RT Journal Article
SR Electronic
T1 Systematic phenomics analysis of ASD-associated genes reveals shared functions and parallel networks underlying reversible impairments in habituation learning
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 687194
DO 10.1101/687194
A1 Troy A. McDiarmid
A1 Manuel Belmadani
A1 Joseph Liang
A1 Fabian Meili
A1 Eleanor A. Mathews
A1 Gregory P. Mullen
A1 James B. Rand
A1 Kota Mizumoto
A1 Kurt Haas
A1 Paul Pavlidis
A1 Catharine H. Rankin
YR 2019
UL http://biorxiv.org/content/early/2019/06/30/687194.abstract
AB A major challenge facing the genetics of Autism Spectrum Disorders (ASD) is the large and growing number of candidate risk genes and gene variants of unknown functional significance. Here, we used Caenorhabditis elegans to systematically functionally characterize ASD-associated genes in vivo. Using our custom machine vision system we quantified 26 phenotypes spanning morphology, locomotion, tactile sensitivity, and habituation learning in 87 strains each carrying a mutation in an ortholog of an ASD-associated gene. We identified hundreds of novel genotype-phenotype relationships ranging from severe developmental delays and uncoordinated movement to subtle deficits in sensory and learning behaviors. We 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. We then leveraged our data for in vivo functional assays to gauge missense variant effect. Expression of wild-type NLG-1 in nlg-1 mutant C. elegans rescued their sensory and learning impairments. Testing the rescuing ability of all conserved ASD-associated neuroligin variants revealed varied partial loss-of-function despite proper subcellular localization. Finally, we used CRISPR-Cas9 auxin inducible degradation to determine that phenotypic abnormalities caused by developmental loss of NLG-1 can be reversed by adult expression. This work charts the phenotypic landscape of ASD-associated genes, offers novel in vivo variant functional assays, and potential therapeutic targets for ASD.