Genetic effects at pleiotropic loci are context-dependent with consequences for the maintenance of genetic variation in populations

Abstract

Context-dependent genetic effects, including genotype-by-environment and genotype-by-sex interactions, are a potential mechanism by which genetic variation of complex traits is maintained in populations. Pleiotropic genetic effects are also thought to play an important role in evolution, reflecting functional and developmental relationships among traits. We examine context-dependent genetic effects at pleiotropic loci associated with normal variation in multiple metabolic syndrome (MetS) components (obesity, dyslipidemia, and diabetes-related traits). MetS prevalence is increasing in Western societies and, while environmental in origin, presents substantial variation in individual response. We identify 23 pleiotropic MetS quantitative trait loci (QTL) in an F(16) advanced intercross between the LG/J and SM/J inbred mouse strains (Wustl:LG,SM-G16; n = 1002). Half of each family was fed a high-fat diet and half fed a low-fat diet; and additive, dominance, and parent-of-origin imprinting genotypic effects were examined in animals partitioned into sex, diet, and sex-by-diet cohorts. We examine the context-dependency of the underlying additive, dominance, and imprinting genetic effects of the traits associated with these pleiotropic QTL. Further, we examine sequence polymorphisms (SNPs) between LG/J and SM/J as well as differential expression of positional candidate genes in these regions. We show that genetic associations are different in different sex, diet, and sex-by-diet settings. We also show that over- or underdominance and ecological cross-over interactions for single phenotypes may not be common, however multidimensional synthetic phenotypes at loci with pleiotropic effects can produce situations that favor the maintenance of genetic variation in populations. Our findings have important implications for evolution and the notion of personalized medicine.

Figure 1. Context-dependent genetic effects at DMetS1b.

Each single trait's genotypic value is represented on the y-axis, and the genotypes are represented on the x-axis. The different values reflect the different traits’ and cohorts’ different genotypic means. All of these traits map to the same genomic locus, however the cohort-specific genetic effects among these traits are highly context dependent, as illustrated in the patterns of the genotypic means. For cholesterol, there is an additive effect in the full population (A). For gonadal fatpad weight, high-fat fed females have bipolar dominance imprinting (B). For total fatpad weight, high-fat fed females have bipolar dominance imprinting and high-fat fed males have an additive effect (C). For free-fatty acid levels, in addition to additive effects, high-fat fed females have maternal expression imprinting, low-fat fed females have paternal expression imprinting, and high-fat fed males have polar dominance imprinting. Low fat-fed males have underdominance effects with no additive or imprinting effects (D). ***p≤0.001, **p≤0.01, *p≤0.05.

Figure 2. Differential dominance at DMetS6c.

Variation in d/a ratios (dominance:additive genotypic values) between the two traits leads to differential dominance at this locus. Here the reciprocal heterozygotes have been pooled for simplicity because there are no significant imprinting effects at this locus. The two traits display antagonistic pleiotropy, meaning the additive genotypic values are significantly different between the two traits (A). Antagonistic pleiotropy is an example of a multidimensional synthetic crossing-over interaction, wherein the ranks of the homozygote genotypes change in different environments for some multivariate combination of traits. In this example the traits are serum glucose levels in low-fat fed females and serum insulin levels in high-fat fed males. In panel 2.B, the additive and dominance genotypic values for the homozygotes (LL and SS) and the heterozygotes (pooled LS and SL) have been standardized for graphical representation. The standardized insulin genotypic means in high-fat fed males are represented on the y-axis and the standardized glucose genotypic means in low-fat fed females are represented on the x-axis. The heterozygote values do not fall at the midpoint of the additive vector as expected under within-locus additivity. Directional selection on the orthogonal overdominance (represented by pooled LS and SL genotypic values) vector, for lower glucose and insulin levels, could result in balancing selection and maintenance of variation at this locus (B). ***p≤0.001, **p≤0.01, *p≤0.05.

Figure 3. Crossing interactions at single traits comprising pleiotropic QTL.

Significant crossing interactions, where the homozygote genotypic values change rank between environments (here diet and/or sex environment) for a trait, were found at 4 QTL. These genotype-by-environmental interactions, while rare, are consistent with an evolutionary ‘ecological cross-over’ hypothesis. Crossing interactions can act to maintain allelic variation at a locus.

Figure 4. A scenario of fitness between traits at a pleiotropic locus.

When considering differential dominance effects (as seen at DMetS6c) and the relationship not only among the genotypes, but also between insulin and glucose (as illustrated in Figure 2b), it is tempting to speculate that directional selection for the synthetic trait of “fitness” could result in balancing selection at a locus that would favor alleles contributing to low levels of both insulin and glucose. This is illustrated in the ‘Ideal’ quadrant representing relatively low levels of both insulin and glucose.