Genetic variation in pleiotropy: differential epistasis as a source of variation in the allometric relationship between long bone lengths and body weight

Pleiotropy is an aspect of genetic architecture underlying the phenotypic covariance structure. The presence of genetic variation in pleiotropy is necessary for natural selection to shape patterns of covariation between traits. We examined the contribution of differential epistasis to variation in the intertrait relationship and the nature of this variation. Genetic variation in pleiotropy was revealed by mapping quantitative trait loci (QTLs) affecting the allometry of mouse limb and tail length relative to body weight in the mouse-inbred strain LG/J by SM/J intercross. These relationship QTLs (rQTLs) modify relationships between the traits affected by a common pleiotropic locus. We detected 11 rQTLs, mostly affecting allometry of multiple bones. We further identified epistatic interactions responsible for the observed allometric variation. Forty loci that interact epistatically with the detected rQTLs were identified. We demonstrate how these epistatic interactions differentially affect the body size variance and the covariance of traits with body size. We conclude that epistasis, by differentially affecting both the canalization and mean values of the traits of a pleiotropic domain, causes variation in the covariance structure. Variation in pleiotropy maintains evolvability of the genetic architecture, in particular the evolvability of its modular organization.     

Evolutionary quantitative genetics of nonlinear developmental systems

In quantitative genetics, the effects of developmental relationships among traits on microevolution are generally represented by the contribution of pleiotropy to additive genetic covariances. Pleiotropic additive genetic covariances arise only from the average effects of alleles on multiple traits, and therefore the evolutionary importance of nonlinearities in development is generally neglected in quantitative genetic views on evolution. However, nonlinearities in relationships among traits at the level of whole organisms are undeniably important to biology in general, and therefore critical to understanding evolution. I outline a system for characterizing key quantitative parameters in nonlinear developmental systems, which yields expressions for quantities such as trait means and phenotypic and genetic covariance matrices. I then develop a system for quantitative prediction of evolution in nonlinear developmental systems. I apply the system to generating a new hypothesis for why direct stabilizing selection is rarely observed. Other uses will include separation of purely correlative from direct and indirect causal effects in studying mechanisms of selection, generation of predictions of medium‐term evolutionary trajectories rather than immediate predictions of evolutionary change over single generation time‐steps, and the development of efficient and biologically motivated models for separating additive from epistatic genetic variances and covariances.     

Developmental interactions and the constituents of quantitative variation

Development is the process by which genotypes are transformed into phenotypes. Consequently, development determines the relationship between allelic and phenotypic variation in a population and, therefore, the patterns of quantitative genetic variation and covariation of traits. Understanding the developmental basis of quantitative traits may lead to insights into the origin and evolution of quantitative genetic variation, the evolutionary fate of populations, and, more generally, the relationship between development and evolution. Herein, we assume a hierarchical, modular structure of trait development and consider how epigenetic interactions among modules during ontogeny affect patterns of phenotypic and genetic variation. We explore two developmental models, one in which the epigenetic interactions between modules result in additive effects on character expression and a second model in which these epigenetic interactions produce nonadditive effects. Using a phenotype landscape approach, we show how changes in the developmental processes underlying phenotypic expression can alter the magnitude and pattern of quantitative genetic variation. Additive epigenetic effects influence genetic variances and covariances, but allow trait means to evolve independently of the genetic variances and covariances, so that phenotypic evolution can proceed without changing the genetic covariance structure that determines future evolutionary response. Nonadditive epigenetic effects, however, can lead to evolution of genetic variances and covariances as the mean phenotype evolves. Our model suggests that an understanding of multivariate evolution can be considerably enriched by knowledge of the mechanistic basis of character development.     

WHY ONTOGENY MATTERS DURING ADAPTATION: DEVELOPMENTAL NICHE CONSTRUCTION AND PLEIOTORPY ACROSS THE LIFE CYCLE IN ARABIDOPSIS THALIANA

This case study of adaptation in Arabidopsis thaliana shows that natural selection on early life stages can be intense and can influence the evolution of subsequent traits. Two mechanisms contribute to this influence: pleiotropy across developmental stages and developmental niche construction. Examples are given of pleiotropy of environmentally cued development across life stages, and potential ways that pleiotropy can be relieved are discussed. In addition, this case study demonstrates how the timing of prior developmental transitions determines the seasonal environment experienced subsequently, and that such developmental niche construction alters phenotypic expression of subsequent traits, the expression of genetic variation of those traits, and natural selection on those traits and alleles associated with them. As such, developmental niche construction modifies pleiotropic relationships across the life cycle in ways that influence the dynamics of adaptation. Understanding the genetic basis of life‐cycle variation therefore requires consideration of environmental effects on pleiotropy.     

