Pleiotropic effects on mandibular morphology II: differential epistasis and genetic variation in morphological integration

The evolution of morphological modularity through the sequestration of pleiotropy to sets of functionally and developmentally related traits requires genetic variation in the relationships between traits. Genetic variation in relationships between traits can result from differential epistasis, where epistatic relationships for pairs of loci are different for different traits. This study maps relationship quantitative trait loci (QTLs), specifically QTLs that affect the relationship between individual mandibular traits and mandible length, across the genome in an F2 intercross of the LG/J and SM/J inbred mouse strains (N = 1045). We discovered 23 relationship QTLs scattered throughout the genome. All mandibular traits were involved in one or more relationship QTL. When multiple traits were affected at a relationship QTL, the traits tended to come from a developmentally restricted region of the mandible, either the muscular processes or the alveolus. About one-third of the relationship QTLs correspond to previously located trait QTLs affecting the same traits. These results comprise examples of genetic variation necessary for an evolutionary response to selection on the range of pleiotropic effects.     

The contribution of epistatic pleiotropy to the genetic architecture of covariation among polygenic traits in mice

The contribution that pleiotropic effects of individual loci make to covariation among traits is well understood theoretically and is becoming well documented empirically. However, little is known about the role of epistasis in determining patterns of covariation among traits. To address this problem we combine a quantitative trait locus (QTL) analysis with a two-locus model to assess the contribution of epistasis to the genetic architecture of variation and covariation of organ weights and limb bone lengths in a backcross population of mice created from the M16i and CAST/Ei strains. Significant epistasis was exhibited by 14 pairwise combinations of QTL for organ weights and 10 combinations of QTL for limb bone lengths, which contributed, on average, about 5% of the variation in organ weights and 8% in limb bone lengths beyond that of single-locus QTL effects. Epistatic pleiotropy was much more common in the limb bones (seven of 10 epistatic combinations affecting limb bone lengths were pleiotropic) than the organs (three of the 14 epistatic combinations affecting organ weights were pleiotropic). In both cases, epistatic pleiotropy was less common than single-locus pleiotropy. Epistatic pleiotropy accounted for an average of 6% of covariation among organ weights and 21% of covariation among limb bone lengths, which represented an average of one-fifth (for organ weights) and one-third (for limb bone lengths) of the total genetic covariance between traits. Thus, although epistatic pleiotropy made a smaller contribution than single-locus pleiotropy, it clearly made a significant contribution to the genetic architecture of variation/covariation.     

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.     

Evolution of pleiotropy: epistatic interaction pattern supports a mechanistic model underlying variation in genotype-phenotype map

The genotype-phenotype (GP) map consists of developmental and physiological mechanisms mapping genetic onto phenotypic variation. It determines the distribution of heritable phenotypic variance on which selection can act. Comparative studies of morphology as well as of gene regulatory networks show that the GP map itself evolves, yet little is known about the actual evolutionary mechanisms involved. The study of such mechanisms requires exploring the variation in GP maps at the population level, which presently is easier to quantify by statistical genetic methods rather than by regulatory network structures. We focus on the evolution of pleiotropy, a major structural aspect of the GP map. Pleiotropic genes affect multiple traits and underlie genetic covariance between traits, often causing evolutionary constraints. Previous quantitative genetic studies have demonstrated population-level variation in pleiotropy in the form of loci, at which genotypes differ in the genetic covariation between traits. This variation can potentially fuel evolution of the GP map under selection and/or drift. Here, we propose a developmental mechanism underlying population genetic variation in covariance and test its predictions. Specifically, the mechanism predicts that the loci identified as responsible for genetic variation in pleiotropy are involved in trait-specific epistatic interactions. We test this prediction for loci affecting allometric relationships between traits in an advanced intercross between inbred mouse strains. The results consistently support the prediction. We further find a high degree of sign epistasis in these interactions, which we interpret as an indication of adaptive gene complexes within the diverged parental lines.     

Epistatic interactions of genes influence within-individual variation of physical activity traits in mice

A number of quantitative trait loci (QTLs) recently have been discovered that affect various activity traits in mice, but their collective impact does not appear to explain the consistently moderate to high heritabilities for these traits. We previously suggested interactions of genes, or epistasis, might account for additional genetic variability of activity, and tested this for the average distance, duration and speed run by mice during a 3 week period. We found abundant evidence for epistasis affecting these traits, although, recognized that epistatic effects may well vary within individuals over time. We therefore conducted a full genome scan for epistatic interactions affecting these traits in each of seven three-day intervals. Our intent was to assess the extent and trends in epistasis affecting these traits in each of the intervals. We discovered a number of epistatic interactions of QTLs that influenced the activity traits in the mice, the majority of which were not previously found and appeared to affect the activity traits (especially distance and speed) primarily in the early or in the late age intervals. The overall impact of epistasis was considerable, its contribution to the total phenotypic variance varying from an average of 22–35% in the three traits across all age intervals. It was concluded that epistasis is more important than single-locus effects of genes on activity traits at specific ages and it is therefore an essential component of the genetic architecture of physical activity.     

