NSF Award
0527023
David Galas, Keck Graduate Institute<br/>Christoph Adami, Alpan Raval, Animesh Ray, Herbert Sauro, James Cregg, Bulbul Chakravarti, Deb Chakravarti, Claus Wilke, Keck Graduate Institute<br/>Eric Phizicky, Elizabeth Grayhack, University of Rochester<br/>Amarnath Gupta, University of California, San Diego; San Diego Supercomputer Center<br/><br/>This project investigates the large-scale architecture of cellular networks. The underlying questions are: (i) To what extent are gene regulatory networks modular? (ii) How do modules originate and how do they evolve? (iii) How do extant and emerging criteria for defining modules in networks affect our ability to predict biological function? The project has integrated computational and experimental components, and the project team consists of experts in molecular biology, genetics, computational science, mathematics, and physics. On the computational side, the project will develop and evaluate new algorithms for module detection, and will use these algorithms to predict modules in budding yeast from both existing and project-generated genomics data. On the experimental side, a high-level, causal interaction map of gene function in budding yeast will be generated. This will be done by systematically screening for individual genes that, when overexpressed, suppress the deleterious effects of known mutant genes. The mutant genes and their suppressors will define an interaction map that will be used to define modules and compare with extant maps. Experimental module boundaries, so defined will then be compared with our computational predictions. This test can validate or amend our current understanding of modularity, and will likely raise questions that will extend this understanding. To obtain insight into rules by which entire modules evolve, a related experimental effort will be conducted in Pichia pastoris, a distant evolutionary relative of the budding yeast, in order to study evolutionary changes in module structure. This project is expected to advance our understanding of networks in modern systems biology, provide new insights and data and promote new engineering-inspired ways of thinking about biological function. <br/><br/>Broader Impacts: Novel research materials, data and software will be openly available to the community at large through our research website. We expect that some of the methods, computational and experimental will be able to be readily extended to more complex eukaryotes. An important component of this project is education and outreach, which will be advanced through a dedicated series of summer workshops for high-school teachers, summer internships for high-school and undergraduate students, and online course material, all focused on integration of physical and biological sciences addressing the evolution of biological complexity. The simple experimental system should lend itself to the development of student experiments that probe the complexity of the yeast network. This project will provide an opportunity for young students to discover complex forces that shape living systems at a fundamental level of organization.