Genetic variance and covariance patterns of larval development in the small white butterflyPieris rapae crucivora Boisduval

Quantitative genetic theory indicates that genetic covariance patterns among life history characters should have played an important role as genetic constraint in life history evolution. Highly positve (and negative) genetic correlations between larval development time (or larval growth rate) and adult size characters were detected by means of sib analysis for the small white butterfly Pieris rapae crucivora. The genetic associations suggested that evolution of developmental characteristics and adult phenotypic traits were constrained by pleiotropy. The positive genetic correlations between development time and adult body size may be compatible with the trade-off between them, but the negative genetic correlations between larval growth rate and adult body size are not predicted from theories of optimal energy allocation. That phenotypic correlations drastically differed from the genetic correlations indicates limitations of evolutionary inferences based only on phenotypic variation.     

What affects the predictability of evolutionary constraints using a G‐matrix? The relative effects of modular pleiotropy and mutational correlation

Phenotypic traits do not always respond to selection independently from each other and often show correlated responses to selection. The structure of a genotype‐phenotype map (GP map) determines trait covariation, which involves variation in the degree and strength of the pleiotropic effects of the underlying genes. It is still unclear, and debated, how much of that structure can be deduced from variational properties of quantitative traits that are inferred from their genetic (co) variance matrix ( G ‐matrix). Here we aim to clarify how the extent of pleiotropy and the correlation among the pleiotropic effects of mutations differentially affect the structure of a G ‐matrix and our ability to detect genetic constraints from its eigen decomposition. We show that the eigenvectors of a G ‐matrix can be predictive of evolutionary constraints when they map to underlying pleiotropic modules with correlated mutational effects. Without mutational correlation, evolutionary constraints caused by the fitness costs associated with increased pleiotropy are harder to infer from evolutionary metrics based on a G ‐matrix's geometric properties because uncorrelated pleiotropic effects do not affect traits' genetic correlations. Correlational selection induces much weaker modular partitioning of traits' genetic correlations in absence then in presence of underlying modular pleiotropy.     

FISHER'S MODEL AND THE GENOMICS OF ADAPTATION: RESTRICTED PLEIOTROPY,HETEROGENOUS MUTATION,AND PARALLEL EVOLUTION

Genetic theories of adaptation generally overlook the genes in which beneficial substitutions occur, and the likely variation in their mutational effects. We investigate the consequences of heterogeneous mutational effects among loci on the genetics of adaptation. We use a generalization of Fisher's geometrical model, which assumes multivariate Gaussian stabilizing selection on multiple characters. In our model, mutation has a distinct variance–covariance matrix of phenotypic effects for each locus. Consequently, the distribution of selection coefficients s varies across loci. We assume each locus can only affect a limited number of independent linear combinations of phenotypic traits (restricted pleiotropy), which differ among loci, an effect we term “orientation heterogeneity.” Restricted pleiotropy can sharply reduce the overall proportion of beneficial mutations. Orientation heterogeneity has little impact on the shape of the genomic distribution, but can substantially increase the probability of parallel evolution (the repeated fixation of beneficial mutations at the same gene in independent populations), which is highest with low pleiotropy. We also consider variation in the degree of pleiotropy and in the mean s across loci. The latter impacts the genomic distribution of s, but has a much milder effect on parallel evolution. We discuss these results in the light of evolution experiments.     

Pleiotropic Effects of methoprene-tolerant(Met), a Gene Involved in Juvenile Hormone Metabolism, on Life History Traits in Drosophila melanogaster

Life history theory assumes that there are alleles with pleiotropic effects on fitness components. Although quantitative genetic data are often consistent with pleiotropy, there are few explicit examples of pleiotropic loci. The Drosophila melanogaster gene Methoprene-tolerant (Met) may be such a locus. The Met gene product, a putative juvenile hormone receptor, facilitates the action of juvenile hormone (JH) and JH analogs; JH affects many life history traits in arthropods. Here we use quantitative complementation to investigate effects of Met mutant and wildtype alleles on female developmental time, onset of reproduction, and fecundity. Whereas the alleles did not differ in their effects on developmental time, we detected allelic variation for the onset of reproduction and for age-specific fecundity. Alleles influenced phenotypic co-variances among traits (developmental time and onset of reproduction; onset of reproduction and both early and late fecundity; early and late fecundity), suggesting that alleles of Met vary in their pleiotropic effects upon life history. Furthermore, the genetic covariance between developmental time and early fecundity attributed to alleles of Met was negative, indicating consistent pleiotropic effects among alleles on these traits. The allelic effects of Met support genetic models where pleiotropy at genes associated with hormone regulation can contribute to the evolution of life history traits.     

