Epistasis can increase multivariate trait diversity in haploid non-recombining populations

We evaluate the effect of epistasis on genetically-based multivariate trait variation in haploid non-recombining populations. In a univariate setting, past work has shown that epistasis reduces genetic variance (additive plus epistatic) in a population experiencing stabilizing selection. Here we show that in a multivariate setting, epistasis also reduces total genetic variation across the entire multivariate trait in a population experiencing stabilizing selection. But, we also show that the pattern of variation across the multivariate trait can be more even when epistasis occurs compared to when epistasis is absent, such that some character combinations will have more genetic variance when epistasis occurs compared to when epistasis is absent. In fact, a measure of generalized multivariate trait variation can be increased by epistasis under weak to moderate stabilizing selection conditions, as well as neutral conditions. Likewise, a measure of conditional evolvability can be increased by epistasis under weak to moderate stabilizing selection and neutral conditions. We investigate the nature of epistasis assuming a multivariate-normal model genetic effects and investigate the nature of epistasis underlying the biophysical properties of RNA. Increased multivariate diversity occurs for populations that are infinite in size, as well as populations that are finite in size. Our model of finite populations is explicitly genealogical and we link our findings about the evenness of eigenvalues with epistasis to prior work on the genealogical mapping of epistatic effects.     

Epistasis can accelerate adaptive diversification in haploid asexual populations

A fundamental goal of the biological sciences is to determine processes that facilitate the evolution of diversity. These processes can be separated into ecological, physiological, developmental and genetic. An ecological process that facilitates diversification is frequency-dependent selection caused by competition. Models of frequency-dependent adaptive diversification have generally assumed a genetic basis of phenotype that is non-epistatic. Here, we present a model that indicates diversification is accelerated by an epistatic basis of phenotype in combination with a competition model that invokes frequency-dependent selection. Our model makes use of a genealogical model of epistasis and insights into the effects of balancing selection on the genealogical structure of a population to understand how epistasis can facilitate diversification. The finding that epistasis facilitates diversification may be informative with respect to empirical results that indicate an epistatic basis of phenotype in experimental bacterial populations that experienced adaptive diversification.     

Epistasis and the temporal change in the additive variance-covariance matrix induced by drift

The effect of population bottlenecks on the components of the genetic covariance generated by two neutral independent epistatic loci has been studied theoretically (additive, covA; dominance, covD; additive-by-additive, covAA; additive-by-dominance, covAD; and dominance-by-dominance, covDD). The additive-by-additive model and a more general model covering all possible types of marginal gene action at the single-locus level (additive/dominance epistatic model) were considered. The covariance components in an infinitely large panmictic population (ancestral components) were compared with their expected values at equilibrium over replicates randomly derived from the base population, after t consecutive bottlenecks of equal size N (derived components). Formulae were obtained in terms of the allele frequencies and effects at each locus, the corresponding epistatic effects and the inbreeding coefficient Ft. These expressions show that the contribution of nonadditive loci to the derived additive covariance (covAt) does not linearly decrease with inbreeding, as in the pure additive case, and may initially increase or even change sign in specific situations. Numerical examples were also analyzed, restricted for simplicity to the case of all covariance components being positive. For additive-by-additive epistasis, the condition covAt > covA only holds for high frequencies of the allele decreasing the metric traits at each locus (negative allele) if epistasis is weak, or for intermediate allele frequencies if it is strong. For the additive/dominance epistatic model, however, covAt > covA applies for low frequencies of the negative alleles at one or both loci and mild epistasis, but this result can be progressively extended to intermediate frequencies as epistasis becomes stronger. Without epistasis the same qualitative results were found, indicating that marginal dominance induced by epistasis can be considered as the primary cause of an increase of the additive covariance after bottlenecks. For all models, the magnitude of the ratio covAt/covA was inversely related to N and t.     

