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UBC Theses and Dissertations

Sytematic phenomics analysis of autism risk genes and variants McDiarmid, Troy A.


Two major challenges facing the genetics of Autism Spectrum Disorders (ASD) are the large and growing number of candidate risk genes and gene variants of unknown functional significance. The goals of this dissertation were to combine emerging methods in CRISPR-Cas9 genome engineering with machine vision phenomics to gain insight into the functions of ASD risk genes and the functional impact of specific variants. I developed a pipeline to discover the functions of ASD risk genes by obtaining strains of the genetic model organism Caenorhabditis elegans with inactivating mutations in each gene and observed the phenotypic consequences using machine vision. I quantified 26 phenotypes spanning morphology, locomotion, tactile sensitivity, and learning in >27,000 animals representing 135 genotypes (98 strains with mutations in different genes and 37 strains with additional alleles of a subset of these genes), allowing us to identify disruptions in habituation (a neural circuit’s plastic ability to decrease responding to repeated sensory stimuli) as a common impairment. I then clustered genes by similarity in phenomic profiles and used epistasis analysis to discover parallel networks centered on CHD8•chd-7 and NLGN3•nlg-1 that underlie mechanosensory hyper-responsivity and impaired habituation learning. Next, I demonstrated how this database can facilitate experiments that determine the functional consequences of missense variants and whether phenotypic alterations are reversible. Further, I developed a broadly applicable CRSIRP-Cas9 genome editing strategy to replace C. elegans genes with human genes that allows for in vivo analysis of human genetic variation with unprecedented precision. Finally, I contributed to the development of a multi-model system pipeline for high-confidence assessment of missense variants in the ASD risk gene PTEN. This work charts the phenotypic landscape of ASD-associated genes, offers in vivo variant functional assays, and potential therapeutic targets for ASD.

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