Systems genomics of complex traits

PROJECT SUMMARY The last decade of work in genetics has shifted from examining the effects of single genes to an understanding that most features of organisms, including human health and disease, are influenced by complex interactions among genes and with the environment. Part of the challenge is addressing these questions is one of scale: how can the effect of every gene in the genome be assessed in a comprehensive manner? New approaches that take full advantage of recent developments in genomics and genome engineering are needed. We have developed new genomic engineering and library-based barcoding approaches using the nematode Caenorhabditis elegans that allows individual lineages to be manipulated and traced for the first time in an animal system. We will use this method to estimate the distribution of effects for both naturally occurring and induced mutations and multiple environments. This information will be complemented by a novel analysis of genomic variation in the hyper-diverse species C. brenneri and mapping pleiotropic effects for oxidative stress resistance in C. elegans. Finally, the structure of these various independent examinations of new and standing genetic variation will be tested using genome-based simulations of the evolution of complex genetic networks. Overall, this research uses a systems-genetics approach that integrates an understanding of natural genetic variation within a strong functional hypothesis-testing framework to understand the function and evolution of complex regulatory systems with critical implications for human health.