The Dunham Lab combines experimental evolution with genomic analysis to study the structure and function of genetic networks in yeast. Cultures of S. cerevisiae can be maintained for hundreds of generations of nutrient-limited, steady-state growth in chemostats. During this time, more fit mutants appear and sweep through the culture. By comparing the "evolved" strains to the ancestral founders, we can study the adaptations selected in the chemostat. Growth phenotypes, cell morphology, global gene expression, and DNA copy number all change during the course of chemostat evolution. Genetic dissection of the small number of mutations responsible for these many changes should allow us to recognize the rate limiting steps and control points regulating the cells' response to long-term, narrow selection.
One type of mutation commonly observed in these experiments is genome rearrangement, ranging from focal amplifications to entire chromosome aneuploidy and translocations. Many of these are reproducible in independently evolved cultures, even down to the exact breakpoints.
Further work on these novel chromosomes will determine their exact fitness consequences and which genes in the amplified and deleted regions contribute to the fitness. Since these events so closely resemble the types of aneuploidies almost universally observed in cancers, we hope the work will be of broader interest. We have further explored this connection through studying lab-created aneuploid strains in collaboration with Angelika Amon.
As we've developed new technologies, we've expanded this approach to find point mutations and transposon insertions in evolved strains. In addition, classical genetic approaches and a novel mapping technique are being employed to dissect the features of the evolved strains.
Finally, our work on short-term adaptations has led to a broader interest in comparative genomics over longer timescales. With Amy Caudy and Olga Troyanskaya, we've recently functionally annotated the genome of the sequenced but otherwise unstudied yeast S. bayanus. Our combined labs and the Integrated Science Project Labs collected over 300 gene expression experiments over a wide range of carefully chosen conditions, and we are now comparing these to the S. cerevisiae gene expression literature. We hope to further connect changes in gene function and gene regulation to comparative sequence analysis.
