Abstract

Autism spectrum disorders (ASD) are a heterogeneous group of disorders rooted in genetic bases. Although genetic studies have identified many ASD-risk genes over the past few years, it remains essentially unknown whether mutations in different genes result in similar molecular and cellular states within the brain. Over the past years, we have generated a large cohort of ASD mouse models carrying mutations in top, high-risk ASD genes. The cohort includes 11 mouse lines and span chromatin remodelers, ubiquitin-related genes, metabolically relevant genes, and synaptic proteins. Employing these validated mouse models, we performed simultaneous single nucleus RNA and ATAC sequencing across brain regions, developmental stages, and sexes, totaling over 300 samples. We achieved this by pioneering an approach that allowed us to sequence RNA and DNA from the same nucleus on a large scale. With this unique dataset, we could address precise questions regarding convergence and divergences across different ASD models, time windows affected, and sex differences.