compare these results to allele frequency changes at the Eda gene in an Alaskan lake population colonized by marine stickleback in the 1980s. The frequency of the freshwater Eda allele rose steadily over multiple generations and reached 95% within 20 y, yielding a similar estimate of selection, s = 0.49 ± 0.05, but a different degree of dominance. These findings are consistent with other studies suggesting strong selection on this gene (and/or linked genes) in fresh water. Selection on ancient genetic variants carried by colonizing ancestors is likely to increase the prevalence of large-effect fitness variants in adaptive evolution.

The role of beneficial mutations of large effect during adaptation of wild populations to new and changing environments is a question of enduring interest (1–3). Large-effect mutations were once seen as unlikely to contribute to adaptation, because de novo mutations of small effect are much more likely to be advantageous than mutations of large effect (4). Yet, genetic studies of divergence between natural populations and species frequently detect genomic regions of apparently large phenotypic effect (5–10). Such genes of large effect are easier to detect and validate than genes of small effect, causing an ascertainment bias, but at least they are not rare or peculiar. On the other hand, these loci explaining large phenotypic differences might harbor multiple mutations of individually smaller effect (11–13).Theory has found a plausible role for large-effect fitness variants during adaptive divergence under certain conditions. New mutations of large effect can be beneficial early in the process of adaptation to a new environment, when the population is still far from the optimum, and when populations perpetually track a distant moving optimum (4, 14). Gene flow between diverging populations can inhibit fixation of small-effect mutations and thereby increase the importance of genes of relatively large effect (15).Adaptation from standing genetic variation can also favor large-effect variants, especially if these mutations have migrated from populations already adapted to similar selective pressures. Large-effect variants might then fix rapidly in the new environment (16–19). Examples include the repeated fixation of a relatively ancient low-armor Ectodysplasin (Eda) allele in young freshwater populations of threespine stickleback (7), color pattern mutations in Heliconius butterflies (20), opsin variants affecting color vision in Lake Victoria cichlids (21), and mutations adapting Rhagoletis fruit flies to apple (22). Large-effect standing variants that flow in from previously adapted populations might harbor a cluster of multiple beneficial, closely linked mutations constructed over time via a series of mutations and selective sweeps. Even so, in a new population such a group of alleles can behave as a single, large-effect beneficial allele that sweeps to fixation in unison.A major limitation of the evidence for large-effect variants in divergence of populations is the scarcity of information on fitness effects. Most evidence for large-effect mutations in adaptation is based instead on phenotypic effect sizes. Yet, a gene with a large phenotypic effect need not have a large fitness effect if selection on the trait is not strong. Genetic drift, environmental factors, and natural selection on other traits will also contribute to total variation in fitness. Fitness across a generation, or similarly the change in allele frequency between parent and offspring generations, at loci involved in adaptation has rarely been mapped. Hence, the fitness-effect sizes of variants are almost unknown in wild populations.We addressed this gap in two ways. First, we carried out a quantitative trait locus (QTL) study to map the number of surviving offspring (hereafter, fitness) in an experimental field population of threespine stickleback (Gasterosteus aculeatus). We crossed an individual from a postglacial freshwater population having reduced armor with an individual from a high-armor marine population representing the ancestral form (Fig. 1). Second-generation (F2) progeny were then introduced to a freshwater pond where fitness was mapped across a generation. Our aim was to test whether genomic regions known to contain genes with large phenotypic effects, such as Eda, also affect fitness in a freshwater environment. The experiment additionally allowed us to test one of the main hypotheses to explain the advantage of the low-armor Eda allele in fresh water, namely that it stems from faster growth associated with the reduced costs of producing armor (23–25). We use QTL mapping to estimate fitness-effect sizes and compare the projected change in allele frequency in the next generation with that observed.Open in a separate windowFig. 1.Design of the pond experiment. (A) Entrance to the Little Campbell River from the Strait of Georgia, BC. (B) Cranby Lake, BC. (C) A single intercross (F0) was made between a marine (anadromous) stickleback collected in the Little Campbell River and a freshwater-resident stickleback from Cranby Lake. Example specimens are stained with alizarin red to highlight bone. The marine population is fully plated (MM genotype at the Eda locus), whereas the freshwater population has few lateral plates (FF at Eda). First generation (F1) hybrids were crossed in the laboratory to produce second-generation (F2) hybrids that were introduced to a freshwater pond at the University of British Columbia. (D) Author M.E.A. on the experimental pond. (E) Author K.B.M. returning adult F2 hybrids to the pond after measurement.Second, we compared the fitness effects mapped in a single generation with empirical observations and modeling of multigenerational allele frequency change in an Alaskan lake population recently formed when the lake was recolonized by high-armor marine threespine stickleback (26). A drawback of the QTL and modeling approaches is that they cannot distinguish a single mutation from multiple linked mutations having cumulative effects. Nevertheless, our experimental and observational studies provide an opportunity to rule out the presence of individual regions with large fitness effects and therefore represent a valuable first step in mapping fitness to genes.     