Epistasis and Its Contribution to Genetic Variance Components

We present a new parameterization of physiological epistasis that allows the measurement of epistasis separate from its effects on the interaction (epistatic) genetic variance component. Epistasis is the deviation of two-locus genotypic values from the sum of the contributing single-locus genotypic values. This parameterization leads to statistical tests for epistasis given estimates of two-locus genotypic values such as can be obtained from quantitative trait locus studies. The contributions of epistasis to the additive, dominance and interaction genetic variances are specified. Epistasis can make substantial contributions to each of these variance components. This parameterization of epistasis allows general consideration of the role of epistasis in evolution by defining its contribution to the additive genetic variance.     

A TEST OF THE ROLE OF EPISTASIS IN DIVERGENCE UNDER UNIFORM SELECTION

Five populations of Drosophila melanogaster have previously been shown to be replicably different in their responses to artificial selection for knockdown resistance to ethanol fumes (Cohan and Hoffmann, 1986). The present study tests whether this divergence could be attributed to the epistatic mechanism assumed by Wright's shifting-balance model of evolution, in which alleles favored in the genetic background of one population are not favored in that of another. If this were the mechanism of divergence, crosses between selected lines from different populations would be expected to yield an epistatic loss of the selected phenotype. However, all such crosses showed a good fit to an additive model with dominance. Divergence by an epistatic mechanism may also be associated with epistatic variance within populations, but no evidence for such epistasis was found. The populations therefore appear to have responded in different ways to selection not because of epistasis but because knockdown-resistance alleles that were common in some populations were absent (or at least less common) in others.     

The effect of genetic drift on the variance/covariance components generated by multilocus additive x additive epistatic systems

The effect of population bottlenecks on the components of the genetic variance/covariance generated by n neutral independent additive x additive loci has been studied theoretically. In its simplest version, this situation can be modelled by specifying the allele frequencies and homozygous effects at each locus, and an additional factor measuring the strength of the n-th order epistatic interaction. The variance/covariance components in an infinitely large panmictic population (ancestral components) were compared with their expected values at equilibrium over replicates randomly derived from the base population, after t bottlenecks of size N (derived components). Formulae were obtained giving the derived components (and the between-line variance) as functions of the ancestral ones (alternatively, in terms of allele frequencies and effects) and the corresponding inbreeding coefficient F(t). The n-th order derived component of the genetic variance/covariance is continuously eroded by inbreeding, but the remaining components may increase initially until a critical F(t) value is attained, which is inversely related to the order of the pertinent component, and subsequently decline to zero. These changes can be assigned to the between-line variances/covariances of gene substitution and epistatic effects induced by drift. Numerical examples indicate that: (1) the derived additive variance/covariance component will generally exceed its ancestral value unless epistasis is weak; (2) the derived epistatic variance/covariance components will generally exceed their ancestral values unless allele frequencies are extreme; (3) for systems showing equal ancestral additive and total non-additive variance/covariance components, those including a smaller number of epistatic loci may generate a larger excess in additive variance/covariance after bottlenecks than others involving a larger number of loci, provided that F(t) is low. Our results indicate that it is unlikely that the rate of evolution may be significantly accelerated after population bottlenecks, in spite of occasional increments of the derived additive variance over its ancestral value.     

Evolution of genetic architecture under directional selection

We investigate the multilinear epistatic model under mutation-limited directional selection. We confirm previous results that only directional epistasis, in which genes on average reinforce or diminish each other's effects, contribute to the initial evolution of mutational effects. Thus, either canalization or decanalization can occur under directional selection, depending on whether positive or negative epistasis is prevalent. We then focus on the evolution of the epistatic coefficients themselves. In the absence of higher-order epistasis, positive pairwise epistasis will tend to weaken relative to additive effects, while negative pairwise epistasis will tend to become strengthened. Positive third-order epistasis will counteract these effects, while negative third-order epistasis will reinforce them. More generally, gene interactions of all orders have an inherent tendency for negative changes under directional selection, which can only be modified by higher-order directional epistasis. We identify three types of nonadditive quasi-equilibrium architectures that, although not strictly stable, can be maintained for an extended time: (1) nondirectional epistatic architectures; (2) canalized architectures with strong epistasis; and (3) near-additive architectures in which additive effects keep increasing relative to epistasis.     

