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1.
《Genomics》2022,114(2):110290
Deleterious mutations can reduce the fitness of crop varieties, which limits the plant breeding efficacy. While crop deleterious mutations have been extensively examined, most studies focused on one specific crop with different analyzing methods, which hinders unveiling shared genomic characteristics of deleterious mutations across diverse crops. Here we used standardized approaches to characterize the deleterious mutations in genomes of domesticated inbreeding (i.e., rice, soybean, and tomato) and clonally propagated crops (i.e., grape and pineapple). We found that deleterious mutations are commonly targeted by purifying selection, and are over-presented in a nearly fixed derived allele frequency in the course of plant domestication. Further, a generally negative correlation between genetic load and the artificial selection strength is observed. Importantly, we consistently uncovered the higher derived genomic heterozygosity for deleterious mutations compared to other genic variants. This study broadens our understanding of the evolution of deleterious mutations in plant genomes. 相似文献
2.
Evolutionary forces like Hill-Robertson interference and negative epistasis can lead to deleterious mutations being found on distinct haplotypes. However, the extent to which these forces depend on the selection and dominance coefficients of deleterious mutations and shape genome-wide patterns of linkage disequilibrium (LD) in natural populations with complex demographic histories has not been tested. In this study, we first used forward-in-time simulations to predict how negative selection impacts LD. Under models where deleterious mutations have additive effects on fitness, deleterious variants less than 10 kb apart tend to be carried on different haplotypes relative to pairs of synonymous SNPs. In contrast, for recessive mutations, there is no consistent ordering of how selection coefficients affect LD decay, due to the complex interplay of different evolutionary effects. We then examined empirical data of modern humans from the 1000 Genomes Project. LD between derived alleles at nonsynonymous SNPs is lower compared to pairs of derived synonymous variants, suggesting that nonsynonymous derived alleles tend to occur on different haplotypes more than synonymous variants. This result holds when controlling for potential confounding factors by matching SNPs for frequency in the sample (allele count), physical distance, magnitude of background selection, and genetic distance between pairs of variants. Lastly, we introduce a new statistic HR(j) which allows us to detect interference using unphased genotypes. Application of this approach to high-coverage human genome sequences confirms our finding that nonsynonymous derived alleles tend to be located on different haplotypes more often than are synonymous derived alleles. Our findings suggest that interference may play a pervasive role in shaping patterns of LD between deleterious variants in the human genome, and consequently influences genome-wide patterns of LD. 相似文献
3.
Joint effects of genetic hitchhiking and background selection on neutral variation 总被引:14,自引:0,他引:14
Due to relatively high rates of strongly selected deleterious mutations, directional selection on favorable alleles (causing hitchhiking effects on linked neutral polymorphisms) is expected to occur while a deleterious mutation-selection balance is present in a population. We analyze this interaction of directional selection and background selection and study their combined effects on neutral variation, using a three-locus model in which each locus is subjected to either deleterious, favorable, or neutral mutations. Average heterozygosity is measured by simulations (1) at the stationary state under the assumption of recurrent hitchhiking events and (2) as a transient level after a single hitchhiking event. The simulation results are compared to theoretical predictions. It is shown that known analytical solutions describing the hitchhiking effect without background selection can be modified such that they accurately predict the joint effects of hitchhiking and background on linked, neutral variation. Generalization of these results to a more appropriate multilocus model (such that background selection can occur at multiple sites) suggests that, in regions of very low recombination rates, stationary levels of nucleotide diversity are primarily determined by hitchhiking, whereas in regions of high recombination, background selection is the dominant force. The implications of these results on the identification and estimation of the relevant parameters of the model are discussed. 相似文献
4.
