Variation in the modality of a yeast signaling pathway is mediated by a single regulator

Bimodal gene expression by genetically identical cells is a pervasive feature of signaling networks and has been suggested to allow organisms to hedge their ‘bets’ in uncertain conditions. In the galactose-utilization (GAL) pathway of Saccharomyces cerevisiae, gene induction is unimodal or bimodal depending on natural genetic variation and pre-induction conditions. Here, we find that this variation in modality arises from regulation of two features of the pathway response: the fraction of cells that show induction and their level of expression. GAL3, the galactose sensor, controls the fraction of induced cells, and titrating its expression is sufficient to control modality; moreover, all the observed differences in modality between different pre-induction conditions and among natural isolates can be explained by changes in GAL3’s regulation and activity. The ability to switch modality by tuning the activity of a single protein may allow rapid adaptation of bet hedging to maximize fitness in complex environments.