A major challenge that researchers face in attempting to understand the molecular mechanisms underlying autism spectrum disorders (ASD) is that thousands of gene mutations have been linked to the disease. Adding to this complexity is that, for many of the implicated genes, different variants have been found in distinct individuals with ASD. Assessing this complexity has proven difficult using traditional low-throughput methods, resulting in a wealth of ASD gene variants without functional phenotyping. To address this issue, Kurt Haas and his colleagues at the University of British Columbia will use a combined approach taking advantage of both high- and low-throughput assays to identify ASD gene variants with strong phenotypes, and to provide information on physiological roles for many poorly characterized ASD-associated genes.
In their initial screen, Haas and his colleagues plan to use a bioinformatics approach to prioritize thousands of putative ASD genes and gene variants, and then run these these prioritized genes through a variety of rapid, unbiased assays. Specifically, the researchers will assess gene interactions using Saccharomyces, neuronal structural and functional development in Drosophila, and learned and motor behaviors in Drosophila and C. elegans systems. Using multivariance analyses, Haas and his team will then narrow the candidate gene pool to the top 10 to 30 ASD gene variants that produce strong, unique phenotypes.
Haas and his colleagues will subsequently test this small subset of gene variants for their effects on aspects of neuronal development known to be altered in individuals with ASD. To this end, the researchers will assess neuronal growth and synaptogenesis in rat hippocampal cell cultures, and experience-dependent neural circuit formation and refinement using in vivo imaging in awake, behaving Xenopus tadpoles.
The results of these studies are expected to provide a major advance by identifying which ASD gene variants produce measurable functional phenotypes. In addition, the large number and wide range of assays that will be conducted on each mutation will provide important insights about how ASD gene variants alter brain circuit development and function, greatly advancing our understanding of the molecular mechanisms underlying ASD.