Systematic phenomics analysis of autism-associated genes reveals parallel networks underlying reversible impairments in habituation.

TitleSystematic phenomics analysis of autism-associated genes reveals parallel networks underlying reversible impairments in habituation.
Publication TypeJournal Article
Year of Publication2020
AuthorsMcDiarmid TA, Belmadani M, Liang J, Meili F, Mathews EA, Mullen GP, Hendi A, Wong W-R, Rand JB, Mizumoto K, Haas K, Pavlidis P, Rankin CH
JournalProc Natl Acad Sci U S A
Volume117
Issue1
Pagination656-667
Date Published2020 01 07
ISSN1091-6490
KeywordsAnimals, Animals, Genetically Modified, Autism Spectrum Disorder, Behavior Observation Techniques, Behavior, Animal, Caenorhabditis elegans, Cell Adhesion Molecules, Neuronal, Disease Models, Animal, DNA-Binding Proteins, Epistasis, Genetic, Habituation, Psychophysiologic, Humans, Immunoglobulins, Locomotion, Membrane Proteins, Mutation, Missense, Phenomics, Phenotype, Transcription Factors
Abstract

A major challenge facing the genetics of autism spectrum disorders (ASDs) is the large and growing number of candidate risk genes and gene variants of unknown functional significance. Here, we used 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 135 strains each carrying a mutation in an ortholog of an ASD-associated gene. We identified hundreds of 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 and that underlie mechanosensory hyperresponsivity 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 mutant rescued their sensory and learning impairments. Testing the rescuing ability of 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 in vivo variant functional assays, and potential therapeutic targets for ASD.

DOI10.1073/pnas.1912049116
Alternate JournalProc Natl Acad Sci U S A
PubMed ID31754030
PubMed Central IDPMC6968627
Grant ListP40 OD010440 / OD / NIH HHS / United States
MOP 130287 / / CIHR / Canada