Epistasis causes outbreeding depression in eucalypt hybrids

The genetic architecture underlying species differentiation is essential for understanding the mechanisms of speciation and post-zygotic reproductive barriers which exist between species. We undertook line-cross analysis of multiple hybrid (F₁, F₂ and backcrosses) and pure-species populations of two diploid eucalypt species from different subseries, Eucalyptus globulus and Eucalyptus nitens, to unravel the genetic architecture of their differentiation. The populations were replicated on two sites and monitored for growth and survival over a 14-year period. The hybrids exhibited severe outbreeding depression which increased with age. Of the composite additive, dominance and epistatic effects estimated, the additive × additive epistatic component was the most important in determining population divergence in both growth and survival. Significant dominance × dominance epistasis was also detected for survival at several ages. While favourable dominance and, in the case of survival, dominance × dominance epistasis could produce novel gene combinations which enhance hybrid fitness, at the population level, these effects were clearly overridden by adverse additive × additive epistasis which appears to be a major driver of overall outbreeding depression in the hybrid populations. The lack of model fit at older ages suggested that even high-order epistatic interactions may potentially have a significant contribution to outbreeding depression in survival. The estimated composite genetic parameters were generally stable across sites. Our results argue that the development of favourable epistasis is a key mechanism underlying the genetic divergence of eucalypt species, and epistasis is an important mechanism underlying the evolution of post-zygotic reproductive barriers.     

Identifying quantitative trait locus by genetic background interactions in association studies

Association studies are designed to identify main effects of alleles across a potentially wide range of genetic backgrounds. To control for spurious associations, effects of the genetic background itself are often incorporated into the linear model, either in the form of subpopulation effects in the case of structure or in the form of genetic relationship matrices in the case of complex pedigrees. In this context epistatic interactions between loci can be captured as an interaction effect between the associated locus and the genetic background. In this study I developed genetic and statistical models to tie the locus by genetic background interaction idea back to more standard concepts of epistasis when genetic background is modeled using an additive relationship matrix. I also simulated epistatic interactions in four-generation randomly mating pedigrees and evaluated the ability of the statistical models to identify when a biallelic associated locus was epistatic to other loci. Under additive-by-additive epistasis, when interaction effects of the associated locus were quite large (explaining 20% of the phenotypic variance), epistasis was detected in 79% of pedigrees containing 320 individuals. The epistatic model also predicted the genotypic value of progeny better than a standard additive model in 78% of simulations. When interaction effects were smaller (although still fairly large, explaining 5% of the phenotypic variance), epistasis was detected in only 9% of pedigrees containing 320 individuals and the epistatic and additive models were equally effective at predicting the genotypic values of progeny. Epistasis was detected with the same power whether the overall epistatic effect was the result of a single pairwise interaction or the sum of nine pairwise interactions, each generating one ninth of the epistatic variance. The power to detect epistasis was highest (94%) at low QTL minor allele frequency, fell to a minimum (60%) at minor allele frequency of about 0.2, and then plateaued at about 80% as alleles reached intermediate frequencies. The power to detect epistasis declined when the linkage disequilibrium between the DNA marker and the functional polymorphism was not complete.     

The contrasting genetic architecture of wing size, viability, and development time in a rainforest species and its more widely distributed relative

Divergence among populations can occur via additive genetic effects and/or because of epistatic interactions among genes. Here we use line-cross analysis to compare the importance of epistasis in divergence among two sympatric Drosophila species from eastern Australia, one (D. serrata) distributed continuously and the other (D. birchii) confined to rainforest habitats that are often disjunct. For D. serrata, crosses indicated that development time and wing size differences were due to additive genetic effects, while for viability there were digenic epistatic effects. Crosses comparing geographically close populations as well as those involving the most geographically distant populations (including the southern species border) revealed epistatic interactions, whereas crosses at an intermediate distance showed no epistasis. In D. birchii, there was no evidence of epistasis for viability, although for development time and wing size there was epistasis in the cross between the most geographically diverged populations. Strong epistasis has not developed among the D. birchii populations, and this habitat specialist does not show stronger epistasis than D. serrata. Given that epistasis has been detected in crosses with other species from eastern Australia, including the recently introduced D. melanogaster, the results point to epistasis not being directly linked to divergence times among populations.     

