Genetic load in subdivided populations: interactions between the migration rate, the size and the number of subpopulations

We assess the relative importance of migration rate, size and number of subpopulations on the genetic load of subdivided populations. Using diffusion approximations, we show that in most cases subdivision has detrimental effects on fitness. Moreover, our results suggest that fitness increases with subpopulation size, so that for the same total population size, genetic load is relatively lower when there are a small number of large subpopulations. Using elasticity analysis, we show that the size of the subpopulations appears to be the parameter that most strongly determines genetic load. interconnecting subpopulations via migration would also be of importance for population fitness when subpopulations are small and gene flow is low. Interestingly, the number of subpopulations has minor influence on genetic load except for the case of both very slightly deleterious mutations and small subpopulations. Elasticities decrease as the magnitude of deleterious effects increases. In other words, population structure does not matter for very deleterious alleles, but strongly affects fitness for slightly deleterious alleles.     

The distribution of fitness effects of new deleterious amino acid mutations in humans

The distribution of fitness effects of new mutations is a fundamental parameter in genetics. Here we present a new method by which the distribution can be estimated. The method is fairly robust to changes in population size and admixture, and it can be corrected for any residual effects if a model of the demography is available. We apply the method to extensively sampled single-nucleotide polymorphism data from humans and estimate the distribution of fitness effects for amino acid changing mutations. We show that a gamma distribution with a shape parameter of 0.23 provides a good fit to the data and we estimate that >50% of mutations are likely to have mild effects, such that they reduce fitness by between one one-thousandth and one-tenth. We also infer that <15% of new mutations are likely to have strongly deleterious effects. We estimate that on average a nonsynonymous mutation reduces fitness by a few percent and that the average strength of selection acting against a nonsynonymous polymorphism is approximately 9 x 10(-5). We argue that the relaxation of natural selection due to modern medicine and reduced variance in family size is not likely to lead to a rapid decline in genetic quality, but that it will be very difficult to locate most of the genes involved in complex genetic diseases.     

Natural history of Ashkenazi intelligence

This paper elaborates the hypothesis that the unique demography and sociology of Ashkenazim in medieval Europe selected for intelligence. Ashkenazi literacy, economic specialization, and closure to inward gene flow led to a social environment in which there was high fitness payoff to intelligence, specifically verbal and mathematical intelligence but not spatial ability. As with any regime of strong directional selection on a quantitative trait, genetic variants that were otherwise fitness reducing rose in frequency. In particular we propose that the well-known clusters of Ashkenazi genetic diseases, the sphingolipid cluster and the DNA repair cluster in particular, increase intelligence in heterozygotes. Other Ashkenazi disorders are known to increase intelligence. Although these disorders have been attributed to a bottleneck in Ashkenazi history and consequent genetic drift, there is no evidence of any bottleneck. Gene frequencies at a large number of autosomal loci show that if there was a bottleneck then subsequent gene flow from Europeans must have been very large, obliterating the effects of any bottleneck. The clustering of the disorders in only a few pathways and the presence at elevated frequency of more than one deleterious allele at many of them could not have been produced by drift. Instead these are signatures of strong and recent natural selection.     

SYMPATRIC SPECIATION VIA HABITAT SPECIALIZATION DRIVEN BY DELETERIOUS MUTATIONS

Theoretical studies have suggested that the evolution of habitat (host) races, regarded as a prelude to sympatric speciation, requires strong trade-offs in adaptation to different habitats: alleles that improve fitness in some habitats and have deleterious effects of similar magnitude in other habitats must be segregating in the population. I argue that such trade-offs are not necessary; the evolution of habitat races can also be driven by genetic variation due to loci that affect fitness in one habitat and are neutral or nearly so in others, that is, when performance in different habitats is genetically independent. One source of such genetic variation are deleterious mutations with habitat-specific fitness effects. I use deterministic two-locus and multilocus models to show that the presence of such mutations in the gene pool results in indirect selection favoring habitat fidelity or habitat preference over acceptance of both suitable habitats. This leads to the evolution of largely genetically isolated populations that use different habitats, from a single panmictic population of individuals accepting both habitats. This study suggests that the conditions favoring habitat race formation, and thus possibly sympatric speciation, are much less stringent than previously thought.     

