In August, Biology assistant professor Patrick McGrath was awarded a 5 year, $1.47 million grant by the National Institutes of Health to study the genetic architecture of aging. Most common diseases have a strong but complex genetic component. Understanding their genetic underpinnings will allow for their predictions and suggest targets for their amelioration. McGrath and colleagues will identify how age and epistasis affect traits in model organisms with the goal of identifying principles that can be applied to better predict the genetic variants responsible for human diseases.

A complex mixture of common and rare variants typically shape most biological traits – their exact effects mediated by extensive genetic interactions and organismal age. These observations are mainly correlative as little is known about the mechanisms that generate epistasis and age-dependence. Improved understanding of these processes could identify principles useful for predicting how causal factors act in novel genetic backgrounds and therapeutic techniques to take advantage of their non-linear effects to ameliorate disease. The broad objective of the proposed research is the identification of causative genetic variants affecting reproduction in the round worm C. elegans with age-dependent effect sizes and epistatic interactions. McGrath intends to mechanistically dissect their causes in the context of organ and multicellular circuit function. His team will study how life history changes in sperm number, a limited resource necessary for reproduction, creates age-dependent genetic architecture. Finally, they will study how epistasis and aging are shaped by the function of the underlying neural circuits responsible for the regulation of reproduction. These experiments will leverage C. elegans tractability to identify principles relevant to the study of human diseases.