Deleterious Mutations, Apparent Stabilizing Selection and the Maintenance of Quantitative Variation 总被引:3,自引:0,他引:3
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Apparent stabilizing selection on a quantitative trait that is not causally connected to fitness can result from the pleiotropic effects of unconditionally deleterious mutations, because as N. Barton noted, "...individuals with extreme values of the trait will tend to carry more deleterious alleles...." We use a simple model to investigate the dependence of this apparent selection on the genomic deleterious mutation rate, U; the equilibrium distribution of K, the number of deleterious mutations per genome; and the parameters describing directional selection against deleterious mutations. Unlike previous analyses, we allow for epistatic selection against deleterious alleles. For various selection functions and realistic parameter values, the distribution of K, the distribution of breeding values for a pleiotropically affected trait, and the apparent stabilizing selection function are all nearly Gaussian. The additive genetic variance for the quantitative trait is kQa2, where k is the average number of deleterious mutations per genome, Q is the proportion of deleterious mutations that affect the trait, and a2 is the variance of pleiotropic effects for individual mutations that do affect the trait. In contrast, when the trait is measured in units of its additive standard deviation, the apparent fitness function is essentially independent of Q and a2; and beta, the intensity of selection, measured as the ratio of additive genetic variance to the "variance" of the fitness curve, is very close to s = U/k, the selection coefficient against individual deleterious mutations at equilibrium. Therefore, this model predicts appreciable apparent stabilizing selection if s exceeds about 0.03, which is consistent with various data. However, the model also predicts that beta must equal Vm/VG, the ratio of new additive variance for the trait introduced each generation by mutation to the standing additive variance. Most, although not all, estimates of this ratio imply apparent stabilizing selection weaker than generally observed. A qualitative argument suggests that even when direct selection is responsible for most of the selection observed on a character, it may be essentially irrelevant to the maintenance of variation for the character by mutation-selection balance. Simple experiments can indicate the fraction of observed stabilizing selection attributable to the pleiotropic effects of deleterious mutations. 相似文献
5.
Deleterious mutations present a significant obstacle to adaptive evolution. Deleterious mutations can inhibit the spread of linked adaptive mutations through a population; conversely, adaptive substitutions can increase the frequency of linked deleterious mutations and even result in their fixation. To assess the impact of adaptive mutations on linked deleterious mutations, we examined the distribution of deleterious and neutral amino acid polymorphism in the human genome. Within genomic regions that show evidence of recent hitchhiking, we find fewer neutral but a similar number of deleterious SNPs compared to other genomic regions. The higher ratio of deleterious to neutral SNPs is consistent with simulated hitchhiking events and implies that positive selection eliminates some deleterious alleles and increases the frequency of others. The distribution of disease-associated alleles is also altered in hitchhiking regions. Disease alleles within hitchhiking regions have been associated with auto-immune disorders, metabolic diseases, cancers, and mental disorders. Our results suggest that positive selection has had a significant impact on deleterious polymorphism and may be partly responsible for the high frequency of certain human disease alleles. 相似文献
6.
This study addresses the question of how purifying selection operates during recent rapid population growth such as has been experienced by human populations. This is not a straightforward problem because the human population is not at equilibrium: population genetics predicts that, on the one hand, the efficacy of natural selection increases as population size increases, eliminating ever more weakly deleterious variants; on the other hand, a larger number of deleterious mutations will be introduced into the population and will be more likely to increase in their number of copies as the population grows. To understand how patterns of human genetic variation have been shaped by the interaction of natural selection and population growth, we examined the trajectories of mutations with varying selection coefficients, using computer simulations. We observed that while population growth dramatically increases the number of deleterious segregating sites in the population, it only mildly increases the number carried by each individual. Our simulations also show an increased efficacy of natural selection, reflected in a higher fraction of deleterious mutations eliminated at each generation and a more efficient elimination of the most deleterious ones. As a consequence, while each individual carries a larger number of deleterious alleles than expected in the absence of growth, the average selection coefficient of each segregating allele is less deleterious. Combined, our results suggest that the genetic risk of complex diseases in growing populations might be distributed across a larger number of more weakly deleterious rare variants. 相似文献
7.
Lohmueller KE Albrechtsen A Li Y Kim SY Korneliussen T Vinckenbosch N Tian G Huerta-Sanchez E Feder AF Grarup N Jørgensen T Jiang T Witte DR Sandbæk A Hellmann I Lauritzen T Hansen T Pedersen O Wang J Nielsen R 《PLoS genetics》2011,7(10):e1002326
A major question in evolutionary biology is how natural selection has shaped patterns of genetic variation across the human genome. Previous work has documented a reduction in genetic diversity in regions of the genome with low recombination rates. However, it is unclear whether other summaries of genetic variation, like allele frequencies, are also correlated with recombination rate and whether these correlations can be explained solely by negative selection against deleterious mutations or whether positive selection acting on favorable alleles is also required. Here we attempt to address these questions by analyzing three different genome-wide resequencing datasets from European individuals. We document several significant correlations between different genomic features. In particular, we find that average minor allele frequency and diversity are reduced in regions of low recombination and that human diversity, human-chimp divergence, and average minor allele frequency are reduced near genes. Population genetic simulations show that either positive natural selection acting on favorable mutations or negative natural selection acting against deleterious mutations can explain these correlations. However, models with strong positive selection on nonsynonymous mutations and little negative selection predict a stronger negative correlation between neutral diversity and nonsynonymous divergence than observed in the actual data, supporting the importance of negative, rather than positive, selection throughout the genome. Further, we show that the widespread presence of weakly deleterious alleles, rather than a small number of strongly positively selected mutations, is responsible for the correlation between neutral genetic diversity and recombination rate. This work suggests that natural selection has affected multiple aspects of linked neutral variation throughout the human genome and that positive selection is not required to explain these observations. 相似文献
8.
