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

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.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

McDiarmid TA,Belmadani M,Liang J,Meili F,Mathews EA,Mullen GP,Hendi A,Wong WR,Rand JB,Mizumoto K,Haas K,Pavlidis P,Rankin CH

doi

10.1073/pnas.1912049116

subject

Has Abstract

pub_date

2020-01-07 00:00:00

pages

656-667

issue

eissn

0027-8424

issn

1091-6490

pii

1912049116

journal_volume

117

pub_type

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