Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

A primary challenge in investigations of genes associated with Autism Spectrum Disorder (ASD) is the lack of a model system in which to characterize the large number of candidate risk genes in a rapid, cost-effective manner. The time and money constraints associated with modelling psychiatric disease in higher-order organisms necessitates an alternative approach. I propose using Caenorhabditis elegans, a microscopic worm commonly used in neuroscience and genetics research, to characterize ASD-associated genes and mutations within those genes. C. elegans is an ideal genetic model organism with which genetic screens and precise genetic engineering can rapidly correlate genotype to phenotype and determine the biological pathways in which genes function. Also, we have developed an automated machine vision system, the Multi-Worm Tracker (MWT), to collect 15 phenotypic measures of development, locomotion, and habituation - a form of learning that is impaired in ASD. I will use the MWT to rapidly characterize hundreds of ASD-associated genes by analyzing the morphology and behaviour of different strains of C. elegans each carrying a mutation in a different ASD-associated gene. After an unbiased characterization of all genes, I will use multivariate analyses to identify genes that induce strong and unique effects to prioritize them for detailed analysis. I will use CRISPR genome engineering to insert human mutations identified in individuals with ASD to determine how these mutations disrupt normal neurodevelopment and learning. This research will generate a large number of novel genotype to phenotype relationships and detailed mechanistic information of how ASD-associated genes alter a nervous system to disrupt normal development, locomotion, and learning. This data can be used to inform future, targeted studies in higher-order organisms and humans. Importantly, this work will identify novel therapeutic targets for ameliorating the effects of ASD.