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. In eight glucose-limited cultures founded by the same diploid ancestor, we found that six carried nonreciprocal translocations. Moreover, these changes in copy number were not randomly distributed, but the same regions were rearranged in multiple independent evolved strains. The breakpoints were strongly associated with transposons and repeated tRNAs, and three strains even shared identical breakpoints adjacent to the citrate synthase gene CIT1.

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 point mutations and transposon insertions. In addition, classical genetic approaches and a novel mapping technique are being employed to dissect the features of the evolved strains.