Fixation of new alleles and the extinction of small populations: drift load, beneficial alleles, and sexual selection

With a small effective population size, random genetic drift is more important than selection in determining the fate of new alleles. Small populations therefore accumulate deleterious mutations. Left unchecked, the effect of these fixed alleles is to reduce the reproductive capacity of a species, eventually to the point of extinction. New beneficial mutations, if fixed by selection, can restore some of this lost fitness. This paper derives the overall change in fitness due to fixation of new deleterious and beneficial alleles, as a function of the distribution of effects of new mutations and the effective population size. There is a critical effective size below which a population will on average decline in fitness, but above which beneficial mutations allow the population to persist. With reasonable estimates of the relevant parameters, this critical effective size is likely to be a few hundred. Furthermore, sexual selection can act to reduce the fixation probability of deleterious new mutations and increase the probability of fixing new beneficial mutations. Sexual selection can therefore reduce the risk of extinction of small populations.     

EFFECTIVENESS OF SELECTION IN REDUCING THE GENETIC LOAD IN POPULATIONS OF PEROMYSCUS POLIONOTUS DURING GENERATIONS OF INBREEDING

It has been hypothesized that natural selection reduces the “genetic load” of deleterious alleles from populations that inbreed during bottlenecks, thereby ameliorating impacts of future inbreeding. We tested the efficiency with which natural selection purges deleterious alleles from three subspecies of Peromyscus polionotus during 10 generations of laboratory inbreeding by monitoring pairing success, litter size, viability, and growth in 3604 litters produced from 3058 pairs. In P. p. subgriseus, there was no reduction across generations in inbreeding depression in any of the fitness components. Strongly deleterious recessive alleles may have been removed previously during episodes of local inbreeding in the wild, and the residual genetic load in this population was not further reduced by selection in the lab. In P. p. rhoadsi, four of seven fitness components did show a reduction of the genetic load with continued inbreeding. The average reduction in the genetic load was as expected if inbreeding depression in this population is caused by highly deleterious recessive alleles that are efficiently removed by selection. For P. p. leucocephalus a population that experiences periodic bottlenecks in the wild, the effect of further inbreeding in the laboratory was to exacerbate rather than reduce the genetic load. Recessive deleterious alleles may have been removed from this population during repeated bottlenecks in the wild; the population may be close to a threshold level of heterozygosity below which fitness declines rapidly. Thus, the effects of selection on inbreeding depression varied substantially among populations, perhaps due to different histories of inbreeding and selection.     

Most rare missense alleles are deleterious in humans: implications for complex disease and association studies

The accumulation of mildly deleterious missense mutations in individual human genomes has been proposed to be a genetic basis for complex diseases. The plausibility of this hypothesis depends on quantitative estimates of the prevalence of mildly deleterious de novo mutations and polymorphic variants in humans and on the intensity of selective pressure against them. We combined analysis of mutations causing human Mendelian diseases, of human-chimpanzee divergence, and of systematic data on human genetic variation and found that ~20% of new missense mutations in humans result in a loss of function, whereas ~27% are effectively neutral. Thus, the remaining 53% of new missense mutations have mildly deleterious effects. These mutations give rise to many low-frequency deleterious allelic variants in the human population, as is evident from a new data set of 37 genes sequenced in >1,500 individual human chromosomes. Surprisingly, up to 70% of low-frequency missense alleles are mildly deleterious and are associated with a heterozygous fitness loss in the range 0.001-0.003. Thus, the low allele frequency of an amino acid variant can, by itself, serve as a predictor of its functional significance. Several recent studies have reported a significant excess of rare missense variants in candidate genes or pathways in individuals with extreme values of quantitative phenotypes. These studies would be unlikely to yield results if most rare variants were neutral or if rare variants were not a significant contributor to the genetic component of phenotypic inheritance. Our results provide a justification for these types of candidate-gene (pathway) association studies and imply that mutation-selection balance may be a feasible evolutionary mechanism underlying some common diseases.     

