quantitative epistasis analysis and pathway inference from genetic interaction data定量上位从基因交互数据分析和路径推理.pdfVIP

Quantitative Epistasis Analysis and Pathway Inference from Genetic Interaction Data Hilary Phenix1,2, Katy Morin1,3, Cory Batenchuk1,2, Jacob Parker4,5, Vida Abedi1,2, Liu Yang1,2,5, Lioudmila Tepliakova1,2, Theodore J. Perkins3,4, Mads Kærn1,2,6* 1 Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada, 2 Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada, 3 Department of Biochemistry, Immunology and Microbiology, University of Ottawa, Ottawa, Ontario, Canada, 4 Ottawa Hospital Research Institute, Ottawa, Ontario, Canada, 5 Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, Canada, 6 Department of Physics, University of Ottawa, Ottawa, Ontario, Canada Abstract Inferring regulatory and metabolic network models from quantitative genetic interaction data remains a major challenge in systems biology. Here, we present a novel quantitative model for interpreting epistasis within pathways responding to an external signal. The model provides the basis of an experimental method to determine the architecture of such pathways, and establishes a new set of rules to infer the order of genes within them. The method also allows the extraction of quantitative parameters enabling a new level of information to be added to genetic network models. It is applicable to any system where the impact of combinatorial loss-of-function mutations can be quantified with sufficient accuracy. We test the method by conducting a systematic analysis of a thoroughly characterized eukaryotic gene network, the galactose utilization pathway in Saccharomyces cerevisiae. For this purpose, we quantify the effects of single and double gene deletions on two phenotypic traits, fitness and reporter gene expression. We show that applyin