Ultra Deep Sequencing of a Baculovirus Population Reveals Widespread Genomic Variations

Viruses rely on widespread genetic variation and large population size for adaptation. Large DNA virus populations are thought to harbor little variation though natural populations may be polymorphic. To measure the genetic variation present in a dsDNA virus population, we deep sequenced a natural strain of the baculovirus Autographa californica multiple nucleopolyhedrovirus. With 124,221X average genome coverage of our 133,926 bp long consensus, we could detect low frequency mutations (0.025%). K-means clustering was used to classify the mutations in four categories according to their frequency in the population. We found 60 high frequency non-synonymous mutations under balancing selection distributed in all functional classes. These mutants could alter viral adaptation dynamics, either through competitive or synergistic processes. Lastly, we developed a technique for the delimitation of large deletions in next generation sequencing data. We found that large deletions occur along the entire viral genome, with hotspots located in homologous repeat regions (hrs). Present in 25.4% of the genomes, these deletion mutants presumably require functional complementation to complete their infection cycle. They might thus have a large impact on the fitness of the baculovirus population. Altogether, we found a wide breadth of genomic variation in the baculovirus population, suggesting it has high adaptive potential.     

Evolution and maintenance of quantitative genetic variation by mutations.

The genotypic variance within, sigma 2w, and between, sigma 2b, random mating populations and rates and times for convergence to equilibrium values from different founder populations are formulated for an additive genetic model with an arbitrary number of alleles k, number of loci m, population size N, and mutation rate u, with unequal mutation rates for alleles. As a base of reference, the additive variance sigma 2a in an infinite equilibrium population is used. sigma 2a increases as k increases and decreases with variation in the mutation rates. Both transitional and equilibrium values of the variance within populations could be expressed as sigma 2w = (1 - theta)sigma 2a, where theta is the coancestry with mutations of individuals within populations. Thus, rates of convergence and evolutionary times are a function of those for theta, which involves both N and u. When the founder population is fixed, very long times are required to obtain a perceptible increase in sigma 2w and equilibrium values of sigma 2w are very small when 4Nu less than or equal to 10(-1). The variance between populations can be expressed as sigma 2b = 2 theta sigma 2a when the founder population is an infinite equilibrium population, and as sigma 2b = 2(theta - alpha)sigma 2a when the founder population is fixed, where alpha is a function only of u. In this latter case, rates of divergence, while affected by both N and u, are dominated by u and asymptotically a function of u only. With u = 10(-5), very long times (10(3) generations) are required for any perceptible divergence, even for N = 1-10. At equilibrium, most of the variance is between small populations and within very large populations. Migration increases the variance within populations and decreases the variance between populations.     

Accelerated evolution of resistance in multidrug environments

The emergence of resistance during multidrug chemotherapy impedes the treatment of many human diseases, including malaria, TB, HIV, and cancer. Although certain combination therapies have long been known to be more effective in curing patients than single drugs, the impact of such treatments on the evolution of drug resistance is unclear. In particular, very little is known about how the evolution of resistance is affected by the nature of the interactions—synergy or antagonism—between drugs. Here we directly measure the effect of various inhibitory and subinhibitory drug combinations on the rate of adaptation. We develop an automated assay for monitoring the parallel evolution of hundreds of Escherchia coli populations in a two-dimensional grid of drug gradients over many generations. We find a correlation between synergy and the rate of adaptation, whereby evolution in more synergistic drug combinations, typically preferred in clinical settings, is faster than evolution in antagonistic combinations. We also find that resistance to some synergistic combinations evolves faster than resistance to individual drugs. The accelerated evolution may be due to a larger selective advantage for resistance mutations in synergistic treatments. We describe a simple geometric model in which mutations conferring resistance to one drug of a synergistic pair prevent not only the inhibitory effect of that drug but also its enhancing effect on the other drug. Future study of the profound impact that synergy and other drug-pair properties can have on the rate of adaptation may suggest new treatment strategies for combating the spread of antibiotic resistance.     