Orr HA 《Genetics》2000,155(2):961-968
I study the population genetics of adaptation in asexuals. I show that the rate of adaptive substitution in an asexual species or nonrecombining chromosome region is a bell-shaped function of the mutation rate: at some point, increasing the mutation rate decreases the rate of substitution. Curiously, the mutation rate that maximizes the rate of adaptation depends solely on the strength of selection against deleterious mutations. In particular, adaptation is fastest when the genomic rate of mutation, U, equals the harmonic mean of selection coefficients against deleterious mutations, where we assume that selection for favorable alleles is milder than that against deleterious ones. This simple result is independent of the shape of the distribution of effects among favorable and deleterious mutations, population size, and the action of clonal interference. In the course of this work, I derive an approximation to the probability of fixation of a favorable mutation in an asexual genome or nonrecombining chromosome region in which both favorable and deleterious mutations occur. 相似文献
9.
Maintenance of Genetic Variability under the Pressure of Neutral and Deleterious Mutations in a Finite Population
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Wen-Hsiung Li 《Genetics》1979,92(2):647-667
In order to assess the effect of deleterious mutations on various measures of genic variation, approximate formulas have been developed for the frequency spectrum, the mean number of alleles in a sample, and the mean homozygosity; in some particular cases, exact formulas have been obtained. The assumptions made are that two classes of mutations exist, neutral and deleterious, and that selection is strong enough to keep deleterious alleles in low frequencies, the mode of selection being either genic or recessive. The main findings are: (1) If the expected value (q) of the sum of the frequencies of deleterious alleles is about 10% or less, then the presence of deleterious alleles causes only a minor reduction in the mean number of neutral alleles in a sample, as compared to the case of q = 0. Also, the low- and intermediate-frequency parts of the frequency spectrum of neutral alleles are little affected by the presence of deleterious alleles, though the high-frequency part may be changed drastically. (2) The contribution of deleterious mutations to the expected total number of alleles in a sample can be quite large even if q is only 1 or 2%. (3) The mean homozygosity is roughly equal to (1--2q)/(1 + theta 1), where theta 1 is twice the number of new neutral mutations occurring in each generation in the total population. Thus, deleterious mutations increase the mean heterozygosity by about 2q/(1 + theta 1). The present results have been applied to study the controversial problem of how deleterious mutations may affect the testing of the neutral mutation hypothesis. 相似文献
10.
Mutator alleles, which elevate an individual's mutation rate from 10 to 10,000-fold, have been found at high frequencies in many natural and experimental populations. Mutators are continually produced from nonmutators, often due to mutations in mismatch-repair genes. These mutators gradually accumulate deleterious mutations, limiting their spread. However, they can occasionally hitchhike to high frequencies with beneficial mutations. We study the interplay between these effects. We first analyze the dynamics of the balance between the production of mutator alleles and their elimination due to deleterious mutations. We find that when deleterious mutation rates are high in mutators, there will often be many "young," recently produced mutators in the population, and the fact that deleterious mutations only gradually eliminate individuals from a population is important. We then consider how this mutator-nonmutator balance can be disrupted by beneficial mutations and analyze the circumstances in which fixation of mutator alleles is likely. We find that dynamics is crucial: even in situations where selection on average acts against mutators, so they cannot stably invade, the mutators can still occasionally generate beneficial mutations and hence be important to the evolution of the population. 相似文献
11.
Here we present results of a Drosophila long term experiment where we study the fitness consequences of equating the number of breeding offspring contributed per family (EC) compared to a random contribution (RC) protocol. The EC strategy slows inbreeding and drift. However, it also prevents natural selection on fecundity and limits selection on viability to that occurring within families, and this includes purge against unconditionally deleterious alleles as well as adaptation to captive conditions. We used populations maintained with 5 or 25 single mated pairs, monitored inbreeding and selection intensity, and assayed competitive and non competitive fitness, as well as fecundity and viability components, in lines maintained with or without EC. In the small lines, EC showed modest advantage for viability during the whole experiment and for fitness up to generation 15 while, in the large lines, fitness increased steadily under both strategies, and EC led in the medium term to a slight fitness disadvantage. On the light of recent theory, these results can be explained as the joint consequence of new and standing deleterious mutations undergoing drift, inbreeding and selection and of adaptation to captive conditions. 相似文献
12.
