A Drosophila screen identifies domino as a link between chromatin regulation and synaptic organization

Autism spectrum disorder (ASD) is associated with diverse genetic risk factors. To identify conserved mechanisms underlying ASD-related phenotypes, we conducted a targeted screen in Drosophila using MiMIC insertion mutants of high-confidence genes from the Simons Foundation Autism Research Initiative (SFARI) database. Behavioral assays identified 52 heterozygous lines with significant changes in sleep, activity, or social behavior in one or both sexes. Among these, the chromatin remodeler domino (dom), the ortholog of human SRCAP, emerged as a particularly compelling candidate. Heterozygous dom mutants exhibited altered social spacing and male-biased sleep and activity dysregulation, phenotypes that were replicated in an additional allele. RNA-sequencing of adult brains showed that reduced dom expression affected genes involved in signaling and structural pathways in both sexes, offering potential molecular links to the behavioral outcomes. In addition, dom disruption caused widespread splicing dysregulation, with differentially spliced genes enriched for pathways related to synaptic signaling, further implicating synaptic communication as a convergent mechanism. Consistent with these results, immunofluorescence revealed increased synaptic architecture in the antennal lobe, a brain region associated with sleep and sensory processing. Together, these findings highlight the utility of Drosophila for modeling conserved ASD risk genes and implicate domino in the regulation of synaptic communication and behavior through transcriptional and splicing regulation.