A key challenge of systems biology is to understand how genes function as networks to carry out and regulate cellular process. Many important insights have emerged in recent years from studies using the yeast Saccharomyces cerevisiae. A partial genetic-interaction network has been compiled using double knockout mutations. Analysis of this network has provided many important insights about gene function and human genetics and disease. We will use reverse engineering principles to map cellular processes in yeast, in collaboration with the University of Toronto and the Sanger Institute. By disrupting an unknown process in diverse ways and observing the effects, a model for how the process works can be deduced. For this project, chemical compounds and genetic mutations will be used to perturb the yeast cell, and we will analyse their effects on growth rate. This ‘chemical genomic’ method has already been proven successful as it revealed important new connections in the DNA damage repair process in yeast. The Giaever and Nislow groups in Toronto have developed two chemical genomic assays called HIP and HOP assay which can measure the perturbation on the cell due to the presence of chemical probes. We plan to apply computational chemistry techniques to help streamline the process of finding and understanding the effects of new chemical probes using HIP and HOP screening technology. More importantly we will also apply bioinformatics techniques to extract meaningful network information from the results of the HIP-HOP assays.
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