Network topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism.
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 functio...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-06-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003523&type=printable |
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| _version_ | 1850224456232861696 |
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| author | Hyun Ji Noh Chris P Ponting Hannah C Boulding Stephen Meader Catalina Betancur Joseph D Buxbaum Dalila Pinto Christian R Marshall Anath C Lionel Stephen W Scherer Caleb Webber |
| author_facet | Hyun Ji Noh Chris P Ponting Hannah C Boulding Stephen Meader Catalina Betancur Joseph D Buxbaum Dalila Pinto Christian R Marshall Anath C Lionel Stephen W Scherer Caleb Webber |
| author_sort | Hyun Ji Noh |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-fb31c2e77b0f4cce9f9517e06dcbc7bf |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2013-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-fb31c2e77b0f4cce9f9517e06dcbc7bf2025-08-20T02:05:37ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042013-06-0196e100352310.1371/journal.pgen.1003523Network topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism.Hyun Ji NohChris P PontingHannah C BouldingStephen MeaderCatalina BetancurJoseph D BuxbaumDalila PintoChristian R MarshallAnath C LionelStephen W SchererCaleb WebberAutism 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003523&type=printable |
| spellingShingle | Hyun Ji Noh Chris P Ponting Hannah C Boulding Stephen Meader Catalina Betancur Joseph D Buxbaum Dalila Pinto Christian R Marshall Anath C Lionel Stephen W Scherer Caleb Webber Network topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism. PLoS Genetics |
| title | Network topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism. |
| title_full | Network topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism. |
| title_fullStr | Network topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism. |
| title_full_unstemmed | Network topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism. |
| title_short | Network topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism. |
| title_sort | network topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1003523&type=printable |
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