Network Topologies and Convergent Aetiologies Arising from Deletions and Duplications Observed in Individuals with Autism
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Autism Spectrum Disorders (ASD) are highly heritable and characterised by impairments in social interaction and communication, and restricted and repetitive behaviours. Considering four sets of de novo copy number variants (CNVs) identified in 181 individuals with autism and exploiting mouse functional genomics and known protein-protein interactions, we identified a large and significantly interconnected interaction network. This network contains 187 genes affected by CNVs drawn from 45% of the patients we considered and 22 genes previously implicated in ASD, of which 192 form a single interconnected cluster. On average, those patients with copy number changed genes from this network possess changes in 3 network genes, suggesting that epistasis mediated through the network is extensive. Correspondingly, genes that are highly connected within the network, and thus whose copy number change is predicted by the network to be more phenotypically consequential, are significantly enriched among patients that possess only a single ASD-associated network copy number changed gene (p = 0.002). Strikingly, deleted or disrupted genes from the network are significantly enriched in GO-annotated positive regulators (2.3-fold enrichment, corrected p = 2×10(-5)), whereas duplicated genes are significantly enriched in GO-annotated negative regulators (2.2-fold enrichment, corrected p = 0.005). The direction of copy change is highly informative in the context of the network, providing the means through which perturbations arising from distinct deletions or duplications can yield a common outcome. These findings reveal an extensive ASD-associated molecular network, whose topology indicates ASD-relevant mutational deleteriousness and that mechanistically details how convergent aetiologies can result extensively from CNVs affecting pathways causally implicated in ASD.
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Another approach evaluating CNV duplications and deletions found an interconnected PPI network enriched for synaptic transmission proteins, validating that pathogenic CNVs affect similar gene networks.
“Another approach130 has evaluated CNV duplications in addition to CNV deletions and also found an interconnected PPI network that was enriched for proteins involved in synaptic transmission, validating the observation that pathogenic CNVs affect similar gene networks127.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [130]
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- Authors
- Noh, H. J., Ponting, C. P., Boulding, H. C., Meader, S., Betancur, C., Buxbaum, J. D., Pinto, D., Marshall, C. R., Lionel, A. C., Scherer, S. W., & Webber, C.
- Affiliations
- University of Oxford (GB)
- Centre National de la Recherche Scientifique (FR)
- Icahn School of Medicine at Mount Sinai (US)
- University of Toronto (CA)
- Corresponding author
- Webber, Caleb
- ORCID
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-06-06
- Volume
- 9
- Issue
- 6
- Pages
- e1003523
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3675007
- OpenAlex
- W1974384340
- Cited by
- 54
- References
- 68
- Citations by year
- 2026: 1 · 2021: 2 · 2020: 3 · 2019: 7 · 2018: 1 · 2017: 4 · 2016: 7 · 2015: 11 · 2014: 15 · 2013: 3
- FWCI
- 6.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- HAL (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- European Commission (241995)
- Medical Research Council
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- autism spectrum disorder, copy number variation, de novo CNVs, protein-protein interaction network, network topology, gene deletion, gene duplication, epistasis
- MeSH terms
- Animals, Child, Child Development Disorders, Pervasive, Humans, Genome, Human, Gene Deletion, Gene Dosage, Genetic Predisposition to Disease, Gene Duplication, Mice, Gene Regulatory Networks, Protein Interaction Maps
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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