Evolutionary Divergence of the Genetic Architecture Underlying Photoperiodism in the Pitcher-Plant Mosquito, Wyeomyia Smithii

We determine the contribution of composite additive, dominance, and epistatic effects to the genetic divergence of photoperiodic response along latitudinal, altitudinal, and longitudinal gradients in the pitcher-plant mosquito, Wyeomyia smithii. Joint scaling tests of crosses between populations showed wide-spread epistasis as well as additive and dominance differences among populations. There were differences due to epistasis between an alpine population in North Carolina and populations in Florida, lowland North Carolina, and Maine. Longitudinal displacement resulted in differences due to epistasis between Florida and Alabama populations separated by 300 km but not between Maine and Wisconsin populations separated by 2000 km. Genetic differences between New Jersey and Ontario did not involve either dominance or epistasis and we estimated the minimum number of effective factors contributing to a difference in mean critical photoperiod of 5 SD between them as n(E) = 5. We propose that the genetic similarity of populations within a broad northern region is due to their more recent origin since recession of the Laurentide Ice Sheet and that the unique genetic architecture of each population is the result of both mutation and repeated migration-founder-flush episodes during the dispersal of W. smithii in North America. Our results suggest that differences in composite additive and dominance effects arise early in the genetic divergence of populations while differences due to epistasis accumulate after more prolonged isolation.     

Quantitative Genetics of Doubled Haploid Populations and Application to the Theory of Line Development

The line value of a genotype is defined as the expected value of all lines that can be derived from this genotype. Specific genetic effects are defined for this value: only additive and additive by additive epistatic effects are necessary. There is no dominance effect for such a value. A general expression for the covariances between related lines is given. From a design with several lines per haplodiploidized plant taken at random from a population it is possible to estimate the additive variance for line value and the variance of additive by additive epistasis for line value. Variances of higher order epistasis can be estimated with a two-factor mating design in which a cross is replaced by the population of lines that can be derived from it. With a diallel or a factorial design a direct test for the presence of homozygous by homozygous epistasis is possible. The application of the concept of line value to the theory of line development leads to simple expressions of genetic advance in one cycle of recurrent selection according to the testing system. A brief consideration of these expressions leads to the conclusion that single doubled haploid descent recurrent selection will be one of the most efficient methods for low heritabilities and with a rapid development of doubled haploid lines.     

The role of epistatic gene interactions in the response to selection and the evolution of evolvability

It has been argued that the architecture of the genotype-phenotype map determines evolvability, but few studies have attempted to quantify these effects. In this article we use the multilinear epistatic model to study the effects of different forms of epistasis on the response to directional selection. We derive an analytical prediction for the change in the additive genetic variance, and use individual-based simulations to understand the dynamics of evolvability and the evolution of genetic architecture. This shows that the major determinant for the evolution of the additive variance, and thus the evolvability, is directional epistasis. Positive directional epistasis leads to an acceleration of evolvability, while negative directional epistasis leads to canalization. In contrast, pure non-directional epistasis has little effect on the response to selection. One consequence of this is that the classical epistatic variance components, which do not distinguish directional and non-directional effects, are useless as predictors of evolutionary dynamics. The build-up of linkage disequilibrium also has negligible effects. We argue that directional epistasis is likely to have major effects on evolutionary dynamics and should be the focus of empirical studies of epistasis.     