Natural variation in the genetic architecture of a host-parasite interaction in the bumblebee Bombus terrestris

The genetic architecture of fitness-relevant traits in natural populations is a topic that has remained almost untouched by quantitative genetics. Given the importance of parasitism for the host's fitness, we used QTL mapping to study the genetic architecture of traits relevant for host-parasite interactions in the trypanosome parasite, Crithidia bombi and its host, Bombus terrestris. The three traits analysed were the parasite's infection intensity, the strength of the general immune response (measured as the encapsulation of a novel antigen) and body size. The genetic architecture of these traits was examined in three natural, unmanipulated mapping populations of B. terrestris. Our results indicate that the intracolonial phenotypic variation of all three traits is based on a network of QTLs and epistatic interactions. While these networks are similar between mapping populations in complexity and number of QTLs, as well as in their epistatic interactions, the variability in the position of QTL and the interacting loci was high. Only one QTL for body size was plausibly found in at least two populations. QTLs for encapsulation and Crithidia infection intensity were located on the same linkage groups.     

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.     

An epistatic genetic basis for fluctuating asymmetry of tooth size and shape in mice

Although there typically is little additive genetic variation for fluctuating asymmetry (FA), or variation in nondirectional differences between left and right sides of bilateral characters, several investigators have hypothesized that FA may have an epistatic genetic basis. We tested this hypothesis by conducting a whole genome scan of FA of size and shape of the mandibular molars in house mice from an F2 intercross population generated from crossing the Large (LG/J) and Small (SM/J) inbred strains. Although no individual genes (QTLs=quantitative trait loci) on any of the 19 autosomes significantly affected FA for centroid size, and only two affected shape FA, a number of pairwise combinations of QTLs exhibited significant epistasis for FA in both molar size and shape. The QTLs involved in these interactions differed for FA in molar size versus FA in molar shape, but their epistatic contributions to the total variance was nearly the same (about 20%) for FA in both molar characters. It was noted that the genetic architecture of FA in the molar characters, consisting of little or no additive genetic variance but an abundance of epistatic genetic variance, is consistent with that of other typical fitness components such as litter size.     

Genetic variation in the pleiotropic association between physical activity and body weight in mice

Background

A sedentary lifestyle is often assumed to lead to increases in body weight and potentially obesity and related diseases but in fact little is known about the genetic association between physical activity and body weight. We tested for such an association between body weight and the distance, duration, and speed voluntarily run by 310 mice from the F₂ generation produced from an intercross of two inbred lines that differed dramatically in their physical activity levels.

Methods

We used a conventional interval mapping approach with SNP markers to search for QTLs that affected both body weight and activity traits. We also conducted a genome scan to search for relationship QTLs (relQTLs), or chromosomal regions that affected an activity trait variably depending on the phenotypic value of body weight.

Results

We uncovered seven quantitative trait loci (QTLs) affecting body weight, but only one co-localized with another QTL previously found for activity traits. We discovered 19 relQTLs that provided evidence for a genetic (pleiotropic) association of physical activity and body weight. The three genotypes at each of these loci typically exhibited a combination of negative, zero, and positive regressions of the activity traits on body weight, the net effect of which was to produce overall independence of body weight from physical activity. We also demonstrated that the relQTLs produced these varying associations through differential epistatic interactions with a number of other epistatic QTLs throughout the genome.

Conclusion

It was concluded that individuals with specific combinations of genotypes at the relQTLs and epiQTLs might account for some of the variation typically seen in plots of the association of physical activity with body weight.     

