(692c) Linking Genotype and Phenotype Through a Graded Dominant Mutant Phenotype Approach

Systems biology seeks to establish a relationship between genotype and phenotype.  As a result, it is necessary to accurately determine causative linkages between genes and function.  Moreover, understanding global gene regulation has significant applications in genetics, biotechnology, and disease treatment.  However, commonly invoked approaches for probing this regulation (such as gene deletions) do not accurately link protein function and phenotype in a causative manner.  Here we describe a novel approach to extract quantitative, causative links between specific protein function and downstream gene expression.  This approach is especially useful for multifunctional proteins.  Specifically, we develop an approach termed “graded dominant mutant phenoytpes” in which a dominant allele is used to competitively inhibit and grade a specific protein function.  Using the yeast histone acetyltransferase Gcn5p as a case study, we demonstrate the utility of this approach by identifying previously unknown gene targets and interactions and implicating a strong role for Gcn5p-acetylation in global gene repression.  Our results demonstrate that traditional genetic approaches (can significantly misrepresent the number and identity of gene interactions and phenotypes.  Thus, this approach serves as a novel genetic approach for systems biology.