Effect on linkage disequilibrium of selection for a quantitative character with epistasis

Summary Selection for a character controlled by additive genes induces linkage disequilibrium which reduces the additive genetic variance usable for further selective gains. Additive x additive epistasis contributes to selection response through development of linkage disequilibrium between interacting loci. To investigate the relative importance of the two effects of linkage disequilibrium, formulae are presented and results are reported of simulations using models involving additive, additive x additive and dominance components. The results suggest that so long as epistatic effects are not large relative to additive effects, and the proportion of pairs of loci which show epistasis is not very high, the predominant effect of linkage disequilibrium will be to reduce the rate of selection response.     

Epistatic pleiotropy and the genetic architecture of covariation within early and late-developing skull trait complexes in mice

The role of epistasis as a source of trait variation is well established, but its role as a source of covariation among traits (i.e., as a source of "epistatic pleiotropy") is rarely considered. In this study we examine the relative importance of epistatic pleiotropy in producing covariation within early and late-developing skull trait complexes in a population of mice derived from an intercross of the Large and Small inbred strains. Significant epistasis was found for several pairwise combinations of the 21 quantitative trait loci (QTL) affecting early developing traits and among the 20 QTL affecting late-developing traits. The majority of the epistatic effects were restricted to single traits but epistatic pleiotropy still contributed significantly to covariances. Because of their proportionally larger effects on variances than on covariances, epistatic effects tended to reduce within-group correlations of traits and reduce their overall degree of integration. The expected contributions of single-locus and two-locus epistatic pleiotropic QTL effects to the genetic covariance between traits were analyzed using a two-locus population genetic model. The model demonstrates that, for single-locus or epistatic pleiotropy to contribute to trait covariances in the study population, both traits must show the same pattern of single-locus or epistatic effects. As a result, a large number of the cases where loci show pleiotropic effects do not contribute to the covariance between traits in this population because the loci show a different pattern of effect on the different traits. In general, covariance patterns produced by single-locus and epistatic pleiotropy predicted by the model agreed well with actual values calculated from the QTL analysis. Nearly all single-locus and epistatic pleiotropic effects contributed positive components to covariances between traits, suggesting that genetic integration in the skull is achieved by a complex combination of pleiotropic effects.     

Effect of inter- and intragenic epistasis on the heritability of oil content in rapeseed (Brassica napus L.)

The loci detected by association mapping which are involved in the expression of important agronomic traits in crops often explain only a small proportion of the total genotypic variance. Here, 17 SNPs derived from 9 candidate genes from the triacylglycerol biosynthetic pathway were studied in an association analysis in a population of 685 diverse elite rapeseed inbred lines. The 685 lines were evaluated for oil content, as well as for glucosinolates, yield, and thousand-kernel weight in field trials at 4 locations. We detected main effects for most of the studied genes illustrating that genetic diversity for oil content can be exploited by the selection of favorable alleles. In addition to main effects, both intergenic and intragenic epistasis was detected that contributes to a considerable amount to the genotypic variance observed for oil content. The proportion of explained genotypic variance was doubled when in addition to main effects epistasis was considered. Therefore, a knowledge-based improvement of oil content in rapeseed should also take such favorable epistatic interactions into account. Our results suggest, that the observed high contribution of epistasis may to some extent explain the missing heritability in genome-wide association studies.     

Modeling quantitative trait Loci and interpretation of models

A quantitative genetic model relates the genotypic value of an individual to the alleles at the loci that contribute to the variation in a population in terms of additive, dominance, and epistatic effects. This partition of genetic effects is related to the partition of genetic variance. A number of models have been proposed to describe this relationship: some are based on the orthogonal partition of genetic variance in an equilibrium population. We compare a few representative models and discuss their utility and potential problems for analyzing quantitative trait loci (QTL) in a segregating population. An orthogonal model implies that estimates of the genetic effects are consistent in a full or reduced model in an equilibrium population and are directly related to the partition of the genetic variance in the population. Linkage disequilibrium does not affect the estimation of genetic effects in a full model, but would in a reduced model. Certainly linkage disequilibrium would complicate the detection of QTL and epistasis. Using different models does not influence the detection of QTL and epistasis. However, it does influence the estimation and interpretation of genetic effects.     

