Genetics plays a central role in autism spectrum disorder (ASD), yet much remains unknown about how DNA sequence variation predisposes individuals to ASD. Rare mutations have emerged as critical in ASD, and there is great hope that whole-genome sequencing will reveal many more causal mutations and lead to a better understanding of genetics and pathogenesis in ASD. This presumes that we will be able to identify which DNA mutations predispose individuals to ASD against the background of the millions of benign or unrelated DNA mutations present in every human genome. For mutations that disrupt proteins, such causal relationships have been successfully demonstrated, leading to significant new insights into the etiology of ASD. However, the majority of the human genome does not code for proteins, and predicting which mutations are pathogenic in noncoding regions is much more challenging. Enhancers — regulatory DNA sequences within our genomes that control when genes are activated — have emerged as critically important to human health and development. It is likely that noncoding mutations that disrupt enhancers also contribute to the pathogenesis of ASD.
Alex Nord and his team at the University of California, Davis have developed methods to identify and characterize dynamic enhancer function in the mouse1. They plan to apply functional screening approaches in vivo in the mouse brain to identify noncoding mutations in Simons Simplex Collection probands that perturb enhancer function. Little is known about how these variants are involved in ASD and no animal models of enhancer mutations in ASD exist. For this project, Nord and his colleagues will generate and characterize new mouse models to study how losing the function of enhancers may drive pathogenesis in ASD. This work represents a path toward understanding and diagnosing ASD mediated by pathogenic mutations in noncoding regions of the genome.