Modeling of a negative feedback mechanism explains antagonistic pleiotropy in reproduction in domesticated Caenorhabditis elegans strains

Most biological traits and common diseases have a strong but complex genetic basis, controlled by large numbers of genetic variants with small contributions to a trait or disease risk. The effect-size of most genetic variants is not absolute and is instead dependent upon multiple factors such as the age and genetic background of an organism. In order to understand the mechanistic basis of these changes, we characterized heritable trait differences between two domesticated strains of C. elegans. We previously identified a major effect locus, caused in part by a mutation in a component of the NURF chromatin remodeling complex, that regulates reproductive output in an age-dependent manner. The effect-size of this locus changes from positive to negative over the course of an animal's reproductive lifespan. Here, we use a previously published macroscale model of the egg-laying rate in C. elegans to show that time-dependent effect-size is explained by an unequal use of sperm combined with negative feedback between sperm and ovulation rate. We validate key predictions of this model with controlled mating experiments and quantification of oogenesis and sperm use. Incorporation of this model into QTL mapping allows us to identify and partition new QTLs into specific aspects of the egg-laying process. Finally, we show how epistasis between two genetic variants is predicted by this modeling as a consequence of the unequal use of sperm. This work demonstrates how modeling of multicellular communication systems can improve our ability to predict and understand the role of genetic variation on a complex phenotype. Negative autoregulatory feedback loops, common in transcriptional regulation, could play an important role in modifying genetic architecture in other traits.