Design Principles of Signal Integration and Robustness in Saccharomyces Cerevisiae

Abstract

All cells must integrate conflicting information and choose an appropriate response in order to function. To consider this, one can examine the simplest scenario of binary choice: given two options, what signaling mechanisms enable cells choose between them, and what are they robust to? Saccharomyces cerevisiae, a well-studied model organism, provides a tractable model system in which to begin to answer these questions. This thesis focuses on two distinct lines of investigation with a common goal of elucidating the basics of cellular decision-making. In the first, we examine the decision-making mechanisms at play in the galactose-utilization (GAL) pathway. In mixtures of glucose and galactose, yeast must choose when to induce GAL genes to begin metabolizing galactose, the less-preferred carbon source. Here, we found that when and to what level cells induce are two decoupled features of their response, with the pathway regulation acting much like a mechanical switch-and-dimmer. Interestingly, this decoupling is simply achieved by independent regulation of the level and activity of the pathway activator Gal4p, suggesting a general mechanism that could be a feature of many signal integration systems. In a second body of work, we analyze how aneuploidy disrupts the delicate balance that underlies these signaling systems. By varying the copy number of individual chromosomes in haploid yeast, we discover that the aneuploid state leads to greater cell-to-cell variation even within isogenic populations. This form of non-genetic individuality may help to explain the phenotypic variation seen in diseases caused by aneuploidy, and emphasizes the significance that cumulative small changes in gene dosage can have in broadly disrupting signaling robustness. Overall, our results illustrate basic design principles for signal integration motifs, as well as the limitations of their capabilities.