Reciprocal F1 Hybrids of Two Inbred Mouse Strains Reveal Parent-of-Origin and Perinatal Diet Effects on Behavior and Expression

Parent-of-origin effects (POE) in mammals typically arise from maternal effects or imprinting. In some instances, such POE have been associated with psychiatric disorders, as well as with changes in a handful of animal behaviors. However, POE on complex traits such as behavior remain largely uncharacterized. Moreover, although both behavior and epigenetic effects are known to be modified by perinatal environmental exposures such as nutrient deficiency, the architecture of such environment-by-POE is mostly unexplored. To study POE and environment-by-POE, we employ a relatively neglected but especially powerful experimental system for POE-detection: reciprocal F1 hybrids (RF1s). We exposed female NOD/ShiLtJ [Formula: see text] C57Bl/6J and C57Bl/6J×NOD/ShiLtJ mice, perinatally, to one of four different diets, then after weaning recorded a set of behaviors that model psychiatric disease. Whole-brain microarray expression data revealed an imprinting-enriched set of 15 genes subject to POE. The most-significant expression POE, on the non-imprinted 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. Bayesian mediation analysis suggested Carmil1 expression suppresses behavioral POE, and that the imprinted gene Airn suppresses POE on Carmil1 expression. A suggestive diet-by-POE was observed on percent center time in the open field test, and a significant diet-by-POE was observed on one imprinted gene, Mir341, and on 16 non-imprinted genes. The relatively small, tractable set of POE and diet-by-POE detected on behavior and expression here motivates further studies examining such effects across RF1s on multiple genetic backgrounds.