Experimental evolution

The Dunham Lab combines experimental evolution with genomic analysis to study the structure and function of genetic networks in yeast. Cultures of yeast 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.

Aneuploidy and copy number variation

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.

One of the most common gene amplifications we observe adopts a novel inverted tandem repeat configuration. With Bonny Brewer's lab, we have proposed a mechanism responsible for these amplifications via an error in DNA replication.

Genome characterization technology development

As we've developed new technologies, we've been able to look at not just CNVs, but also 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. Most recently, we've turned to next generation sequencing technologies to simply sequence interesting genomes.

Comparative genomics

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 poorly studied yeast S. bayanus. Our combined labs and the Princeton 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. Orthogonal functional assays are also being extended to different strains and species. We hope to further connect changes in gene function and gene regulation to comparative sequence analysis.

Comparative genomics of other genome elements, such as DNA replication origins, is also ongoing. Hybrids between different yeast species, which we've been studying with Doug Koshland and Yixian Zheng, are also proving fertile ground.

for more information

talks

SB 5.0: "Understanding the Path of Evolution" a technical talk, but for a broad audience

SB 5.0: "Genome Scale Engineering" panel moderated by Eric Lander

Yeast Synthetic Biology Workshop: "Use of Fermentors for Strain Selection" another technical talk, but still for a somewhat broad audience

Wednesday night at the Genome: "Watching evolution in action" talk geared to the general public

National Academy of Sciences Synthetic Biology for the Next Generation: panel discussion on Synthetic Biology for Exploring Fundamental Questions in Biology

articles

UW Medicine Report to the Community: 2011 (PDF) The article I'm in starts on page 18.

Genome Technology: Young Investigators Feature, requires free registration to read

Cell: "Superpostdocs Reach for the Stars" [PDF]

AWIS Magazine: "Research Advances: A Conversation with New Voices in Biology: Amy Caudy and Maitreya Dunham" (PDF)