Fitness Tradeoffs, Bimodality, and the Genetics of Natural Variation in Glucose-Galactose Sensing Across Saccharomyces Cerevisiae

Abstract

In nature, cells must constantly sense their environment and respond appropriately. These cellular “decisions” are implemented by molecular components that can mutate and evolve. How do mutations lead to changes in cellular decision-making? How do the decisions made by cells affect their fitness? This thesis explores these questions by examining the same metabolic decision made by geographically and ecologically diverse strains of Saccharomyces cerevisiae (budding yeast). When yeast encounter a mixture of the sugars glucose and galactose, they utilize glucose while repressing galactose-utilization (GAL) genes. When glucose is exhausted, cells undergo a “diauxic lag” while inducing GAL genes, and then resume growth on galactose. We found that some yeast strains can induce GAL genes before glucose is exhausted, which reduces their diauxic lag but imposes an initial growth cost. The degree of pre-induction depends on the sugar-sensing threshold of the GAL circuit, which we map to a natural allelic series of the signaling gene GAL3. However, because the GAL response is bimodal, we find that GAL3 alleles only modulate the fraction of cells that induced in a given condition, while the expression level attained by those induced cells is tuned by alleles of other genes. Overall, our results reveal the repertoire of mutations that can quantitatively tune a cellular decision in nature, as well as the downstream effects of this tuning on physiology and fitness.