Project 452134

In this proposal, we have developed a strategy for generating inactivating mutations in multiple genes in a multicellular animal. Using this strategy, we will test thousands of combinations of mutations for their effect on aspects of animal development and health. We will focus our attention on studying an important family of genes encoding RNA binding proteins, key regulators of how genes themselves are turned on and off in specific tissues and organs of the body. We will also introduce known disease-associated mutations into genes, and search for inactivating mutations in other genes that modify the effects of the disease- associated mutations. Our study will use the genetically accessible roundworm C. elegans, which shares many of the same genes in humans and has served as an excellent model for aspects of human biology. Together, our study will shed light on how members of a key family of genes work together to control aspects of animal development and provide insight into disease mechanisms. Moreover, our novel approach will represent the largest systematic analysis to date testing the effects of losing combinations of genes in a multicellular animal.