Pleiotropic effects of trans-regulatory mutations on gene expression and fitness

Variation in gene expression arises from cis- and trans-regulatory mutations, which contribute differentially to expression divergence. Here, we compare the impacts on gene expression and fitness for cis- and trans-regulatory mutations affecting expression of the TDH3 gene in Saccharomyces cerevisiae. We use the effects of cis-regulatory mutations to isolate effects of trans-regulatory mutations caused by impacts on TDH3 from pleiotropic impacts on other genes, providing a rare distribution of pleiotropic effects. These pleiotropic effects were often, but not always, deleterious. For cis- and trans-regulatory mutations with similar effects on TDH3, trans-regulatory mutations had more widespread effects on gene expression, with distinct impacts on expression of genes downstream of TDH3. These differences between cis-and trans-regulatory mutations help explain their different contributions to regulatory evolution.