Reciprocal F1 hybrids of two inbred mouse strains reveal parent-of-origin and perinatal diet effects on behavior and expression

Abstract

Parent-of-origin effects (POEs) in mammals typically arise from maternal effects or from imprinting. Mutations in imprinted genes have been associated with psychiatric disorders, as well as with changes in a handful of animal behaviors. Nonetheless, POEs on complex traits such as behavior remain largely uncharacterized. Furthermore, although perinatal environmental exposures, such as nutrient deficiency, are known to modify both behavior and epigenetic effects generally, the architecture of environment-by-POE is almost completely unexplored. To study POE and environment-by-POE, we employ a relatively neglected but maximally powerful POE-detection system: a reciprocal F1 hybrid population. We exposed female NOD/ShiLtJxC57Bl/6J and C57Bl/6JxNOD/ShiLtJ mice, in utero, to one of four different diets, then after weaning recorded their whole-brain gene expression, as well as a set of behaviors that model psychiatric disease. Microarray expression data revealed an imprinting-enriched set of over a dozen genes subject to POE; the POE on the most significantly affected gene, Carmil1 (a.k.a. Lrrc16a), was validated using qPCR in the same and in a new set of mice. Several behaviors, especially locomotor behaviors, also showed POE. Interestingly, Bayesian mediation analysis suggests Carmil1 expression suppresses behavioral POE, and Airn suppresses POE on Carmil1 expression. A significant diet-by-POE was observed on one behavior, one imprinted gene, and over a dozen non-imprinted genes. Beyond our particular results, our study demonstrates a reciprocal F1 hybrid framework for studying POE and environment-by-POE on behavior.