Genetic architecture and balancing selection: the life and death of differentiated variants
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Balancing selection describes any form of natural selection, which results in the persistence of multiple variants of a trait at intermediate frequencies within populations. By offering up a snapshot of multiple co‐occurring functional variants and their interactions, systems under balancing selection can reveal the evolutionary mechanisms favouring the emergence and persistence of adaptive variation in natural populations. We here focus on the mechanisms by which several functional variants for a given trait can arise, a process typically requiring multiple epistatic mutations. We highlight how balancing selection can favour specific features in the genetic architecture and review the evolutionary and molecular mechanisms shaping this architecture. First, balancing selection affects the number of loci underlying differentiated traits and their respective effects. Control by one or few loci favours the persistence of differentiated functional variants by limiting intergenic recombination, or its impact, and may sometimes lead to the evolution of supergenes. Chromosomal rearrangements, particularly inversions, preventing adaptive combinations from being dissociated are increasingly being noted as features of such systems. Similarly, due to the frequency of heterozygotes maintained by balancing selection, dominance may be a key property of adaptive variants. High heterozygosity and limited recombination also influence associated genetic load, as linked recessive deleterious mutations may be sheltered. The capture of deleterious elements in a locus under balancing selection may reinforce polymorphism by further promoting heterozygotes. Finally, according to recent genomewide scans, balanced polymorphism might be more pervasive than generally thought. We stress the need for both functional and ecological studies to characterize the evolutionary mechanisms operating in these systems. 相似文献
13.
The Effect of Deleterious Mutations on Neutral Molecular Variation 总被引:12,自引:12,他引:0
Selection against deleterious alleles maintained by mutation may cause a reduction in the amount of genetic variability at linked neutral sites. This is because a new neutral variant can only remain in a large population for a long period of time if it is maintained in gametes that are free of deleterious alleles, and hence are not destined for rapid elimination from the population by selection. Approximate formulas are derived for the reduction below classical neutral values resulting from such background selection against deleterious mutations, for the mean times to fixation and loss of new mutations, nucleotide site diversity, and number of segregating sites. These formulas apply to random-mating populations with no genetic recombination, and to populations reproducing exclusively asexually or by self-fertilization. For a given selection regime and mating system, the reduction is an exponential function of the total mutation rate to deleterious mutations for the section of the genome involved. Simulations show that the effect decreases rapidly with increasing recombination frequency or rate of outcrossing. The mean time to loss of new neutral mutations and the total number of segregating neutral sites are less sensitive to background selection than the other statistics, unless the population size is of the order of a hundred thousand or more. The stationary distribution of allele frequencies at the neutral sites is correspondingly skewed in favor of rare alleles, compared with the classical neutral result. Observed reductions in molecular variation in low recombination genomic regions of sufficiently large size, for instance in the centromere-proximal regions of Drosophila autosomes or in highly selfing plant populations, may be partly due to background selection against deleterious mutations. 相似文献
14.
Traditionally, population genetics focuses on the dynamics of frequencies of alleles acquired by mutations on germ-lines, because only such mutations are heritable. Typical genotyping experiments, however, use DNA from some somatic tissues such as blood, which harbors somatic mutations at the current generation in addition to germ-line mutations accumulated since the most recent common ancestor of the sample. This common practice may sometimes cause erroneous interpretations of polymorphism data, unless we properly understand the role of somatic mutations in population genetics. We here introduce a very basic theoretical framework of population genetics with somatic mutations taken into account. It is easy to imagine that somatic mutations at the current generation simply add individual-specific variations, as errors in mutation detection do. Our theory quantifies this increment under various conditions. We find that the major contribution of somatic mutations plus errors is to very rare variants, particularly to singletons. The relative contribution is markedly large when mutations are deleterious. Because negative selection also increases rare variants, it is important to distinguish the roles of these mutually confounding factors when we interpret the data, even after correcting for demography. We apply this theory to human copy number variations (CNVs), for which the composite effect of somatic mutations and errors may not be negligible. Using genome-wide CNV data, we demonstrate how the joint action of the two factors, selection and somatic mutations plus errors, shapes the observed pattern of polymorphism. 相似文献
15.
