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Systematic phenomics analysis of autism-associated genes reveals parallel networks underlying reversible impairments in habituation.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Jan 07; Vol. 117 (1), pp. 656-667. Date of Electronic Publication: 2019 Nov 21. - Publication Year :
- 2020
-
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 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 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 CHD8•chd-7 and NLGN3•nlg-1 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 nlg-1 mutant C. elegans 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.<br />Competing Interests: The authors declare no competing interest.
- Subjects :
- Animals
Animals, Genetically Modified
Autism Spectrum Disorder physiopathology
Behavior Observation Techniques methods
Behavior, Animal physiology
Caenorhabditis elegans
DNA-Binding Proteins genetics
Disease Models, Animal
Epistasis, Genetic
Humans
Immunoglobulins genetics
Locomotion genetics
Membrane Proteins genetics
Mutation, Missense
Phenotype
Transcription Factors genetics
Autism Spectrum Disorder genetics
Cell Adhesion Molecules, Neuronal genetics
Habituation, Psychophysiologic genetics
Phenomics methods
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 117
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 31754030
- Full Text :
- https://doi.org/10.1073/pnas.1912049116