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

Abstract

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.

Figure 1

Interaction effect resulting in the variation in the relationship between two traits. A) The effect of interaction on univariate trait-variance within genotype classes at a rQTL A. Note that the interaction effect can be due to another locus (i.e., epistasis, here with locus B), or due to environment (an allele having different effects in different environments). Different lines represent different genotypes at the interacting locus B. B) Simultaneous effect of the interaction with locus A on two traits. Note that interaction affects the rQTL-genotype differently for the two traits, causing the relationship between the two variances to vary across the genotypes at locus A, as shown in C). C) The lines represent regression lines of trait 2 on trait 1. The slopes vary depending on the genotype at the rQTL A.

Figure 2

Mechanistic model for the appearance of rQTL-type variation in pleiotropy. A) The single gene product is involved in two pathways, in this example determining the color and the growth (size) of the yeast colony. There is no genetic variation (“wildtype”). The resulting colony is white and large. B) A mutation happens at the pleiotropic locus that affects both pathways, resulting in a change in both traits: the phenotype is a slow-growing, orange colony. C) A compensatory mutation occurs in one of the pathways, affecting the result of one, but not another pathway. The colony hence manifests mutated color, but “wildtype” growth rate (it is not necessarily a fully compensating mutation, but it causes variation that is independent of the other trait).

Figure 3

Venn diagrams illustrating the numbers of trait-specific and overlapping interactions, separately for each trait relationship. All presented interactions involve rQTL. Note that in all cases, the number of trait-specific interactions is higher than the number of overlapping ones.

Figure 4

Distribution of average epistatic factors across loci for each trait. A) Each box in a box plot represents the distribution of average weighed epistatic factors, where weighed averages were calculated within the subset of interactions with single rQTL. Thus boxes show the distribution of average epistatic modifications of rQTL. B) Each box in a plot represents the distribution of average modifications due to epistasis across general interactions (not limited to rQTL). The widths of the boxes are proportional to the number of loci included. lt: length, wt: weight.