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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.

Our further work on these novel chromosomes has determined 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.

Technology development

As we've developed new genome analysis 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. We have also developed new methods for miniaturing and customizing continuous culture, including a mini-chemostat array and, in collaboration with Eric Klavins, a flexible turbidostat platform.

Comparative genomics

Our work on short-term adaptations has led to a broader interest in comparative genomics over longer timescales. With Amy Caudy, Olga Troyanskaya, and several other collaborators, we've functionally annotated the genome of the sequenced but otherwise poorly studied yeast S. bayanus var uvarum. 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 compared them 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. We developed a suite of genomic tools to map and characterize replication origins, in collaboration with Bonny Brewer and M.K. Raghuraman's lab. We've applied these tools to study origins across a wide swatch of budding yeast, over which they evolve in remarkable ways. These studies have also led to the discovery of some useful strain engineering parts, such as the pan-ARS, an optimized replication origin element that works in every budding yeast we have attempted.

Comparative experimental evolution

The two major arms of our research have merged back into a new area where we use experimental evolution to understand differences in evolvability between strains and species. Hybrids between different yeast species are also proving fertile ground.

Human genetics in yeast

Finally, we are using yeast as a platform to "functionalize" human genetic variation. With Doug Fowler, Allan Rettie, and Debbie Nickerson, we are transplanting human pharmacogenes into yeast to test the function of libraries of variants. In a second project, we are recreating human mutations associated with cancer in the yeast gene equivalent. We hope our results will help prioritize variants for further analysis in more difficult systems, and maybe even guide clinical practice for patients carrying variants of unknown significance.

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

feature by Singer Instruments on Discovering the Power of Yeast. Includes some discussion of my research and teaching the CSHL Yeast Course.

article (Google drive link) in Beer Advocate featuring our beer metagenomics project

UW Today article on me and the other UW HHMI Faculty Scholars

Interview at the Buck Institute: SAGE

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

Genome Technology: Profile for 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)

NASW: review of the 2010 AAAS meeting

articles about people in the lab

The Daily: story on SACNAS featuring Monica Sanchez

The Daily: story about the UW Undergraduate Research Symposium featuring Erica Alcantara

GSA: Poster award for Ivan Liachko at Fungal Genetics meeting


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