Genetic architecture of adiposity in the cross of LG/J and SM/J inbred mice

The genetic basis of variation in obesity in human populations is thought to be owing to many genes of relatively small effect and their interactions. The LG/J by SM/J intercross of mouse inbred strains provides an excellent model system in which to investigate multigenic obesity. We previously mapped a large number of quantitative trait loci (QTLs) affecting adult body weight in this cross. We map body composition traits, adiposity, and skeletal size, in a replicate F₂ intercross of the same two strains containing 510 individuals. Using interval-mapping methods, we located eight QTLs affecting adiposity (Adip1–8). Two of these adiposity loci also affected tail length (Adip4 and Adip6) along with seven additional tail length QTLs (Skl1–7). A further four QTLs (Wt1–4) affect adult weight but not body composition. These QTLs have relatively small effects, typically about 0.2–0.4 standard deviation units, and account for between 3% and 10% of the variance in individual characters. All QTLs participated in epistatic interactions with other QTLs. Most of these interactions were due to additive-by-additive epistasis, which can nullify the apparent effects of single loci in our population. Adip8 interacts with all the other adiposity QTLs and seems to play a central role in the genetic system affecting obesity in this cross. Only two adiposity QTLs, Adip4 and Adip6, also affect tail length, indicating largely separate genetic control of variation in adiposity and skeletal size. Body size and obesity QTLs in the same locations as those discovered here are commonly found in mapping experiments with other mouse strains. Received: 11 January 2000 / Accepted: 17 August 2000     

Signals of demographic expansion in Drosophila virilis

Background

The antagonistic co-evolution of hosts and their parasites is considered to be a potential driving force in maintaining host genetic variation including sexual reproduction and recombination. The examination of this hypothesis calls for information about the genetic basis of host-parasite interactions – such as how many genes are involved, how big an effect these genes have and whether there is epistasis between loci. We here examine the genetic architecture of quantitative resistance in animal and plant hosts by concatenating published studies that have identified quantitative trait loci (QTL) for host resistance in animals and plants.

Results

Collectively, these studies show that host resistance is affected by few loci. We particularly show that additional epistatic interactions, especially between loci on different chromosomes, explain a majority of the effects. Furthermore, we find that when experiments are repeated using different host or parasite genotypes under otherwise identical conditions, the underlying genetic architecture of host resistance can vary dramatically – that is, involves different QTLs and epistatic interactions. QTLs and epistatic loci vary much less when host and parasite types remain the same but experiments are repeated in different environments.

Conclusion

This pattern of variability of the genetic architecture is predicted by strong interactions between genotypes and corroborates the prevalence of varying host-parasite combinations over varying environmental conditions. Moreover, epistasis is a major determinant of phenotypic variance for host resistance. Because epistasis seems to occur predominantly between, rather than within, chromosomes, segregation and chromosome number rather than recombination via cross-over should be the major elements affecting adaptive change in host resistance.     

Epistasis plays an important role as genetic basis of heterosis in rice

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Bayesian analyses of multiple epistatic QTL models for body weight and body composition in mice

To comprehensively investigate the genetic architecture of growth and obesity, we performed Bayesian analyses of multiple epistatic quantitative trait locus (QTL) models for body weights at five ages (12 days, 3, 6, 9 and 12 weeks) and body composition traits (weights of two fat pads and five organs) in mice produced from a cross of the F1 between M16i (selected for rapid growth rate) and CAST/Ei (wild-derived strain of small and lean mice) back to M16i. Bayesian model selection revealed a temporally regulated network of multiple QTL for body weight, involving both strong main effects and epistatic effects. No QTL had strong support for both early and late growth, although overlapping combinations of main and epistatic effects were observed at adjacent ages. Most main effects and epistatic interactions had an opposite effect on early and late growth. The contribution of epistasis was more pronounced for body weights at older ages. Body composition traits were also influenced by an interacting network of multiple QTLs. Several main and epistatic effects were shared by the body composition and body weight traits, suggesting that pleiotropy plays an important role in growth and obesity.     

The extent and genetic basis of phenotypic divergence in life history traits in Mimulus guttatus

Differential natural selection acting on populations in contrasting environments often results in adaptive divergence in multivariate phenotypes. Multivariate trait divergence across populations could be caused by selection on pleiotropic alleles or through many independent loci with trait‐specific effects. Here, we assess patterns of association between a suite of traits contributing to life history divergence in the common monkey flower, Mimulus guttatus, and examine the genetic architecture underlying these correlations. A common garden survey of 74 populations representing annual and perennial strategies from across the native range revealed strong correlations between vegetative and reproductive traits. To determine whether these multitrait patterns arise from pleiotropic or independent loci, we mapped QTLs using an approach combining high‐throughput sequencing with bulk segregant analysis on a cross between populations with divergent life histories. We find extensive pleiotropy for QTLs related to flowering time and stolon production, a key feature of the perennial strategy. Candidate genes related to axillary meristem development colocalize with the QTLs in a manner consistent with either pleiotropic or independent QTL effects. Further, these results are analogous to previous work showing pleiotropy‐mediated genetic correlations within a single population of M. guttatus experiencing heterogeneous selection. Our findings of strong multivariate trait associations and pleiotropic QTLs suggest that patterns of genetic variation may determine the trajectory of adaptive divergence.     