Sexual conflict and gene expression: exploring sex-specific associations between fitness and transcriptional variation

In recent years, the field of evolutionary biology received a fresh impulse from the increased technical and logistical availability and cost-effectiveness of genomics techniques. In particular, we have for the first time the opportunity to effectively explore and understand the genetic basis of traits variation in laboratory (and ultimately wild) populations. Traits that are most relevant in evolutionary and ecological contexts (e.g. morphological, life-history and behavioural traits) typically show a complex genetic architecture, being affected by many loci with small effect. Such loci often interact with one another over the same trait (epistasis), affect several traits simultaneously (pleiotropy), and/or depend in their effects on the "environmental condition" in which they are expressed (genotype by environment interactions). Modern genomics offers tools, such as microarrays and high-throughput sequencing, to gather an unprecedented amount of data on gene expression and sequence variation, and can be used in the attempt to construct a genotype-phenotype map, linking genes (or gene networks), and the variation in their sequence and expression, with the natural variation of phenotypic characters.     

Fly wing evolution explained by a neutral model with mutational pleiotropy

To what extent the speed of mutational production of phenotypic variation determines the rate of long-term phenotypic evolution is a central question. Houle et al. recently addressed this question by studying the mutational variances, additive genetic variances, and macroevolution of locations of vein intersections on fly wings, reporting very slow phenotypic evolution relative to the rates of mutational input, high phylogenetic signals, and a strong, linear relationship between the mutational variance of a trait and its rate of evolution. Houle et al. found no existing model of phenotypic evolution to be consistent with all these observations, and proposed the improbable scenario of equal influence of mutational pleiotropy on all traits. Here, we demonstrate that the purported linear relationship between mutational variance and evolutionary divergence is artifactual. We further show that the data are explainable by a simple model in which the wing traits are effectively neutral at least within a range of phenotypic values but their evolutionary rates are differentially reduced because mutations affecting these traits are purged owing to their different pleiotropic effects on other traits that are under stabilizing selection. Thus, the evolutionary patterns of fly wing morphologies are explainable under the existing theoretical framework of phenotypic evolution.     

The role of pleiotropy and linkage in genes affecting a sexual ornament and bone allocation in the chicken

Sexual selection and the ornaments that inform such choices have been extensively studied, particularly from a phenotypic perspective. Although more is being revealed about the genetic architecture of sexual ornaments, much still remains to be discovered. The comb of the chicken is one of the most widely recognized sexual ornaments, which has been shown to be correlated with both fecundity and bone allocation. In this study, we use a combination of multiple intercrosses between White Leghorn populations and wild‐derived Red Junglefowl to, first, map quantitative trait loci (QTL) for bone allocation and, second, to identify expression QTL that correlate and colocalize with comb mass. These candidate quantitative genes were then assessed for potential pleiotropic effects on bone tissue and fecundity traits. We identify genes that correlate with both relative comb mass and bone traits suggesting a combination of both pleiotropy and linkage mediates gene regulatory variation in these traits.     

The genetic architecture of domestication in the chicken: effects of pleiotropy and linkage

The extent of pleiotropy and epistasis in quantitative traits remains equivocal. In the case of pleiotropy, multiple quantitative trait loci are often taken to be pleiotropic if their confidence intervals overlap, without formal statistical tests being used to ascertain if these overlapping loci are statistically significantly pleiotropic. Additionally, the degree to which the genetic correlations between phenotypic traits are reflected in these pleiotropic quantitative trait loci is often variable, especially in the case of antagonistic pleiotropy. Similarly, the extent of epistasis in various morphological, behavioural and life-history traits is also debated, with a general problem being the sample sizes required to detect such effects. Domestication involves a large number of trade-offs, which are reflected in numerous behavioural, morphological and life-history traits which have evolved as a consequence of adaptation to selective pressures exerted by humans and captivity. The comparison between wild and domestic animals allows the genetic analysis of the traits that differ between these population types, as well as being a general model of evolution. Using a large F(2) intercross between wild and domesticated chickens, in combination with a dense SNP and microsatellite marker map, both pleiotropy and epistasis were analysed. The majority of traits were found to segregate in 11 tight 'blocks' and reflected the trade-offs associated with domestication. These blocks were shown to have a pleiotropic 'core' surrounded by more loosely linked loci. In contrast, epistatic interactions were almost entirely absent, with only six pairs identified over all traits analysed. These results give insights both into the extent of such blocks in evolution and the development of domestication itself.     

