Human genetic studies have identified hundreds of genes with variants associated with autism. However, the significance of most of these variants is unknown. At least half of the genes are present in all animals and thus can be studied in genetic model organisms that allow rapid, rigorous genetic analysis.
Paul Sternberg and his colleagues at the California Institute of Technology will use a simple, small animal, the roundworm C. elegans, to study the function of evolutionarily conserved signaling pathways, proteins and protein domains. The utility of C. elegans as a model organism is multifaceted, allowing researchers to carry out experiments readily because of the animals’ short generation time, small size, transparency, invariant development and stereotyped behavior, their completely sequenced and well-annotated genome, and susceptibility to genome editing.
The researchers have chosen potential candidate autism alleles from the Simons Simplex Collection (SSC) that can be studied with C. elegans molecular genetics, having identified C. elegans equivalents of many of the human autism-associated variants. Sternberg and his team will construct C. elegans strains that that replace the normal C. elegans allele with human variants, comparing the phenotypes of autism-variant strains with those carrying the standard allele as well as with strains lacking the protein. These comparisons will allow the researchers to infer how a variant allele affects activity of the gene, determining whether that allele eliminates, decreases, increases or alters gene activity, or has no effect. All of the strains produced will be available through the Caenorhabditis Genetics Center, and the phenotypic and strain information will be made publically available through WormBase.org and SFARI.org soon after the results are generated so that other researchers can study these variants further. In this way, Sternberg’s team will help prioritize more intensive studies of particular autism variants and will allow for more targeted experiments to further our understanding of autism-affected gene(s) and the pathway(s) in which they act.