Effects of linkage on rates of molecular evolution.

When an advantageous mutation is fixed in a population by selection, a closely linked selectively neutral or mildly detrimental mutation may "hitchhike" to fixation along with it. It has been suggested that hitchhiking might increase the rate of molecular evolution. Computer simulations and a mathematical argument show that complete linkage to either advantageous or deleterious mutations does not affect the substitution of selectively neutral mutations. However, the simulations show that linkage to selected background mutations decreases the rate of fixation of advantageous mutations and increases the rate of fixation of detrimental mutations. This is true whether the linked background mutations are advantageous or detrimental, and it verifies and extends previous observations that linkage tends to reduce the effects of selection on evolution. These results can be interpreted in terms of the Hill-Robertson effect: a locus linked to another locus under selection experiences a reduction in effective population size. The interpretation of differences in evolutionary rates between different genomes or different regions of a genome may be confounded by the effects of strong linkage and selection. Recombination is expected to reduce the overall rate of molecular evolution while enhancing the rate of adaptive evolution.     

Three types of rescue can avert extinction in a changing environment

Setting aside high-quality large areas of habitat to protect threatened populations is becoming increasingly difficult as humans fragment and degrade the environment. Biologists and managers therefore must determine the best way to shepherd small populations through the dual challenges of reductions in both the number of individuals and genetic variability. By bringing in additional individuals, threatened populations can be increased in size (demographic rescue) or provided with variation to facilitate adaptation and reduce inbreeding (genetic rescue). The relative strengths of demographic and genetic rescue for reducing extinction and increasing growth of threatened populations are untested, and which type of rescue is effective may vary with population size. Using the flour beetle (Tribolium castaneum) in a microcosm experiment, we disentangled the genetic and demographic components of rescue, and compared them with adaptation from standing genetic variation (evolutionary rescue in the strictest sense) using 244 experimental populations founded at either a smaller (50 individuals) or larger (150 individuals) size. Both types of rescue reduced extinction, and those effects were additive. Over the course of six generations, genetic rescue increased population sizes and intrinsic fitness substantially. Both large and small populations showed evidence of being able to adapt from standing genetic variation. Our results support the practice of genetic rescue in facilitating adaptation and reducing inbreeding depression, and suggest that demographic rescue alone may suffice in larger populations even if only moderately inbred individuals are available for addition.Human activities, climate change, and habitat loss are putting thousands of species at risk for extinction (1). Traditional conservation approaches that concentrate on improving habitat quality and size are becoming challenging to implement as human populations expand and degrade natural resources at an ever increasing rate. Thus, conservation efforts that are constrained by the availability of habitat may instead need to focus on improving a species’ prospect of survival by maintaining sufficient population sizes and supporting the ability of populations to adapt to changing conditions. The most successful approaches are likely to be eco-evolutionary in focus, and thus aim to manipulate evolutionary processes such as inbreeding and the potential for adaptation, to influence ecological dynamics and, ultimately, population persistence.Eco-evolutionary approaches often rely on facilitating movement of individuals among small, threatened populations (2). Brown and Kodric-Brown (3) showed theoretically that immigration in natural systems can save small populations from extinction and referred to this process as the “rescue effect.” This phenomenon has since been well documented (4–8), and human-facilitated immigration has been used to rescue populations threatened by degraded habitat or inbreeding depression, and to re-establish populations where they have been locally extirpated.Immigration can rescue a population from extinction by either increasing its size or increasing population fitness (3). The term “demographic rescue” refers to increases in numbers of individuals that buffer a population against stochastic fluctuations and reduce Allee effects, which are processes that small populations often face (3, 9, 10). A larger population size may also have long-term effects on population fitness. For instance, the increase in numbers may give a declining population time to adapt to a challenging environment, even if migrants do not immediately bring about an appreciable genetic change (11). On the other hand, if migrants are not adapted, they may slow the process of adaptation via swamping (12–14).The term “genetic rescue” is defined as an increase in population fitness due to the genetic contributions of immigrants (15) via reducing inbreeding depression or facilitating adaptation by enhancing genetic variation (2, 4, 6, 7, 15, 16). Some authors use genetic rescue to refer only to the reduction in inbreeding depression with outcrossing, excluding adaptive processes (10, 17). Our definition above follows the broader sense (6, 15).Both demographic rescue and genetic rescue can be potent, but their