The distribution of mutational effects on fitness is of fundamental importance for many aspects of evolution. We develop two methods for characterizing the fitness effects of deleterious, nonsynonymous mutations, using polymorphism data from two related species. These methods also provide estimates of the proportion of amino acid substitutions that are selectively favorable, when combined with data on between-species sequence divergence. The methods are applicable to species with different effective population sizes, but that share the same distribution of mutational effects. The first, simpler, method assumes that diversity for all nonneutral mutations is given by the value under mutation-selection balance, while the second method allows for stronger effects of genetic drift and yields estimates of the parameters of the probability distribution of mutational effects. We apply these methods to data on populations of Drosophila miranda and D. pseudoobscura and find evidence for the presence of deleterious nonsynonymous mutations, mostly with small heterozygous selection coefficients (a mean of the order of 10(-5) for segregating variants). A leptokurtic gamma distribution of mutational effects with a shape parameter between 0.1 and 1 can explain observed diversities, in the absence of a separate class of completely neutral nonsynonymous mutations. We also describe a simple approximate method for estimating the harmonic mean selection coefficient from diversity data on a single species. 相似文献
16.
Aurora García‐Dorado 《Evolution; international journal of organic evolution》2017,71(5):1381-1389
I present analytical predictions for the equilibrium inbreeding load expected in a population under mutation, selection, and a regular mating system for any population size and for any magnitude and recessivity of the deleterious effects. Using this prediction, I deduce the relative fitness of mutant alleles with small effect on selfing to explore the situations where selfing or outcrossing are expected to evolve. The results obtained are in agreement with previous literature, showing that natural selection is expected to lead to stable equilibria where populations show either complete outcrossing or complete selfing, and that selfing is promoted by large deleterious mutation rates. I find that the evolution of selfing is favored by a large recessivity of deleterious effects, while the magnitude of homozygous deleterious effects only becomes relevant in relatively small populations. This result contradicts the standard assumption that purging in large populations will only promote selfing when homozygous deleterious effects are large, and implies that previously published results obtained assuming lethal mutations in large populations can be extrapolated to nonlethal alleles of similar recessivity. This conclusion and the general approach used in this analysis can be useful in the study of the evolution of mating systems. 相似文献
17.
Most rare missense alleles are deleterious in humans: implications for complex disease and association studies
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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. 相似文献
18.
The effects of sexual selection on population mean fitness are unclear and a subject of debate. Recent models propose that, because reproductive success may be condition dependent, much of the genome may be a target of sexual selection. Under this scenario, mutations that reduce health, and thus nonsexual fitness, may also be deleterious with respect to reproductive success, meaning that sexual selection may contribute to the purging of deleterious alleles. We tested this hypothesis directly by subjecting replicate Drosophila melanogaster populations to two treatments that altered the opportunity for sexual selection and then tracked changes in the frequency of six separate deleterious alleles with recessive and visible phenotypic effects. While natural selection acted to decrease the frequency of all six mutations, the addition of sexual selection did not aid in the purging of any of them, and for three of them appears to have hampered it. Courtship and mating have harmful effects in this species and mate choice assays showed that males directed more courtship and mating behavior toward wild-type over mutant females, providing a likely explanation for sexual selection's cost. Whether this cost extends to other mutations (e.g., those lacking visible phenotypic effects) is an important topic for future research. 相似文献
19.
Evolutionary success of bacteria relies on the constant fine-tuning of their mutation rates, which optimizes their adaptability to constantly changing environmental conditions. When adaptation is limited by the mutation supply rate, under some conditions, natural selection favours increased mutation rates by acting on allelic variation of the genetic systems that control fidelity of DNA replication and repair. Mutator alleles are carried to high frequency through hitchhiking with the adaptive mutations they generate. However, when fitness gain no longer counterbalances the fitness loss due to continuous generation of deleterious mutations, natural selection favours reduction of mutation rates. Selection and counter-selection of high mutation rates depends on many factors: the number of mutations required for adaptation, the strength of mutator alleles, bacterial population size, competition with other strains, migration, and spatial and temporal environmental heterogeneity. Such modulations of mutation rates may also play a role in the evolution of antibiotic resistance. 相似文献
20.
Fixation of new alleles and the extinction of small populations: drift load, beneficial alleles, and sexual selection 总被引:9,自引:1,他引:8
Whitlock MC 《Evolution; international journal of organic evolution》2000,54(6):1855-1861
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. 相似文献