High-throughput interrogation of autism risk genes: from molecules to behavior

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PROJECT SUMMARY Over 1,000 genes have been implicated in autism spectrum disorder (ASD) but only a handful have been confirmed as causing phenotypes related to ASD in animal models. Understanding if and how each gene contributes to ASD-related phenotypes singly or in combination is not feasible with rodent models, which require enormous time, expense, and labor to generate and characterize. We have previously leveraged the nematode C. elegans as a minimum in vivo animal model to quickly characterize genes related to human neurological conditions. ------ C. elegans displays phenotypes with relevance to ASD including social behaviors represented by how they tend to clump together in piles while eating. To quickly gain insight into whether 109 SFARI gene orthologs play a role in social behaviors in C. elegans, rather than study one mutant at a time, we studied a collection of genetically distinct wild-type strains isolated from around the world. Each strain carries a distinct combination of variants in these 109 ASD risk genes. We discovered that overall, the number and severity of mutations in ASD risk genes correlated with decreased social behaviors. Moreover, we found that mutations in certain ASD risk genes appear to cause social deficits, because we could boost social behaviors by replacing defective ASD risk genes with functional versions. We also found that mutations in orthologs of genes that cause increased social behavior in C. elegans have already been implicated in positively modifying social behavior in ASD and Williams syndrome. The central hypothesis is that C. elegans will be a rapid and inexpensive model organism to determine which combinations of mutations in this vast number of risk genes cause ASD-related defects. The overall goal is to determine which mutations and combinations of mutations in ASD risk genes cause ASD-relevant behaviors, and by what mechanisms. The rationale is that there is an urgent need to understand the in vivo consequences of mutations in genes implicated in autism. The central hypothesis will be tested with three specific aims: 1) Identify which and how natural variants in ASD risk genes causally contribute to decreasing social behaviors and sensory integration in C. elegans. 2) Test which and how variants in ASD risk genes positively modify social behaviors and sensory integration in C. elegans. 3) Determine the mechanism by which genetic variants of uncertain significance identified in ASD patients influence social and sensory integration behaviors and neurobiology of C. elegans. ------ The research proposed in this application is innovative because it uses a minimalist animal model to perform high-throughput in vivo causal functional analyses of ASD risk genes. The work is significant because it will allow researchers working with rodents and human patients to focus their efforts on the most promising ASD risk genes. The results will empower families to understand how patient-specific mutations in unstudied or under-studied ASD risk genes influence basic neurobiology. Ultimately, such knowledge has the potential to guide the development of future pharmacological and genetic treatments for the symptoms of ASD.