Genetic interactions underlie all biology, including complex traits such as susceptibility to common human diseases. This proposal to examine genetic interactions globally has simple overarching goals that characterize both the original and renewal proposals. We aim to determine for each of the -12,500,000 double mutant combinations possible among viable knockout (YKO) mutations in budding yeast, the subset of those pairwise interactions that result in inviability or reduced growth. This set of pair-wise interaction data will allow us to construct a genetic interaction map of the yeast genome. By combining this dataset with other large-scale datasets, in particular protein interaction and transcriptional regulation datasets, we aim to allow the larger community to benefit from thousands of new interactions discovered, and to work with the community to generate a complete description of the "cellular wiring diagram". In the first phase of the project, now complete, we perfected the needed technology, generated a production protocol, constructed two new complete collections of YKO mutants that will allow the project to be carried out as well as facilitate a multitude of projects in other labs. While other groups have reported limited maps of approximately 2% of the possible synthetic lethal interactions in yeast, those methods are too costly to be applied genome scale. The method we developed during the initial funding period is in production and can be applied genome scale. Thus, to our knowledge, we are the only group that can complete the remaining 98% of the yeast synthetic lethal interaction map. [unreadable] [unreadable] [unreadable]