Molecular mechanisms of genetic interactions: unravelling complex disease phenotypes
05 / 2012 - unknown
Genetic interactions, or non-additive effects between genes, are known to play a crucial role in many cellular processes and complex human diseases such as cancer, malaria and AIDS. Which molecular mechanisms underlie these genetic interactions and how they relate to cellular processes and disease has hardly been characterized. Understanding the molecular basis of genetic interactions is vital to deciphering pathway organization, understanding the relationship between genetic variation and disease and effective discovery of new pharmaceuticals. I therefore propose to characterize the molecular mechanisms of genetic interactions for a number of cellular processes in a simple and powerful model organism, Saccharomyces cerevisiae. This will, for the first time, expose the regulatory circuits of the entire spectrum of genetic interactions and the role they play in important cellular processes such as signalling, transcription and chromosome organization, many of which are affected in human disease. DNA microarray gene expression profiles of single and double mutants of genetically interacting pairs will be generated. These will subsequently be characterized and classified based on their gene expression patterns. Advanced statistical and mathematical modelling techniques such as Bayesian networks and differential equations will be employed and further developed to uncover the regulatory circuits underlying the genetic interactions. Model-driven follow-up experimentation will be pursued to further investigate the most interesting mechanisms. This ambitious proposal will be feasible thanks to a unique combination of expertise in bioinformatics, gene expression profiling and molecular-genetic interactions. It will address fundamental questions for understanding genetic interactions in relation to cellular processes and complex human disease.