The Evolution of Multilocus Systems under Weak Selection

The evolution of multilocus systems under weak selection is investigated. Generations are discrete and nonoverlapping; the monoecious population mates at random. The number of multiallelic loci, the linkage map, dominance, and epistasis are arbitrary. The genotypic fitnesses may depend on the gametic frequencies and time. The results hold for s << c(min), where s and c(min) denote the selection intensity and the smallest two-locus recombination frequency, respectively. After an evolutionarily short time of t(1) ~ (ln s)/ln(1 - c(min)) generations, all the multilocus linkage disequilibria are of the order of s [i.e., O(s) as s -> 0], and then the population evolves approximately as if it were in linkage equilibrium, the error in the gametic frequencies being O(s). Suppose the explicit time dependence (if any) of the genotypic fitnesses is O(s(2)). Then after a time t(2) ~ 2t(1), the linkage disequilibria are nearly constant, their rate of change being O(s(2)). Furthermore, with an error of O(s(2)), each linkage disequilibrium is proportional to the corresponding epistatic deviation for the interaction of additive effects on fitness. If the genotypic fitnesses change no faster than at the rate O(s(3)), then the single-generation change in the mean fitness is ΔW = W(-1)V(g) + O(s(3)), where V(g) designates the genic (or additive genetic) variance in fitness. The mean of a character with genotypic values whose single-generation change does not exceed O(s(2)) evolves at the rate ΔZ = W(-1)C(g) + O(s(2)), where C(g) represents the genic covariance of the character and fitness (i.e., the covariance of the average effect on the character and the average excess for fitness of every allele that affects the character). Thus, after a short time t(2), the absolute error in the fundamental and secondary theorems of natural selection is small, though the relative error may be large.     

水稻株高上位性效应和ＱＥ互作效应的ＱＴＬ遗传研究

利用基因混合模型的ＱＴＬ定位方法研究了由籼稻品种ＩＲ６４和粳稻品种Ａzucena杂交衍生的ＤＨ群体在４个环境中的ＱＴＬ上位性效应和环境互作效应,结果表明,上位性是数量性状的重要遗传基础,并揭示了上位性的几个重要特点,所有的ＱＴＬ都参与了上位性效应的形成,６４％的ＱＴＬ还具有本身的加性效应,因此传统方法对ＱＴＬ加性效应的估算会由于上位性的影响而有偏,其他３６％的ＱＴＬ没有本身的加性效应,却参与了４８％的上位性互作用,这些位点可能通过诱发和修饰其他位点而起作用,上位性的特点还包括,经常发现了一个ＱＴＬ与多个ＱＴＬ发生互作;大效应的ＱＴＬ也参与上位性互作;上位性互作受环境影响,ＱＴＬ与环境的互效应比ＱＴＬ的主效应更多地被检测到,表明数量性状基因的表达易受环境影响。     

Epistasis Can Facilitate the Evolution of Reproductive Isolation by Peak Shifts: A Two-Locus Two-Allele Model

The influence of epistasis on the evolution of reproductive isolation by peak shifts is studied in a two-locus two-allele model of a quantitative genetic character under stabilizing selection. Epistasis is introduced by a simple multiplicative term in the function that maps gene effects onto genotypic values. In the model with only additive effects on the trait, the probability of a peak shift and the amount of reproductive isolation are always inversely related, i.e., the higher the peak shift rate, the lower the amount of reproductive isolation caused by the peak shift. With epistatic characters there is no consistent relationship between these two values. Interestingly, there are causes where both transition rates as well as the amount of reproductive isolation are increased relative to the additive model. This effect has two main causes: a shift in the location of the transition point, and the hybrids between the two alternative optimal genotypes have lower average fitness in the epistatic case. A review of the empirical literature shows that the fitness relations resulting in higher peak shift rates and more reproductive isolation are qualitatively the same as those observed for genes causing hybrid inferiority.