GENES WITH SOCIAL EFFECTS ARE EXPECTED TO HARBOR MORE SEQUENCE VARIATION WITHIN AND BETWEEN SPECIES

The equilibrium sequence diversity of genes within a population and the rate of sequence divergence between populations or species depends on a variety of factors, including expression pattern, mutation rate, nature of selection, random drift, and mating system. Here, we extend population genetic theory developed for maternal-effect genes to predict the equilibrium polymorphism within species and sequence divergence among species for genes with social effects on fitness. We show how the fitness effects of genes, mating system, and genetic system affect predicted gene polymorphism. We find that, because genes with indirect social effects on fitness effectively experience weaker selection, they are expected to harbor higher levels of polymorphism relative to genes with direct fitness effects. The relative increase in polymorphism is proportional to the inverse of the genetic relatedness between individuals expressing the gene and their social partners that experience the fitness effects of the gene. We find a similar pattern of more rapid divergence between populations or species for genes with indirect social effects relative to genes with direct effects. We focus our discussion on the social insects, organisms with diverse indirect genetic effects, mating and genetic systems, and we suggest specific examples for testing our predictions with emerging sociogenomic tools.     

HIERARCHICAL ANALYSIS OF INBREEDING DEPRESSION IN PEROMYSCUS POLIONOTUS

The severity of inbreeding depression appears to vary among taxa, but few ecological or other patterns have been identified that predict accurately which taxa are most sensitive to inbreeding. To examine the causes of heterogeneity in inbreeding depression, the effects of inbreeding on reproduction, survival, and growth were measured in three replicate experimental stocks for each of three subspecies of Peromyscus polionotus mice. Inbreeding of the dam reduced the probability of breeding, the probability of producing a second litter, and litter size. Inbreeding of the litter caused depression of litter size, juvenile viability, and mass at weaning, and caused an increase in the within-litter variance in mass. In spite of differences between the subspecies in natural population sizes, genetic variation, and mean rates of reproduction and survival, all variation observed between experimental populations in their responses to inbreeding could be attributed to random founder effects. The genetic load of deleterious alleles in each replicate was unequally partitioned among its founder pairs, and different founders contributed to the load affecting different fitness components. Thus, inbreeding depression for any one fitness component, in our experimental environment, must be due to relatively few deleterious alleles with major effects. Genetic loads so comprised would be expected to diverge among natural populations due to both random drift and selective removal of recessive deleterious alleles during population bottlenecks. The near universality of inbreeding depression would be maintained, however, if different alleles contribute to inbreeding depression of different fitness components and in different environments.     

Heterosis and outbreeding depression in crosses between natural populations of Arabidopsis thaliana

Understanding the causes and architecture of genetic differentiation between natural populations is of central importance in evolutionary biology. Crosses between natural populations can result in heterosis if recessive or nearly recessive deleterious mutations have become fixed within populations because of genetic drift. Divergence between populations can also result in outbreeding depression because of genetic incompatibilities. The net fitness consequences of between-population crosses will be a balance between heterosis and outbreeding depression. We estimated the magnitude of heterosis and outbreeding depression in the highly selfing model plant Arabidopsis thaliana, by crossing replicate line pairs from two sets of natural populations (C↔R, B↔S) separated by similar geographic distances (Italy↔Sweden). We examined the contribution of different modes of gene action to overall differences in estimates of lifetime fitness and fitness components using joint scaling tests with parental, reciprocal F₁ and F₂, and backcross lines. One of these population pairs (C↔R) was previously demonstrated to be locally adapted, but locally maladaptive quantitative trait loci were also found, suggesting a role for genetic drift in shaping adaptive variation. We found markedly different genetic architectures for fitness and fitness components in the two sets of populations. In one (C↔R), there were consistently positive effects of dominance, indicating the masking of recessive or nearly recessive deleterious mutations that had become fixed by genetic drift. The other set (B↔S) exhibited outbreeding depression because of negative dominance effects. Additional studies are needed to explore the molecular genetic basis of heterosis and outbreeding depression, and how their magnitudes vary across environments.     