The molecular population genetics of regulatory genes

Regulatory loci, which may encode both trans acting proteins as well as cis acting promoter regions, are crucial components of an organism's genetic architecture. Although evolution of these regulatory loci is believed to underlie the evolution of numerous adaptive traits, there is little information on natural variation of these genes. Recent molecular population genetic studies, however, have provided insights into the extent of natural variation at regulatory genes, the evolutionary forces that shape them and the phenotypic effects of molecular regulatory variants. These recent analyses suggest that it may be possible to study the molecular evolutionary ecology of regulatory diversification by examining both the extent and patterning of regulatory gene diversity, the phenotypic effects of molecular variation at these loci and their ecological consequences.     

METAMODELS AND PHYLOGENETIC REPLICATION: A SYSTEMATIC APPROACH TO THE EVOLUTION OF DEVELOPMENTAL PATHWAYS

Molecular genetic analysis of phenotypic variation has revealed many examples of evolutionary change in the developmental pathways that control plant and animal morphology. A major challenge is to integrate the information from diverse organisms and traits to understand the general patterns of developmental evolution. This integration can be facilitated by evolutionary metamodels—traits that have undergone multiple independent changes in different species and whose development is controlled by well-studied regulatory pathways. The metamodel approach provides the comparative equivalent of experimental replication, allowing us to test whether the evolution of each developmental pathway follows a consistent pattern, and whether different pathways are predisposed to different modes of evolution by their intrinsic organization. A review of several metamodels suggests that the structure of developmental pathways may bias the genetic basis of phenotypic evolution, and highlights phylogenetic replication as a value-added approach that produces deeper insights into the mechanisms of evolution than single-species analyses.     

A model of developmental evolution: selection, pleiotropy and compensation

Development and physiology translate genetic variation into phenotypic variation and determine the genotype-phenotype map, such as which gene affects which character (pleiotropy). Any genetic change in this mapping reflects a change in development. Here, we discuss evidence for variation in pleiotropy and propose the selection, pleiotropy and compensation model (SPC) for adaptive evolution. It predicts that adaptive change in one character is associated with deleterious pleiotropy in others and subsequent selection to compensate for these pleiotropic effects. The SPC model provides a unifying perspective for a variety of puzzling phenomena, including developmental systems drift and character homogenization. The model suggests that most adaptive signatures detected in genome scans could be the result of compensatory changes, rather than of progressive character adaptations.     

Phenotypic variation and covariation indicate high evolvability of acoustic communication in crickets

Studying the genetic architecture of sexual traits provides insight into the rate and direction at which traits can respond to selection. Traits associated with few loci and limited genetic and phenotypic constraints tend to evolve at high rates typically observed for secondary sexual characters. Here, we examined the genetic architecture of song traits and female song preferences in the field crickets Gryllus rubens and Gryllus texensis. Song and preference data were collected from both species and interspecific F1 and F2 hybrids. We first analysed phenotypic variation to examine interspecific differentiation and trait distributions in parental and hybrid generations. Then, the relative contribution of additive and additive‐dominance variation was estimated. Finally, phenotypic variance–covariance ( P ) matrices were estimated to evaluate the multivariate phenotype available for selection. Song traits and preferences had unimodal trait distributions, and hybrid offspring were intermediate with respect to the parents. We uncovered additive and dominance variation in song traits and preferences. For two song traits, we found evidence for X‐linked inheritance. On the one hand, the observed genetic architecture does not suggest rapid divergence, although sex linkage may have allowed for somewhat higher evolutionary rates. On the other hand, P matrices revealed that multivariate variation in song traits aligned with major dimensions in song preferences, suggesting a strong selection response. We also found strong covariance between the main traits that are sexually selected and traits that are not directly selected by females, providing an explanation for the striking multivariate divergence in male calling songs despite limited divergence in female preferences.     