Impact of epistasis and pleiotropy on evolutionary adaptation

Evolutionary adaptation is often likened to climbing a hill or peak. While this process is simple for fitness landscapes where mutations are independent, the interaction between mutations (epistasis) as well as mutations at loci that affect more than one trait (pleiotropy) are crucial in complex and realistic fitness landscapes. We investigate the impact of epistasis and pleiotropy on adaptive evolution by studying the evolution of a population of asexual haploid organisms (haplotypes) in a model of N interacting loci, where each locus interacts with K other loci. We use a quantitative measure of the magnitude of epistatic interactions between substitutions, and find that it is an increasing function of K. When haplotypes adapt at high mutation rates, more epistatic pairs of substitutions are observed on the line of descent than expected. The highest fitness is attained in landscapes with an intermediate amount of ruggedness that balance the higher fitness potential of interacting genes with their concomitant decreased evolvability. Our findings imply that the synergism between loci that interact epistatically is crucial for evolving genetic modules with high fitness, while too much ruggedness stalls the adaptive process.     

Bayesian mapping of multiple traits in maize: the importance of pleiotropic effects in studying the inheritance of quantitative traits

Pleiotropy has played an important role in understanding quantitative traits. However, the extensiveness of this effect in the genome and its consequences for plant improvement have not been fully elucidated. The aim of this study was to identify pleiotropic quantitative trait loci (QTLs) in maize using Bayesian multiple interval mapping. Additionally, we sought to obtain a better understanding of the inheritance, extent and distribution of pleiotropic effects of several components in maize production. The design III procedure was used from a population derived from the cross of the inbred lines L-14-04B and L-08-05F. Two hundred and fifty plants were genotyped with 177 microsatellite markers and backcrossed to both parents giving rise to 500 backcrossed progenies, which were evaluated in six environments for grain yield and its components. The results of this study suggest that mapping isolated traits limits our understanding of the genetic architecture of quantitative traits. This architecture can be better understood by using pleiotropic networks that facilitate the visualization of the complexity of quantitative inheritance, and this characterization will help to develop new selection strategies. It was also possible to confront the idea that it is feasible to identify QTLs for complex traits such as grain yield, as pleiotropy acts prominently on its subtraits and as this "trait" can be broken down and predicted almost completely by the QTLs of its components. Additionally, pleiotropic QTLs do not necessarily signify pleiotropy of allelic interactions, and this indicates that the pervasive pleiotropy does not limit the genetic adaptability of plants.     

An epistatic genetic basis for physical activity traits in mice

We recently identified several (4-8) quantitative trait loci (QTL) for 3 physical activity traits (daily distance, duration, and speed voluntarily run) in an F(2) population of mice derived from an original intercross of 2 strains that exhibited large differences in activity. These QTL cumulatively explained from 11% to 34% of the variation in these traits, but this was considerably less than their total genetic variability estimated from differences among inbred strains. We therefore decided to test whether epistatic interactions might account for additional genetic variation in these traits in this same population of mice. We conducted a full genome epistasis scan for all possible interactions of QTL between each pair of 20 chromosomes. The results of this scan revealed an abundance of epistasis, with QTL throughout the genome being involved in significant interactions. Overall, epistatic effects contributed an average of 26% of the total variation among the 3 activity traits. These results suggest that epistatic interactions of genes may play as important a role in the genetic architecture of physical activity traits as single-locus effects and need to be considered in future candidate gene identification studies.     

Both additivity and epistasis control the genetic variation for fruit quality traits in tomato

The effect of a gene involved in the variation of a quantitative trait may change due to epistatic interactions with the overall genetic background or with other genes through digenic interactions. The classical populations used to map quantitative trait loci (QTL) are poorly efficient to detect epistasis. To assess the importance of epistasis in the genetic control of fruit quality traits, we compared 13 tomato lines having the same genetic background except for one to five chromosome fragments introgressed from a distant line. Six traits were assessed: fruit soluble solid content, sugar content and titratable acidity, fruit weight, locule number and fruit firmness. Except for firmness, a large part of the variation of the six traits was under additive control, but interactions between QTL leading to epistasis effects were common. In the lines cumulating several QTL regions, all the significant epistatic interactions had a sign opposite to the additive effects, suggesting less than additive epistasis. Finally the re-examination of the segregating population initially used to map the QTL confirmed the extent of epistasis, which frequently involved a region where main effect QTL have been detected in this progeny or in other studies.