relative strengths and effects are completely unknown. Moreover, rescue via managed movement of individuals may not always be needed. In some cases, populations could simply adapt to the changed environment, leading to increased population growth rates and population sizes. This process has been called “evolutionary rescue” (10, 17–21). Research on evolutionary rescue initially focused on adaptation to a challenging environment from standing variation (18, 21), but, clearly, populations might adapt more quickly if migrants arrive carrying alleles that facilitate adaptation to the degraded habitat (22). The concept of evolutionary rescue can include migration as well (10, 23). Thus, there is an area of overlap in the use of the terms “genetic” and “evolutionary” rescue. For our purposes here, we use the term evolutionary rescue in the strictest sense of adaptation to a challenging environment from standing variation. Regardless of the exact process, the defining feature of any rescue effect is higher population size and/or an increase in intrinsic fitness in a given habitat.In an ideal situation, when trying to improve the prospects of a population that is at risk for extinction, a manager would bring in many genetically variable individuals that are adapted to the environment. Such individuals would solve both demographic and genetic challenges faced by the population that is at risk (24). However, such individuals typically are a limiting resource. To aid in effective management, it is therefore critical to disentangle the relative importance of demographic and genetic processes. Because greater numbers of migrants harbor greater genetic diversity in most natural populations (25, 26), the best way to separate these processes is with experiments in which numbers of individuals and the genetic variation they harbor do not covary.Furthermore, the relative importance of demographic and genetic processes may be context-dependent. For instance, the role of purely demographic processes will depend upon population size, potentially being more important when populations are smaller (25, 27). Understanding the relative importance of genetic and demographic processes and how they compare with adaptation from standing variation will fill a fundamental knowledge gap that only experimental eco-evolutionary research can fully resolve.Here, we manipulate immigration to small failing populations to evaluate their eco-evolutionary dynamics and understand better how to rescue populations from extinction. We experimentally partitioned the demographic and genetic effects of immigration using microcosms of the red flour beetle (Tribolium castaneum) (28). We exposed replicate experimental populations to a challenging novel environment (an alternative carbohydrate source and lower nutrient availability) to simulate a degraded habitat pushing a small population toward extinction. Our choice of environment was such that the expected density-independent, finite rate of increase of populations without rescue (i.e., intrinsic fitness) would be less than 1, and thus those populations would decline to extinction without adaptation. We studied experimental populations founded at two sizes: 50 or 150 individuals. These sizes are both small enough to represent situations that would be of immediate concern to natural resource managers but large enough that extinction should take more than one generation in most cases. Below, we refer to these different sets of experimental populations as “small” and “large.” We expected these differences in population size to affect the feasibility of evolutionary rescue and the relative importance of demographic and genetic mechanisms contributing to rescue from extinction.Each experimental population received one of four treatments: evolutionary rescue, in which no immigrants were added; demographic rescue, in which population size was increased; genetic rescue, in which genetic variation was added; and a combination of demographic and genetic rescue. All treatments were implemented one time, in the second generation following exposure to the novel environment, when populations had declined below their initial founding sizes. All migrants had spent a single generation on the challenging experimental medium to minimize carryover of maternal effects from the standard medium. Populations assigned to the demographic rescue treatment received an addition of immigrants to stabilize population size (∼20% increase in numbers) using individuals from the same source population as the receiving population. Thus, the genetic composition of the populations was altered minimally. Populations in the genetic rescue treatment had one (small populations) or three (large populations) beetles replaced one-for-one with individuals from an alternate source population with a different genetic background. This treatment thus had no effect on population size, but the immigrants could both reduce inbreeding and supply adaptive variation because they came from a distinct population that was less maladapted to the experimental environment than the receiving population (SI Methods and 29) and because individuals adapted to a challenging environment are likely to be limiting. We tripled that number for large populations to keep the treatments proportional. The combination of the demographic and genetic rescue treatments entailed increasing population size by adding multiple individuals from the same source population and one (small populations) or three (large populations) migrants from the alternate source population. We tracked populations for six generations (including two generations before adding immigrants) and evaluated extinction, population size, and changes in intrinsic fitness following rescue.

