Most biological traits including common diseases have a strong but poorly understood genetic basis. Recent work suggests that a complex mixture of common and rare variants 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 principals 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 C. elegans with age- dependent effect sizes and epistatic interactions. Once in hand, we will mechanistically dissect their causes in the context of organ and multicellular circuit function. We will study how life history changes in sperm number, a limited resource necessary for reproduction, creates age-dependent genetic architecture. Finally we will study how epistasis and aging are shaped by the function of the underlying neural circuit responsible for regulation of reproduction. These experiments will leverage C. elegans tractability to identify principles relevant to the study of human diseases.
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. We will identify how age and epistasis affect traits in model organisms with the goal of identifying principals that can be applied to better predict the genetic variants responsible for human diseases.
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