Leveraging Scalable Non-Mammalian Systems for Large-Scale Studies of Autism Risk Gene Function

There are over 100 large-effect genes strongly associated with autism spectrum disorder (ASD), yet advancing from risk genes to the discovery of common biological pathways and pharmacological targets remains a central challenge. Scalable non-mammalian systems, including Caenorhabditis elegans (roundworm), Drosophila melanogaster (fruit fly), Danio rerio (zebrafish), and Xenopus tropicalis (frog), provide critical advantages for the functional analysis of ASD genes due to their amenability to high-throughput screens, relatively low cost, and ease of genetic manipulation. Recent studies have leveraged the unique strengths of these systems to address critical challenges in ASD genetics by analyzing the function of human rare variants, evaluating interactions among genes in ASD-associated copy number variants, and investigating multiple ASD genes in parallel. These studies revealed that ASD genes play conserved roles in the neural circuits underlying basic learning, sensory processing, sleep, and social behaviors. Also, they uncovered common biological pathways uniting ASD genes, including neurogenesis, microtubule biology, and mitochondrial function. Interestingly, pharmacological suppressor screens in non-mammalian systems identified estrogenic compounds as modulators of ASD gene-associated phenotypes. Furthermore, by enabling the parallel in vivo analysis of >100 ASD genes, these systems facilitate the identification of ASD gene subgroups with shared biological effects, a critical step in drug discovery. Therefore, non-mammalian systems are emerging as key players along with mammalian and human cellular systems in the search for convergent mechanisms downstream of ASD genes and the discovery of precision medicine-based treatments.