Hypothetical examples of two genes regulated by a single SNP mirroring our observations for (A) down-regulated (putative causal genes) and (B) up-regulated genes. The effect size of the regulatory variant decreases over time, which leads to the down-regulation of gene expression (dashed green and blue lines). The lower effect size implies that the variance explained by the regulatory variant decreased over time, which leads to a loss of heritability (assuming constant environmental variance). Due to the change in effect size of the regulatory variant, the change in gene expression is genotype-dependent (red bars with arrows) (A). The effect size of the regulatory variant is stable over time, but the mean environmental effect on gene expression increases, which implies that gene expression is up-regulated. Assuming that the environmental variance is not changing, the heritability of gene expression remains stable and the heritability of the change is low (red bars with arrows) (B).
