Multidimensional behavioral evaluation of the causal role of high-risk ASD genes in rats

Genomic studies in humans have identified alterations within many genes that drastically increase the risk of being diagnosed with autism spectrum disorder (ASD). However, we still have a very limited understanding of how a mutation to a single gene can change behavior, let alone lead to the complex symptomatology of a psychiatric disorder such as ASD. I will present on our work using transgenic rats with mutations to multiple of these high-risk ASD genes. Using a high-throughput and large-scale behavioral phenotyping pipeline, coupled with data-driven analysis methods, we are able to identify a phenotype consistent with restrictive and repetitive behavior in rats haploinsufficient for two different ASD risk gene. Restrictive and repetitive behavior is one of the core diagnostic features of ASD. Furthermore, a common finding from human genomic studies is one of pleiotropy, where mutations to single genes are associated with different diagnoses. We use our large-scale data to begin to evaluate the origins of this pleiotropy. I will present data showing that different mutations within a single gene can lead to clear behavioral differences, and that even the same mutation within a single gene leads to substantial individual variability in the behavioral phenotype.