Modeling of a negative feedback mechanism explains age-dependent genetic architecture in reproduction in domesticated C. elegans strains

Abstract

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, but can depend on a number of factors including the age and genetic background of an organism. In order to understand the mechanisms that cause these changes, we are studying heritable trait differences between two domesticated strains of C. elegans. We previously identified a major effect locus, caused by a mutation in a component of the NURF chromatin remodeling complex, that regulated reproductive output in an age-dependent manner. The effect-size of this locus changes from positive to negative over the course of an animals reproductive lifespan. Using a previously published macroscale model of egg-laying rate in C. elegans, we show how time-dependent effect-size can be explained by an unequal use of sperm combined with negative feedback between sperm and ovulation rate. We validate a number of key predictions of this model using controlled mating experiments and quantification of oogenesis and sperm use. By incorporating this model into QTL mapping, we 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 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.\n\nAUTHOR SUMMARYComplex traits are influenced not only by the individual effects of genetic variants, but also how these variants interact with the environment, age, and each other. While complex genetic architectures seem to be ubiquitous in natural traits, little is known about the mechanisms that cause them. Here we identify an example of age-dependent genetic architecture controlling the rate and timing of reproduction in the hermaphroditic nematode C. elegans. Using computational modeling, we demonstrate how this age-dependent genetic architecture can arise as a consequence of two factors: hormonal feedback on oocytes mediated by major sperm protein (MSP) released by sperm stored in the spermatheca and life history differences in sperm use caused by genetic variants. Our work also suggests how age-dependent epistasis can emerge from multicellular feedback systems.