PROJECT SUMMARY/ABSTRACT
The long-term goal of this research program is to understand the mechanistic and evolutionary causes of
variation in complex traits. The primary experimental approach is to perform large-scale analyses of single-cell
traits of the budding yeast, Saccharomyces cerevisiae, and follows two major lines of work. One line of work aims
to understand how interaction between genes (epistasis) contributes to natural trait variation. Understanding
the sources of variation in complex traits is a major goal in biomedical research because this knowledge
impinges directly on the prospect of personalized medicine, for example the prediction of disease risk from an
individual’s genotype. If not taken into account, epistasis can confound such predictions. Epistasis is also
important because it can constrain evolutionary adaptation to follow particular paths, making adaptation more
predictable. This predictability could be valuable in the treatment of diseases that have a strong evolutionary
component, such as microbial infections and cancer. Although epistasis has been well studied using lab-
derived mutations, as well as in some cases of viruses or microbes under strong pressures to evolve, its role in
determining how traits vary in natural populations is poorly understood. Key goals of this research program
are to perform experiments with dramatically increased power to detect interactions, and to expand the range
of traits that are studied to include cell shape and size, which are important in many disease processes. These
studies will leverage recent progress in using high-throughput, microscopy-based methods to quantify many
independent cellular features, and they will create and use strains of S. cerevisiae that make searching for
epistasis much more powerful. The other line of work aims to understand molecular mechanisms that allow
clonal cell populations to generate heterogeneity that might be beneficial in the face of environmental
uncertainty. Such heterogeneity is seen in the responses of pathogenic microbes and tumor cells to drugs, and
therefore has major clinical implications, yet there is very little known about how heterogeneity is regulated
and how it can be altered. Recent work has shown that clonal populations of S. cerevisiae contain fast-growing
cells that are susceptible to acute stress and slow-growing cells that are tolerant of acute stress, and that these
differences are mediated by variable activity of the conserved Ras/cyclic AMP/protein kinase A pathway. The
role of this kinase in tuning growth rates and stress tolerances will be probed using chemical-genetic
manipulation. The goal is to better understand the mechanistic basis of adaptive heterogeneity in this model
system, and ultimately to advance treatment of persistent pathogens and cancers.