Project Summary/Abstract Evolutionary forces have important consequences for human diseases of development, social behavior, and metabolism along with the progression of cancers and susceptibility to pathogens. These forces largely determine the types of genetic changes and genes that influence or underlie these traits. The goal of the McGrath lab is to understand the genetic basis of adaptation. What are the genetic changes that can increase fitness and how do they modify cellular activity and phenotypic change to accomplish this? Experimental evolution using the model organism C. elegans is a powerful approach to address these questions. C. elegans, a genetically-tractable, short-lived nematode, can be used to study the evolution of development, behavior, and sexual reproduction. In the next five years, the McGrath lab will identify continue to identify the genetic, cellular, and phenotypic basis of adaptation, focusing on three main areas. First, the genetic and cellular basis of pheromone-dependent trait evolution will be characterized. C. elegans release and sense dozens of acaroside pheromones that modify a large number of behavioral and developmental traits. This work will provide a model for understanding how neural circuits evolve to modify pheromone signaling in new environments. Second, the functional evolution of the NURF chromatin remodeling complex will be characterized in a number of nematode species. Chromatin state regulates gene expression; it is important for determining cell fate and phenotypic plasticity. Genetic mutations in chromatin remodelers are an important risk factor for many cancers. Finally, genes and neurons responsible for differences in food consumption will be identified. Obesity is a common risk factor in Americans. Fundamental work in C. elegans could help us design approaches to decrease obesity in humans. In total, this work will provide a view of adaptation in a multicellular organism.