Evolutionary dynamics of pathogen resistance and tolerance

Abstract.— Host organisms can respond to the threat of disease either through resistance defenses (which inhibit or limit infection) or through tolerance strategies (which do not limit infection, but reduce or offset its fitness consequences). Here we show that resistance and tolerance can have fundamentally different evolutionary outcomes, even when they have equivalent short-term benefit for the host. As a gene conferring disease resistance spreads through a population, the incidence of infection declines, reducing the fitness advantage of carrying the resistance gene. Thus genes conferring complete resistance cannot become fixed (i.e., universal) by selection in a host population, and diseases cannot be eliminated solely by natural selection for host resistance. By contrast, as a gene conferring disease tolerance spreads through a population, disease incidence rises, increasing the evolutionary advantage of carrying the tolerance gene. Therefore, any tolerance gene that can invade a host population will tend to be driven to fixation by selection. As predicted, field studies of diverse plant species infected by rust fungi confirm that resistance traits tend to be polymorphic and tolerance traits tend to be fixed. These observations suggest a new mechanism for the evolution of mutualism from parasitism, and they help to explain the ubiquity of disease.     

Dependence of epistasis on environment and mutation severity as revealed by in silico mutagenesis of phage t7

Understanding how interactions among deleterious mutations affect fitness may shed light on a variety of fundamental biological phenomena, including the evolution of sex, the buffering of genetic variations, and the topography of fitness landscapes. It remains an open question under what conditions and to what extent such interactions may be synergistic or antagonistic. To address this question, we employed a computer model for the intracellular growth of bacteriophage T7. We created in silico 90,000 mutants of phage T7, each carrying from 1 to 30 mutations, and evaluated the fitness of each by simulating its growth cycle. The simulations sought to account for the severity of single deleterious mutations on T7 growth, as well as the effect of the resource environment on our fitness measures. We found that mildly deleterious mutations interacted synergistically in poor-resource environments but antagonistically in rich-resource environments. However, severely deleterious mutations always interacted antagonistically, irrespective of environment. These results suggest that synergistic epistasis may be difficult to experimentally distinguish from nonepistasis because its effects appear to be most pronounced when the effects of mutations on fitness are most challenging to measure. Our approach demonstrates how computer simulations of developmental processes can be used to quantitatively study genetic interactions at the population level.     

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

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

Bottlenecks in large populations: the effect of immigration on population viability

We model a large population that is subject to successive short bottlenecks, in order to investigate the impact of different extents of immigration on the change in genetic load and on viability. A first simple genetic model uncovers the opposite effects of immigration on fitness according to the type of deleterious mutations considered: immigration increases fitness if the genetic load is comprised of mildly deleterious mutations, whereas it decreases fitness if it is comprised of lethals. When considering both types of mutations and adding explicit stochastic demographic considerations, in which bottlenecks are engendered by random catastrophes, the global impact of immigration on viability is dependent upon a balance between its opposite effects on the two components of the genetic load and on demographic stochasticity. In this context, immigration tends to increase the probability of extinction if occurring preferentially when population density is high, while it decreases extinction if occurring preferentially towards low-density populations.     

On the evolutionary advantage of fitness-associated recombination

The adaptive value of recombination remains something of a puzzle. One of the basic problems is that recombination not only creates new and advantageous genetic combinations, but also breaks down existing good ones. A negative correlation between the fitness of an individual and its recombination rate would result in prolonged integrity of fitter genetic combinations while enabling less fit ones to produce new combinations. Such a correlation could be mediated by various factors, including stress responses, age, or direct DNA damage. For haploid population models, we show that an allele for such fitness-associated recombination (FAR) can spread both in asexual populations and in populations reproducing sexually at any uniform recombination rate. FAR also carries an advantage for the population as a whole, resulting in a higher average fitness at mutation-selection balance. These results are demonstrated in populations adapting to new environments as well as in well-adapted populations coping with deleterious mutations. Current experimental results providing evidence for the existence of FAR in nature are discussed.     