Variation and constraint in plant evolution and development

The goal of this short review is to consider the interrelated phenomena of phenotypic variation and genetic constraint with respect to plant diversity. The unique aspects of plants, including sessile habit, modular growth and diverse developmental programs expressed at the phytomer level, merit a specific examination of the genetic basis of their phenotypic variation, and how they experience and escape genetic constraint. Numerous QTL studies with wild and domesticated plants reveal that most phenotypic traits are polygenic but vary in the number and effect of the loci contributing, from a few loci of large effects to many with small effects. Further, somatic mutations, developmental plasticity and epigenetic variation, especially gene methylation, can contribute to increases in phenotypic variation. The flip side of these processes, genetic constraint, can similarly be the result of many factors, including pleiotropy, canalization and genetic redundancy. Genetic constraint is not only a mechanism to prevent change, however, it can also serve to direct evolution along certain paths. Ultimately, genetic constraint often comes full circle and is released through events such as hybridization, genome duplication and epigenetic remodeling. We are just beginning to understand how these processes can operate simultaneously during the evolution of ecologically important traits in plants.     

The beak of the other finch: coevolution of genetic covariance structure and developmental modularity during adaptive evolution

The link between adaptation and evolutionary change remains the most central and least understood evolutionary problem. Rapid evolution and diversification of avian beaks is a textbook example of such a link, yet the mechanisms that enable beak''s precise adaptation and extensive adaptability are poorly understood. Often observed rapid evolutionary change in beaks is particularly puzzling in light of the neo-Darwinian model that necessitates coordinated changes in developmentally distinct precursors and correspondence between functional and genetic modularity, which should preclude evolutionary diversification. I show that during first 19 generations after colonization of a novel environment, house finches (Carpodacus mexicanus) express an array of distinct, but adaptively equivalent beak morphologies—a result of compensatory developmental interactions between beak length and width in accommodating microevolutionary change in beak depth. Directional selection was largely confined to the elimination of extremes formed by these developmental interactions, while long-term stabilizing selection along a single axis—beak depth—was mirrored in the structure of beak''s additive genetic covariance. These results emphasize three principal points. First, additive genetic covariance structure may represent a historical record of the most recurrent developmental and functional interactions. Second, adaptive equivalence of beak configurations shields genetic and developmental variation in individual components from depletion by natural selection. Third, compensatory developmental interactions among beak components can generate rapid reorganization of beak morphology under novel conditions and thus greatly facilitate both the evolution of precise adaptation and extensive diversification, thereby linking adaptation and adaptability in this classic example of Darwinian evolution.     

Reduce, reuse, and recycle: developmental evolution of trait diversification

A major focus of evolutionary developmental (evo-devo) studies is to determine the genetic basis of variation in organismal form and function, both of which are fundamental to biological diversification. Pioneering work on metazoan and flowering plant systems has revealed conserved sets of genes that underlie the bauplan of organisms derived from a common ancestor. However, the extent to which variation in the developmental genetic toolkit mirrors variation at the phenotypic level is an active area of research. Here we explore evidence from the angiosperm evo-devo literature supporting the frugal use of genes and genetic pathways in the evolution of developmental patterning. In particular, these examples highlight the importance of genetic pleiotropy in different developmental modules, thus reducing the number of genes required in growth and development, and the reuse of particular genes in the parallel evolution of ecologically important traits.     

Genotype-Phenotype Maps Maximizing Evolvability: Modularity Revisited

The mechanisms translating genetic to phenotypic variation determine the distribution of heritable phenotypic variance available to selection. Pleiotropy is an aspect of this structure that limits independent variation of characters. Modularization of pleiotropy has been suggested to promote evolvability by restricting genetic covariance among unrelated characters and reducing constraints due to correlated response. However, modularity may also reduce total genetic variation of characters. We study the properties of genotype-phenotype maps that maximize average conditional evolvability, measured as the amount of unconstrained genetic variation in random directions of phenotypic space. In general, maximal evolvability occurs by maximizing genetic variance and minimizing genetic covariance. This does not necessarily require modularity, only patterns of pleiotropy that cancel on average. The detailed structure of the most evolvable genotype-phenotype maps depends on the distribution of molecular variance. When molecular variance is determined by mutation-selection equilibrium either highly pleiotropic or highly modular genotype-phenotype maps can be optimal, depending on the mutation rate and the relative strengths of stabilizing selection on the characters.