Genetic Basis of Natural Variation in Cellular Decision Making in Wild Yeasts

Abstract

In nature, microbes often need to decide which of many potential nutrients to consume. This decision-making process is complex, involving both intracellular constraints and the organism’s perception of the environment. What factors does a cell take into account as it makes this decision? And how is it molecularly encoded? In this thesis, we quantified differences in the concentration of induction galactose-responsive (GAL) genes across wild S. cerevisiae strains. To begin to mimic the complexity of natural environments, we grew cells in mixtures of two sugars, glucose and galactose. Galactose induces the well-studied pathway, while glucose represses the pathway. Using bulk segregant analysis, we mapped genomic loci underlying phenotypic variation in the GAL pathway, identified causal genes, and did a series of allele-replacements to understand the specific effect of these genes. By analyzing crosses of phenotypically different strains, we identified a locus containing the galactose sensor, GAL3, as a gene that can explain upwards of 90% of the variation in the decision to induce GAL genes in a single cross. This gene can also modulate the time required for cells to switch from utilizing glucose to galactose. In a related study, we showed that this gene and other genes not specific to the GAL pathway tune two independent features of the GAL response, which can switch a strain from being bimodal to unimodal. Our results suggest that signaling pathways can be highly variable across strains and thereby might allow for rapid adaption in fluctuating environments. The independent tuning of specific and non-specific pathway genes can help cells adapt to complex environments at various timescales.