Offspring genetic diversity regulates rearing experiences that predict differential susceptibility to haploinsufficiency.

Mouse models of human disease focus on determining the direct impact of genetic mutations on phenotypes related to clinical presentations. For example, loss of function mutations in the autism-associated gene is highly penetrant for trait and behavioral abnormalities in children, but there is substantial clinical heterogeneity in the occurrence and extent of disruptions between individuals. Using a large genetic reference panel of mice, we recently showed that genetic background strongly regulates variability in trait disruptions caused by haploinsufficiency. Here, we hypothesized that genetics could also impact the variability in response to early life experiences, thus contributing to differential susceptibility to neurodevelopmental disorders. To examine how genetic diversity impacts rearing experience, we systematically observed the behavior of genetically diverse offspring raised by genetically identical mothers. The results reveal strain differences in pup and maternal behaviors. Machine learning analysis reveals that early life litter experiences are strong predictors of sex-dependent postweaning social, anxiety-like, and cognitive trait disruptions due to haploinsufficiency. The study suggests that offspring phenotypes in mutant models of disease are due to a combination of heritable and early experience factors, demonstrating the utility of incorporating genetic diversity in studies to model the mechanisms that underlie the heterogeneity of disrupted phenotypes in neurodevelopmental disorders.