# Offspring genetic diversity regulates rearing experiences that predict differential susceptibility to Chd8 haploinsufficiency

## TL;DR

This study shows that genetic diversity in offspring affects how early life experiences influence the severity of traits caused by a genetic mutation linked to autism.

## Contribution

The study demonstrates that genetic background modulates susceptibility to Chd8 haploinsufficiency through early life rearing experiences.

## Key findings

- Strain differences in pup and maternal behaviors were observed in genetically diverse offspring.
- Early life litter experiences predict sex-dependent postweaning behavioral disruptions in Chd8 haploinsufficient mice.
- Combining genetic diversity with rearing experiences better models clinical heterogeneity in neurodevelopmental disorders.

## Abstract

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 CHD8 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 Chd8 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 Chd8 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.