Center for Quantitative Genome Function: Mission, Goals and Origins
From 2002 to 2009, the Center for Quantitative Genome Function (CQGF) was a National Human Genome Research Institute Center of Excellence in Genomic Science (NHGRI-CEGS). It was the only CEGS based at an independent non-profit research institute.
Mission
The mission of the CQGF is to understand how cellular components interact to produce biological outcomes. In this context, we define "understanding" as the ability to predict the future behavior of a cell or organism when faced with specific conditions. To address this challenge, researchers at the CQGF are pursuing an ambitious research program to develop general approaches, tools, conceptual frameworks, and mathematical models that will permit us to quantitatively understand biological responses in the near term, and to predict responses in the long term.
Goals
One of the most important unresolved questions in cell biology is that of how cells recognize and respond to stimuli or perturbations to produce specific biological outcomes. The molecules and events used in this process are collectively called a signaling pathway. At the CQGF we focus on a highly conserved signaling pathway that operates when individual cells of bakers' yeast (Saccharomyces cerevisiae) are responding to a small peptide signal (a mating pheromone) produced by yeast cells of the opposite "sex" (mating type). This signaling pathway, also called the yeast pheromone response, is a well-studied system that shares protein components, mechanisms, and behaviors with many of the signaling systems used in cells of higher organisms. Our goal is to use the yeast system to identify and characterize general quantitative behaviors and regulators that are salient to the response of all signaling systems including those of humans. In fact, a considerable portion of the human genome is devoted to genes that encode components of signaling systems and their regulators. We expect that some of the mutations and genetic variations that contribute to disease in humans will affect pathways and proteins analogous to those studied at the CQGF.
Origins of the Center
We began work in 2002 as the Center for Genomic Experimentation and Computation (CGEC). Our interdisciplinary team sought to understand and predict behavior in the yeast pheromone response system. Our initial priorities included developing tools--both experimental and computational--that permitted us to comprehensively measure molecules and parameters that were key to this signaling pathway. The researchers at CGEC made substantial progress, including the construction of models that were able to predict the behavior of subsystems of the pheromone response pathway, as well as multiple publications in peer-reviewed scientific journals. At the same time, we learned valuable lessons about the sheer scope of work needed for predictive understanding of the entire pheromone response system.
To address these insights, in 2006 we reorganized the Center’s work around a series of smaller, more tractable projects aimed at understanding fundamental processes shared among multiple signaling systems. We call these fundamental processes "systems-level quantitative behaviors". These SLQBs define aspects of quantitative system function that depend on multiple system proteins and molecular events, and are expected to be conserved among different pathways in different cells and organisms. Examples of SLQBs under study at the Center include the concepts of control of dynamic range (how strongly a signaling system can respond); desensitization (the tendency of the system to respond less strongly on repeated stimulation); dose-response alignment (the similarity of response at intermediate steps within the pathway); signal transmission time (how fast a system can respond); and cell-to-cell variation (differences, among cells, in the ability to transmit signals). In recognition of this fundamental shift in emphasis, we changed the name of the CGEC to the Center for Quantitative Genome Function (CQGF).
Our ongoing goal is to develop a comprehensive quantitative understanding of the mechanisms that regulate key SLQBs in the yeast pheromone response system. We will investigate the complex regulatory interactions in this system, including specific feedbacks, sites of protein modification, and the identification of other genes that affect specific SLQBs. The tools, assays, and data we have generated will permit us to continue our investigations in yeast. MSI will continue to serve as a nucleus for an international community focused on the combination of genetics and systems biology of signaling, while training researchers who can continue interdisciplinary work that reveals fundamental principles of quantitative biological function.
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