Table S1.

Ninety-five percent confidence interval for the density independent finite growth rates of experimental and migrant populations on standard medium and 97% corn medium

Deleterious mutations destabilize ribosomal RNA in endosymbiotic bacteria

In populations that are small and asexual, mutations with slight negative effects on fitness will drift to fixation more often than in large or sexual populations in which they will be eliminated by selection. If such mutations occur in substantial numbers, the combined effects of long-term asexuality and small population size may result in substantial accumulation of mildly deleterious substitutions. Prokaryotic endosymbionts of animals that are transmitted maternally for very long periods are effectively asexual and experience smaller effective population size than their free-living relatives. The contrast between such endosymbionts and related free-living bacteria allows us to test whether a population structure imposing frequent bottlenecks and asexuality does lead to an accumulation of slightly deleterious substitutions. Here we show that several independently derived insect endosymbionts, each with a long history of maternal transmission, have accumulated destabilizing base substitutions in the highly conserved 16S rRNA. Stabilities of Domain I of this subunit are 15–25% lower in endosymbionts than in closely related free-living bacteria. By mapping destabilizing substitutions onto a reconstructed phylogeny, we show that decreased ribosomal stability has evolved separately in each endosymbiont lineage. Our phylogenetic approach allows us to demonstrate statistical significance for this pattern: becoming endosymbiotic predictably results in decreased stability of rRNA secondary structure.     

High rate of viral evolution associated with the emergence of carnivore parvovirus

Canine parvovirus (CPV) is an emerging DNA virus that was first observed to cause disease in canines in 1978 and has since become a ubiquitous pathogen worldwide. CPV emerged from feline panleukopenia parvovirus (FPLV) or a closely related virus, differing at several key amino acid residues. Here we characterize the evolutionary processes underlying the emergence of CPV. Although FPLV has remained an endemic infection in its host populations, we show that, since the 1970s, the newly emerged CPV has undergone an epidemic-like pattern of logistic/exponential growth, effectively doubling its population size every few years. This rapid population growth was associated with a lineage of CPV that acquired a broader host range and greater infectivity. Recombination played no role in the emergence of CPV. Rather, any preexisting variation in the donor species and the subsequent rapid adaptation of the virus to canines were likely dependent on a high rate of mutation and the positive selection of mutations in the major capsid gene. Strikingly, although these single-stranded viruses have a DNA genome and use cellular replication machinery, their rate of nucleotide substitution is closer to that of RNA viruses than to that of double-stranded DNA viruses.     

The evolutionary origins of beneficial alleles during the repeated adaptation of garter snakes to deadly prey

Where do the genetic variants underlying adaptive change come from? Are currently adaptive alleles recruited by selection from standing genetic variation within populations, moved through introgression from other populations, or do they arise as novel mutations? Here, we examine the molecular basis of repeated adaptation to the toxin of deadly prey in 3 species of garter snakes (Thamnophis) to determine whether adaptation has evolved through novel mutations, sieving of existing variation, or transmission of beneficial alleles across species. Functional amino acid substitutions in the skeletal muscle sodium channel (Na_v1.4) are largely responsible for the physiological resistance of garter snakes to tetrodotoxin found in their newt (Taricha) prey. Phylogenetic analyses reject the hypotheses that the unique resistance alleles observed in multiple Thamnophis species were present before the split of these lineages, or that alleles were shared among species through occasional hybridization events. Our results demonstrate that adaptive evolution has occurred independently multiple times in garter snakes via the de novo acquisition of beneficial mutations.     

Invasion and maintenance of a gene duplication.

The ubiquity of multigene families is evidence for the frequent occurrence of gene duplication, but the origin of multigene families from a single gene remains a little-studied aspect of genome evolution. Although it is clear that a duplication can arise and become fixed in a population purely by random genetic drift and that the rate of fixation is accelerated if the duplication is directly advantageous, the nature of gene duplication suggests that other factors may influence the fate of a novel duplication. In the face of disadvantageous loss-of-function mutations, duplication of a functional gene may provide a buffer against such mutations. Here the conditions for invasion of a rare duplication starting from a mutation-selection balance are derived with formal population genetic models in both haploids and diploids. Recurrent duplication protects the duplicated chromosome from loss and can be very effective in increasing its frequency in a population. In the absence of recurrent duplication, one might suppose that a duplication would be favored by natural selection because it can mask the effects of deleterious mutations. However, the models show that a duplication can invade only if it provides a direct advantage to the organism. This result is closely related to recent theoretical work on the evolution of ploidy.     

