Autism spectrum disorder (ASD) is a neurodevelopmental disorder often characterized by significant problems with social skills. Human genetic studies have associated ASD with mutations in over 200 genes; however, it is unknown which ASD candidate genes are causal versus coincidentally associated with social deficits. Testing for causality of ASD-related phenotypes in such a large list of genes is challenging, especially when one considers that expressivity of ASD phenotypes may depend on mutations across multiple genes. We sought to leverage the convenient behavioral genetics of Caenorhabditis elegans to test for social deficits in orthologs of ASD-associated genes. C. elegans displays social behaviors through social feeding and clumping. The common wild-type lab strain N2 displays weak social behavior due to a background mutation in the neuropeptide-Y-like receptor,
npr-1, but most natural wild strains are strongly social. We evaluated levels of social behaviors of 24 wild strains that harbor unique, naturally occurring variants predicted to alter function of conserved ASD candidate genes. We discovered that strains with predicted change-of-function mutations in ASD- implicated genes demonstrated significantly lower levels of social behavior compared to control social strains without these mutations. These genes include orthologs of human genes BCL11A, PDCD2, SHANK3, STX1A, NLGN1, IL-17, IL17R, CHD2, and SETD5. In addition to finding strains with dual defects in bordering and clumping, intriguingly, we identified strains that exhibited selective defects in one of the two social behaviors suggesting that they are genetically separable. We also analyzed the evolutionary conservation of ASD-implicated genes to characterize critical regions for naturally occurring variations. Identification of genes and their critical regions that may predict ASD phenotypes when mutated could help medical professionals and genetic counselors identify at-risk families, while also providing useful insight to explain causality in the biological foundations of ASD-related phenotypes.