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

McDiarmid, Troy A. and Belmadani, Manuel and Liang, Joseph and Meili, Fabian and Mathews, Eleanor A. and Mullen, Gregory P. and Hendi, Ardalan and Wong, Wan-Rong and Rand, James B. and Mizumoto, Kota and Haas, Kurt and Pavlidis, Paul and Rankin, Catharine H. (2020) Systematic phenomics analysis of autism-associated genes reveals parallel networks underlying reversible impairments in habituation. Proceedings of the National Academy of Sciences of the United States of America, 117 (1). pp. 656-667. ISSN 0027-8424. PMCID PMC6968627. https://resolver.caltech.edu/CaltechAUTHORS:20191122-111033277

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1073/pnas.1912049116DOIArticle
https://www.pnas.org/content/suppl/2019/11/21/1912049116.DCSupplementalPublisherSupporting Information
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6968627/PubMed CentralArticle
ORCID:
AuthorORCID
Wong, Wan-Rong0000-0002-9757-8145
Additional Information:© 2019 National Academy of Sciences. Published under the PNAS license. Edited by Gene E. Robinson, University of Illinois at Urbana–Champaign, Urbana, IL, and approved October 25, 2019 (received for review July 16, 2019). PNAS first published November 21, 2019. We thank Dr. Evan Ardiel for discussions regarding the manuscript; Dr. Paul Sternberg, Dr. John Calarco, Dr. Erik Jorgensen, and Dr. Don Moerman and their labs for sharing constructs and protocols or making them available; the C. elegans knockout consortium for alleles and the National Bioresource Project and the C. elegans Genetics Center (National Institutes of Health Office of Research Infrastructure Programs, P40623 OD010440) for strains; Lexis Kepler, Aaron Reiss, and Anna Willms for assistance with experiments; and Christine Ackerley for discussions regarding figure design. This work was supported by a Canadian Institutes of Health Research (CIHR) Doctoral Research Award to T.A.M.; Simons Foundation Autism Research Initiative (205081) and Autism Speaks Grants (1975) to J.B.R., a SFARI award (573845) to K.H. (PI), P.P., and C.H.R. (co-PIs); a SFARI award (367560) to Paul Sternberg (PI) supporting W.-R.W.; and a CIHR project grant (CIHR MOP 130287) to C.H.R. Author contributions: T.A.M., J.B.R., K.M., K.H., P.P., and C.H.R. designed research; T.A.M., J.L., E.A.M., G.P.M., A.H., J.B.R., and P.P. performed research; T.A.M., M.B., J.L., F.M., E.A.M., G.P.M., A.H., W.-R.W., J.B.R., K.M., K.H., P.P., and C.H.R. contributed new reagents/analytic tools; T.A.M., M.B., J.L., E.A.M., G.P.M., J.B.R., K.M., K.H., P.P., and C.H.R. analyzed data; T.A.M. and C.H.R. wrote the paper; and M.B., J.B.R., K.M., K.H., and P.P. edited completed manuscript. The authors declare no competing interest. This article is a PNAS Direct Submission. Data deposition: All data generated in this work are available free online in their raw and processed forms at https://dataverse.scholarsportal.info/citation?persistentId=doi:10.5683/SP2/FJWIL8. All analysis code is freely available at https://github.com/PavlidisLab/McDiarmid-etal-2019_Multi-Worm-Tracker-analysis. All strains, sequence confirmation files, and reagents are available from the corresponding author upon request. This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1912049116/-/DCSupplemental.
Funders:
Funding AgencyGrant Number
Canadian Institutes of Health Research (CIHR)MOP 130287
Simons Foundation205081
Autism Speaks1975
Simons Foundation573845
Simons Foundation367560
Subject Keywords:autism spectrum disorder; neurodevelopmental disorders; Caenorhabditis elegans; habituation learning; variants of uncertain significance
Issue or Number:1
PubMed Central ID:PMC6968627
Record Number:CaltechAUTHORS:20191122-111033277
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20191122-111033277
Official Citation:Systematic phenomics analysis of autism-associated genes reveals parallel networks underlying reversible impairments in habituation. Troy A. McDiarmid, Manuel Belmadani, Joseph Liang, Fabian Meili, Eleanor A. Mathews, Gregory P. Mullen, Ardalan Hendi, Wan-Rong Wong, James B. Rand, Kota Mizumoto, Kurt Haas, Paul Pavlidis, Catharine H. Rankin. Proceedings of the National Academy of Sciences Jan 2020, 117 (1) 656-667; DOI: 10.1073/pnas.1912049116
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:100018
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:22 Nov 2019 20:45
Last Modified:02 Jun 2020 18:47

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