Large population solution of the stochastic Luria–Delbrück evolution model

Luria and Delbrück introduced a very useful and subsequently widely adopted framework for quantitatively understanding the emergence of new cellular lineages. Here, we provide an analytical treatment of the fully stochastic version of the model, enabled by the fact that population sizes at the time of measurement are invariably very large and mutation rates are low. We show that the Lea–Coulson generating function describes the “inner solution,” where the number of mutants is much smaller than the total population. We find that the corresponding distribution function interpolates between a monotonic decrease at relatively small populations, (compared with the inverse of the mutation probability), whereas it goes over to a Lévy α-stable distribution in the very large population limit. The moments are completely determined by the outer solution, and so are devoid of practical significance. The key to our solution is focusing on the fixed population size ensemble, which we show is very different from the fixed time ensemble due to the extreme variability in the evolutionary process.     

The evolution of RNA viruses: A population genetics view

RNA viruses are excellent experimental models for studying evolution under the theoretical framework of population genetics. For a proper justification of this thesis we have introduced some properties of RNA viruses that are relevant for studying evolution. On the other hand, population genetics is a reductionistic theory of evolution. It does not consider or make simplistic assumptions on the transformation laws within and between genotypic and phenotypic spaces. However, such laws are minimized in the case of RNA viruses because the phenotypic space maps onto the genotypic space in a much more linear way than on higher DNA-based organisms. Under experimental conditions, we have tested the role of deleterious and beneficial mutations in the degree of adaptation of vesicular stomatitis virus (VSV), a nonsegmented virus of negative strand. We also have studied how effective population size, initial genetic variability in populations, and environmental heterogeneity shapes the impact of mutations in the evolution of vesicular stomatitis virus. Finally, in an integrative attempt, we discuss pros and cons of the quasispecies theory compared with classic population genetics models for haploid organisms to explain the evolution of RNA viruses.     

How can the low levels of DNA sequence variation in regions of the drosophila genome with low recombination rates be explained?

Different regions of the Drosophila genome have very different rates of recombination. For example, near centromeres and near the tips of chromosomes, the rates of recombination are much lower than in other regions. Several surveys of polymorphisms in Drosophila have now documented that levels of DNA polymorphism are positively correlated with rates of recombination; i.e., regions with low rates of recombination tend to have low levels of DNA polymorphism within populations of Drosophila. Three hypotheses are reviewed that might account for these observations. The first hypothesis is that regions of low recombination have low neutral mutation rates. Under this hypothesis between-species divergences should also be low in regions of low recombination. In fact, regions of low recombination have diverged at the same rate as other regions of the genome. On this basis, this strictly neutral hypothesis is rejected. The second hypothesis is that the process of fixation of favorable mutations leads to the observed correlation between polymorphism and recombination. This occurs via genetic hitchhiking, in which linked regions of the genome are swept along with the selectively favored mutant as it increases in frequency and eventually fixes in the population. This hitchhiking model with fixation of favorable mutations is compatible with major features of the data. By assuming this model is correct, one can estimate the rate of fixation of favorable mutations. The third hypothesis is that selection against continually arising deleterious mutations results in reduced levels of polymorphism at linked loci. Analysis of this background selection model shows that it can produce some reduction in levels of polymorphism but cannot explain some extreme cases that have been observed. Thus, it appears that hitchhiking of favorable mutations and background selection against deleterious mutations must be considered together to correctly account for the patterns of polymorphism that are observed in Drosophila.     

Mutators and sex in bacteria: conflict between adaptive strategies

Bacterial mutation rates can increase and produce genetic novelty, as shown by in vitro and in silico experiments. Despite the cost due to a heavy deleterious mutation load, mutator alleles, which increase the mutation rate, can spread in asexual populations during adaptation because they remain associated with the rare favorable mutations they generate. This indirect selection for a genetic system generating diversity (second-order selection) is expected to be highly sensitive to changes in the dynamics of adaptation. Here we show by a simulation approach that even rare genetic exchanges, such as bacterial conjugation or transformation, can dramatically reduce the selection of mutators. Moreover, drift or competition between the processes of mutation and recombination in the course of adaptation reveal how second-order selection is unable to optimize the rate of generation of novelty.     

