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 other parameters 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 governing the cells' response to long-term, narrow selection.
Using new microarray-based technologies developed by my lab and collaborators, we can now look genome-wide for copy number changes, 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.
Further work on these mutations will determine their exact fitness consequences, for example, which genes in the aneuploid regions contribute to 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.
Finally, we have started to study "real" evolution by looking at the functional divergence between S. cerevisiae and a sister yeast, S. bayanus. Hybrids between these species evolve in novel ways and may teach us something about whole genome duplications and the evolution of duplicate genes.
The fitness consequences of aneuploidy are driven by condition-dependent gene effects. Sunshine AB, Payen C, Ong GT, Liachko I, Tan KM, Dunham MJ. PLoS Biology. 2015 May 26;13(5):e1002155. doi: 10.1371/journal.pbio.1002155. eCollection 2015 May.
The enduring utility of continuous culturing in experimental evolution. Gresham D, Dunham MJ. Genomics. 2014 Oct 2. pii: S0888-7543(14)00192-X. doi: 10.1016/j.ygeno.2014.09.015.
Ploidy-regulated variation in biofilm-related phenotypes in natural isolates of Saccharomyces cerevisiae. Hope EA, Dunham MJ. G3. 2014 Jul 24;4(9):1773-86. doi: 10.1534/g3.114.013250.
Species-Level Deconvolution of Metagenome Assemblies with Hi-C-Based Contact Probability Maps. Burton JN, Liachko I, Dunham MJ, Shendure J. G3. 2014 May 22;4(7):1339-46. doi: 10.1534/g3.114.011825.
The Dynamics of Diverse Segmental Amplifications in Populations of Saccharomyces cerevisiae Adapting to Strong Selection. Payen C, Di Rienzi SC, Ong GT, Pogachar JL, Sanchez JC, Sunshine AB, Raghuraman MK, Brewer BJ, Dunham MJ. G3. 2014 Mar 20;4(3):399-409. doi: 10.1534/g3.113.009365.
GC-rich DNA elements enable replication origin activity in the methylotrophic yeast Pichia pastoris. Liachko I, Youngblood RA, Tsui K, Bubb KL, Queitsch C, Raghuraman MK, Nislow C, Brewer BJ, Dunham MJ. PLoS Genet. 2014 Mar 6;10(3):e1004169. doi: 10.1371/journal.pgen.1004169. eCollection 2014 Mar.
Contemporary, yeast-based approaches to understanding human genetic variation. Dunham MJ, Fowler DM. Curr Opin Genet Dev. 2013 Nov 16. doi:pii: S0959-437X(13)00136-6. 10.1016/j.gde.2013.10.001.
A New System for Comparative Functional Genomics of Saccharomyces Yeasts. Caudy AA, Guan Y, Jia Y, Hansen C, Desevo C, Hayes AP, Agee J, Alvarez-Dominguez JR, Arellano H, Barrett D, Bauerle C, Bisaria N, Bradley PH, Breunig JS, Bush EC, Cappel DA, Capra E, Chen W, Clore J, Combs PA, Doucette C, Demuren O, Fellowes P, Freeman S, Frenkel E, Gadala-Maria D, Gawande R, Glass D, Grossberg S, Gupta A, Hammonds-Odie L, Hoisos A, Hsi J, Hsu YH, Inukai S, Karczewski KJ, Ke X, Kojima M, Leachman S, Lieber D, Liebowitz A, Liu J, Liu Y, Martin T, Mena J, Mendoza R, Myhrvold C, Millian C, Pfau S, Raj S, Rich M, Rokicki J, Rounds W, Salazar M, Salesi M, Sharma R, Silverman SJ, Singer C, Sinha S, Staller M, Stern P, Tang H, Weeks S, Weidmann M, Wolf A, Young C, Yuan J, Crutchfield C, McClean MN, Murphy CT, Llinás M, Botstein D, Troyanskaya OG, Dunham MJ. Genetics. 2013 Sep;195(1):275-87.
High-resolution mapping, characterization, and optimization of autonomously replicating sequences in yeast. Liachko I, Youngblood RA, Keich U, Dunham MJ. Genome Res. 2013 Apr;23(4):698-704.
Design and use of multiplexed chemostat arrays. Miller AW, Befort C, Mitchell E, Dunham MJ. J Vis Exp. 2013 (72).
Origin-dependent inverted-repeat amplification: a replication-based model for generating palindromic amplicons. Brewer BJ, Payen C, Raghuraman MK, Dunham MJ. PLoS Genet. 2011 Mar;7(3):e1002016.
Identification of Aneuploidy-tolerating Mutations. Torres EM, Dephoure N, Panneerselvam A, Tucker CM, Whittaker C, Gygi SP, Dunham MJ, Amon A. Cell. 2010 Oct 1;143(1):71-83.
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