Unraveling the layers of cryptic genetic variation in a yeast gene regulatory network

Cryptic genetic variation may be an important contributor to heritable traits, but its extent and regulation are not fully understood. Here, we investigate the cryptic variation underlying a Saccharomyces cerevisiae colony phenotype that is typically suppressed in a cross. Mapping of the trait9s genetic basis after induction by three different genetic perturbations identifies 21 total loci. The perturbations largely uncover distinct loci, and strongly influence additivity, epistasis, and genotype-environment interaction among these loci. Only a single locus—the coding region of the cell surface gene FLO11 —is common to all three perturbations. While the remaining loci mostly influence FLO11 transcription in cis or trans , we detect loci in different pathways and sub-pathways in the presence of each perturbation. Our work shows that complex gene regulatory networks can harbor multiple layers of cryptic variation, each of which may only be visible in highly specific genotypic and environmental contexts.