From the Cover: Genomic patterns of pleiotropy and the evolution of complexity

Pleiotropy refers to the phenomenon of a single mutation or gene affecting multiple distinct phenotypic traits and has broad implications in many areas of biology. Due to its central importance, pleiotropy has also been extensively modeled, albeit with virtually no empirical basis. Analyzing phenotypes of large numbers of yeast, nematode, and mouse mutants, we here describe the genomic patterns of pleiotropy. We show that the fraction of traits altered appreciably by the deletion of a gene is minute for most genes and the gene–trait relationship is highly modular. The standardized size of the phenotypic effect of a gene on a trait is approximately normally distributed with variable SDs for different genes, which gives rise to the surprising observation of a larger per-trait effect for genes affecting more traits. This scaling property counteracts the pleiotropy-associated reduction in adaptation rate (i.e., the “cost of complexity”) in a nonlinear fashion, resulting in the highest adaptation rate for organisms of intermediate complexity rather than low complexity. Intriguingly, the observed scaling exponent falls in a narrow range that maximizes the optimal complexity. Together, the genome-wide observations of overall low pleiotropy, high modularity, and larger per-trait effects from genes of higher pleiotropy necessitate major revisions of theoretical models of pleiotropy and suggest that pleiotropy has not only allowed but also promoted the evolution of complexity.     

Rates of change in quantitative traits from fixation of new mutations.

Expressions are derived for the response to directional selection for a quantitative trait that comes from fixation of new mutations in a finite population. For additive genes with a distribution of mutant gene effects symmetric about zero, the response from fixing mutations occurring in a single generation is 2 Ni sigma 2M/sigma, in which N is the effective population size, i is the selection intensity, sigma is the phenotypic standard deviation, and sigma 2M is the increment in variance in the generation immediately after occurrence of the mutations. This response is 2N times that immediately after occurrence of the mutations. With continuous mutation each generation, the asymptotic rate of response is also 2Ni sigma 2M/sigma and the asymptotic variance is independent of i. For completely dominant mutations with symmetric effects, the rates are Ni sigma 2M/sigma; and for recessive mutations the rates are proportional to (Ni)1/2. If the distribution of mutant gene effects, a, is not symmetric about zero, responses depend on the mean square of effects of mutations with positive effect, rather than on the variance of their effects. Rates of change in fitness and of traits correlated with fitness are also analyzed. It is argued that new mutations have contributed substantially to long-term responses in many laboratory selection experiments.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Causes of natural variation in fitness: Evidence from studies of Drosophila populations

DNA sequencing has revealed high levels of variability within most species. Statistical methods based on population genetics theory have been applied to the resulting data and suggest that most mutations affecting functionally important sequences are deleterious but subject to very weak selection. Quantitative genetic studies have provided information on the extent of genetic variation within populations in traits related to fitness and the rate at which variability in these traits arises by mutation. This paper attempts to combine the available information from applications of the two approaches to populations of the fruitfly Drosophila in order to estimate some important parameters of genetic variation, using a simple population genetics model of mutational effects on fitness components. Analyses based on this model suggest the existence of a class of mutations with much larger fitness effects than those inferred from sequence variability and that contribute most of the standing variation in fitness within a population caused by the input of mildly deleterious mutations. However, deleterious mutations explain only part of this standing variation, and other processes such as balancing selection appear to make a large contribution to genetic variation in fitness components in Drosophila.Advances in DNA sequencing methods have enabled geneticists to measure the amount of genetic variability in natural populations at the most basic level: the frequencies of variants in nucleotide sequences. This achievement has ended one component of a debate on the extent and causes of genetic variability that was initiated in the 1950s by Hermann Muller and Theodosius Dobzhansky (1, 2); we now know that DNA sequences are highly variable within the populations of most species (3). It has, however, been much harder to provide a definitive answer to the other component of this debate, which concerns the nature and intensity of the evolutionary forces that influence the frequencies of genetic variants within populations (1, 2, 4, 5). Are these variants mostly selectively neutral (6), with the fates of new mutations determined by random fluctuations in their frequencies (genetic drift)? Is selection on variants that affect fitness mostly purifying, so that mutations with harmful effects are rapidly removed from the population (1)? Or do many loci have variants maintained by balancing selection (2)? What fraction of newly arisen variants cause higher fitness and are in the process of spreading through the population and replacing their alternatives? How strong is the selection acting on nonneutral variants, and how much variation in fitness among individuals within populations is contributed by such variants? Does the existence of wide variation in fitness among individuals imply a genetic load that threatens the survival of the species (1)?These questions are very broad, and this paper deals only with one aspect of them. It focuses on the question of how recent inferences concerning the strength of purifying selection, derived from genome-wide surveys of DNA sequence variability, can be connected with the results of statistical studies of genetic variation in components of Darwinian fitness such as viability and fertility. I will refer to these two approaches as population genomics and quantitative genetics, respectively. The first approach sheds light on the general nature of the fitness effects of the DNA sequence variants found in natural populations, but says little about how these fitness effects are caused. The second tells us how much genetic variability exists for fitness traits, the rate at which it arise by mutation and something about the type of selection involved, but is silent about the nature of the underlying sequence variants.Surprisingly little attention has been paid to integrating these two lines of inquiry, except for ref. 7. I largely confine myself to results from studies of the fruitfly Drosophila, because this has been the most useful model organism for investigating these problems, especially by quantitative genetics methods. Current information derived from population genomics studies will first be reviewed, followed by an analysis of the results of quantitative genetics experiments on both mutational and standing variation. I show that the quantitative genetics results can only be explained if there is a significant input of new mutations with much larger effects on fitness than those inferred from population genomics. There also appears to be too much genetic variation in fitness components in natural populations to be explained purely by mutation selection balance, so that additional processes such as balancing selection must make an important contribution.     

