RRC ID |
59551
|
Author |
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.
|
Title |
Systematic phenomics analysis of autism-associated genes reveals parallel networks underlying reversible impairments in habituation.
|
Journal |
Proc Natl Acad Sci U S A
|
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.
|
Volume |
117(1)
|
Pages |
656-667
|
Published |
2020-1-7
|
DOI |
10.1073/pnas.1912049116
|
PII |
1912049116
|
PMID |
31754030
|
PMC |
PMC6968627
|
MeSH |
Animals
Animals, Genetically Modified
Autism Spectrum Disorder / genetics*
Autism Spectrum Disorder / physiopathology
Behavior Observation Techniques / methods
Behavior, Animal / physiology
Caenorhabditis elegans
Cell Adhesion Molecules, Neuronal / genetics*
DNA-Binding Proteins / genetics
Disease Models, Animal
Epistasis, Genetic
Habituation, Psychophysiologic / genetics*
Humans
Immunoglobulins / genetics
Locomotion / genetics
Membrane Proteins / genetics
Mutation, Missense
Phenomics / methods*
Phenotype
Transcription Factors / genetics
|
IF |
9.58
|
Times Cited |
2
|
Resource |
C.elegans |
tm2752
tm522
tm9711
tm5775
tm6473
tm1072
tm3577
tm6649
tm4671
tm3318
tm7416
tm846
tm8384
tm3104
tm3197
tm8188
tm1803
tm238
tm2107
tm556
tm1276
tm683
tm748
tm581
tm6676
tm3968
tm5409
tm6724
tm559
tm10242 |