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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Autores principales: 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
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Publicado: Public Library of Science (PLoS) 2013
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spelling oai:doaj.org-article:fb31c2e77b0f4cce9f9517e06dcbc7bf2021-11-18T06:19:35ZNetwork topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism.1553-73901553-740410.1371/journal.pgen.1003523https://doaj.org/article/fb31c2e77b0f4cce9f9517e06dcbc7bf2013-06-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23754953/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Autism 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.Hyun Ji NohChris P PontingHannah C BouldingStephen MeaderCatalina BetancurJoseph D BuxbaumDalila PintoChristian R MarshallAnath C LionelStephen W SchererCaleb WebberPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 9, Iss 6, p e1003523 (2013)
institution DOAJ
collection DOAJ
language EN
topic Genetics
QH426-470
spellingShingle Genetics
QH426-470
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.
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
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
title 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_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_sort network topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism.
publisher Public Library of Science (PLoS)
publishDate 2013
url https://doaj.org/article/fb31c2e77b0f4cce9f9517e06dcbc7bf
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