Slow Recovery from Inbreeding Depression Generated by the Complex Genetic Architecture of Segregating Deleterious Mutations

The deleterious effects of inbreeding have been of extreme importance to evolutionary biology, but it has been difficult to characterize the complex interactions between genetic constraints and selection that lead to fitness loss and recovery after inbreeding. Haploid organisms and selfing organisms like the nematode Caenorhabditis elegans are capable of rapid recovery from the fixation of novel deleterious mutation; however, the potential for recovery and genomic consequences of inbreeding in diploid, outcrossing organisms are not well understood. We sought to answer two questions: 1) Can a diploid, outcrossing population recover from inbreeding via standing genetic variation and new mutation? and 2) How does allelic diversity change during recovery? We inbred C. remanei, an outcrossing relative of C. elegans, through brother-sister mating for 30 generations followed by recovery at large population size. Inbreeding reduced fitness but, surprisingly, recovery from inbreeding at large populations sizes generated only very moderate fitness recovery after 300 generations. We found that 65% of ancestral single nucleotide polymorphisms (SNPs) were fixed in the inbred population, far fewer than the theoretical expectation of ∼99%. Under recovery, 36 SNPs across 30 genes involved in alimentary, muscular, nervous, and reproductive systems changed reproducibly across replicates, indicating that strong selection for fitness recovery does exist. Our results indicate that recovery from inbreeding depression via standing genetic variation and mutation is likely to be constrained by the large number of segregating deleterious variants present in natural populations, limiting the capacity for recovery of small populations.     

The genetic basis of inbreeding depression

Data on the effects of inbreeding on fitness components are reviewed in the light of population genetic models of the possible genetic causes of inbreeding depression. Deleterious mutations probably play a major role in causing inbreeding depression. Putting together the different kinds of quantitative genetic data, it is difficult to account for the very large effects of inbreeding on fitness in Drosophila and outcrossing plants without a significant contribution from variability maintained by selection. Overdominant effects of alleles on fitness components seem not to be important in most cases. Recessive or partially recessive deleterious effects of alleles, some maintained by mutation pressure and some by balancing selection, thus seem to be the most important source of inbreeding depression. Possible experimental approaches to resolving outstanding questions are discussed.     

Social selection in human populations. I. Modification of the fitness of offspring by an affected parent.

The concept of social selection for deleterious genes has been introduced by considering two alleles at one locus. A social selection model is constructed by assuming that the fitness of an individual is determined by his or her own as well as the parental phenotypes. It is shown that the equilibrium gene frequency depends on the loss of fitness of an individual due to the trait (gamma), due to affected parents (beta), and the probability that the heterozygote develops the trait (h). With mutational changes from the wild-type allele to the deleterious gene at a rate of alpha per generation, the equilibrium frequency of deleterious genes is approximately alpha/hs for 0 less than h less than or equal to 1 and square root alpha/s for h = 0, where s = gamma + beta(1 -- gamma)/2. Implications of the social selection model have been discussed for several diseases in man.     

Fitness effects of new mutations in Chlamydomonas reinhardtii across two stress gradients

Most spontaneous mutations affecting fitness are likely to be deleterious, but the strength of selection acting on them might be impacted by environmental stress. Such stress‐dependent selection could expose hidden genetic variation, which in turn might increase the adaptive potential of stressed populations. On the other hand, this variation might represent a genetic load and thus lead to population extinction under stress. Previous studies to determine the link between stress and mutational effects on fitness, however, have produced inconsistent results. Here, we determined the net change in fitness in 29 genotypes of the green algae Chlamydomonas reinhardtii that accumulated mutations in the near absence of selection for approximately 1000 generations across two stress gradients, increasing NaCl and decreasing phosphate. We found mutational effects to be magnified under extremely stressful conditions, but such effects were specific both to the type of stress and to the genetic background. The detection of stress‐dependent fitness effects of mutations depended on accurately scaling relative fitness measures by generation times, thus offering an explanation for the inconsistencies among previous studies.     

Muller's ratchet and the pattern of variation at a neutral locus

The levels and patterns of variation at a neutral locus are analyzed in a haploid asexual population undergoing accumulation of deleterious mutations due to Muller's ratchet. We find that the movement of Muller's ratchet can be associated with a considerable reduction in genetic diversity below classical neutral expectation. The extent to which variability is reduced is a function of the deleterious mutation rate, the fitness effects of the mutations, and the population size. Approximate analytical expressions for the expected genetic diversity are compared with simulation results under two different models of deleterious mutations: a model where all deleterious mutations have equal effects and a model where there are two classes of deleterious mutations. We also find that Muller's ratchet can produce a considerable distortion in the neutral frequency spectrum toward an excess of rare variants.