Historical contingency and the evolution of a key innovation in an experimental population of Escherichia coli

The role of historical contingency in evolution has been much debated, but rarely tested. Twelve initially identical populations of Escherichia coli were founded in 1988 to investigate this issue. They have since evolved in a glucose-limited medium that also contains citrate, which E. coli cannot use as a carbon source under oxic conditions. No population evolved the capacity to exploit citrate for >30,000 generations, although each population tested billions of mutations. A citrate-using (Cit+) variant finally evolved in one population by 31,500 generations, causing an increase in population size and diversity. The long-delayed and unique evolution of this function might indicate the involvement of some extremely rare mutation. Alternately, it may involve an ordinary mutation, but one whose physical occurrence or phenotypic expression is contingent on prior mutations in that population. We tested these hypotheses in experiments that "replayed" evolution from different points in that population's history. We observed no Cit+ mutants among 8.4 x 10(12) ancestral cells, nor among 9 x 10(12) cells from 60 clones sampled in the first 15,000 generations. However, we observed a significantly greater tendency for later clones to evolve Cit+, indicating that some potentiating mutation arose by 20,000 generations. This potentiating change increased the mutation rate to Cit+ but did not cause generalized hypermutability. Thus, the evolution of this phenotype was contingent on the particular history of that population. More generally, we suggest that historical contingency is especially important when it facilitates the evolution of key innovations that are not easily evolved by gradual, cumulative selection.     

High genetic load in an old isolated butterfly population

We investigated inbreeding depression and genetic load in a small (N(e) ～ 100) population of the Glanville fritillary butterfly (Melitaea cinxia), which has been completely isolated on a small island [Pikku Tyt?rsaari (PT)] in the Baltic Sea for at least 75 y. As a reference, we studied conspecific populations from the well-studied metapopulation in the ?land Islands (?L), 400 km away. A large population in Saaremaa, Estonia, was used as a reference for estimating genetic diversity and N(e). We investigated 58 traits related to behavior, development, morphology, reproductive performance, and metabolism. The PT population exhibited high genetic load (L = 1 - W(PT)/W(?L)) in a range of fitness-related traits including adult weight (L = 0.12), flight metabolic rate (L = 0.53), egg viability (L = 0.37), and lifetime production of eggs in an outdoor population cage (L = 0.70). These results imply extensive fixation of deleterious recessive mutations, supported by greatly reduced diversity in microsatellite markers and immediate recovery (heterosis) of egg viability and flight metabolic rate in crosses with other populations. There was no significant inbreeding depression in most traits due to one generation of full-sib mating. Resting metabolic rate was significantly elevated in PT males, which may be related to their short lifespan (L = 0.25). The demographic history and the effective size of the PT population place it in the part of the parameter space in which models predict mutation accumulation. This population exemplifies the increasingly common situation in fragmented landscapes, in which small and completely isolated populations are vulnerable to extinction due to high genetic load.