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Network topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism.

Noh HJ, Ponting CP, Boulding HC, Meader S, Betancur C, Buxbaum JD, Pinto D, Marshall CR, Lionel AC, Scherer SW, Webber C - PLoS Genet. (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: MRC Functional Genomics Unit, University of Oxford, Department of Physiology, Anatomy, and Genetics, Oxford, United Kingdom.

ABSTRACT
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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Distinct duplications and deletions of genes whose proteins interact within the ASD-associated network perturb pathways in the same direction.Genes duplicated within ASD dn CNVs are indicated with green upwards arrows while those deleted are denoted by blue downwards arrows. Previously identified ASD-Implicated genes found to be disrupted in autism patients are denoted with red downwards arrows. The nature of the interactions/regulations between proteins/molecules are shown with different edge types (see in-figure legend). The ASD-associated network (Figure 2) identifies several deletion/duplication pathway cascades, for example the MAPK3 pathway (see Discussion for additional examples). Here, deletions of the MAPK3 pathway components (i.e. SYNGAP1, SHANK2, KRAS, MAPK3, PAK2, and CREBBP) and duplications of their negative regulators (i.e. FMR1, GDI1, ARHGDIA, CAMK2B, and CAMKK2) found in autistic patients identify converging effects on the MAPK pathway, specifically reduced CREB-dependent transcription [9], [62], [63], [64]. CREB-dependent transcription has been implicated in neuroadaptation [20]. In addition, increased NO* production leads to the inhibition of MAPK1/3 activity [65], which fits well with the observed CNV duplications of both NOS1 and DLG4, the latter gene promoting recruitment of NOS1[66]. Similarly, duplication of PRKG1, which is up-regulated by NO* and expresses a product that inhibits IP3 production, is predicted to reduced activation of the calcium-releasing IP3-receptor ITPR1[67], which is in turn found to be deleted.
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pgen-1003523-g003: Distinct duplications and deletions of genes whose proteins interact within the ASD-associated network perturb pathways in the same direction.Genes duplicated within ASD dn CNVs are indicated with green upwards arrows while those deleted are denoted by blue downwards arrows. Previously identified ASD-Implicated genes found to be disrupted in autism patients are denoted with red downwards arrows. The nature of the interactions/regulations between proteins/molecules are shown with different edge types (see in-figure legend). The ASD-associated network (Figure 2) identifies several deletion/duplication pathway cascades, for example the MAPK3 pathway (see Discussion for additional examples). Here, deletions of the MAPK3 pathway components (i.e. SYNGAP1, SHANK2, KRAS, MAPK3, PAK2, and CREBBP) and duplications of their negative regulators (i.e. FMR1, GDI1, ARHGDIA, CAMK2B, and CAMKK2) found in autistic patients identify converging effects on the MAPK pathway, specifically reduced CREB-dependent transcription [9], [62], [63], [64]. CREB-dependent transcription has been implicated in neuroadaptation [20]. In addition, increased NO* production leads to the inhibition of MAPK1/3 activity [65], which fits well with the observed CNV duplications of both NOS1 and DLG4, the latter gene promoting recruitment of NOS1[66]. Similarly, duplication of PRKG1, which is up-regulated by NO* and expresses a product that inhibits IP3 production, is predicted to reduced activation of the calcium-releasing IP3-receptor ITPR1[67], which is in turn found to be deleted.

Mentions: Of the 203 CNV genes identified through the synaptic mouse phenotype associations and the ASD-associated network, 110 (54%) are found only in duplications while 91 (45%) are only in deletions. We next investigated how the two directions – duplications or deletions – of copy number change might reflect common or divergent aetiologies. To achieve this we analysed the GO biological process annotations assigned to duplicated and, separately, to deleted genes for significantly over-represented terms (Table S6). While many of the over-represented annotation terms are shared between the deleted and duplicated gene sets, we noted a striking difference: The deleted candidate genes are significantly enriched only in genes that are positive regulators of biological processes (GO:0048518, 35/82 annotated genes, 2.4-fold enrichment, BH-adjusted p = 3×10−4) while, conversely, an enrichment of genes that are negative regulators of biological processes is only observed amongst the duplicated candidate gene set (GO:0048519, 34/105 annotated genes, 2-fold enrichment, BH-adjusted p = 0.006; Table 3). Each of the 4 CNV set's candidate genes contribute to each of these enrichments with many sets nominally significant individually (Table S7). Furthermore, reclassifying the partially duplicated, and therefore likely-disrupted, genes as deletions enhances these enrichments further (Table S8). These enrichments are complementary and thus immediately suggest a convergent model of action in which the duplication of negative regulator genes or the deletion of positive regulator genes both act to perturb a common target process and affect the same outcome. The unusually frequent deletions of positive regulators and duplications of negative regulators enable specific and biologically-meaningful interpretations of the ASD-associated network (see Figure 3 and Discussion).


Network topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism.

Noh HJ, Ponting CP, Boulding HC, Meader S, Betancur C, Buxbaum JD, Pinto D, Marshall CR, Lionel AC, Scherer SW, Webber C - PLoS Genet. (2013)

Distinct duplications and deletions of genes whose proteins interact within the ASD-associated network perturb pathways in the same direction.Genes duplicated within ASD dn CNVs are indicated with green upwards arrows while those deleted are denoted by blue downwards arrows. Previously identified ASD-Implicated genes found to be disrupted in autism patients are denoted with red downwards arrows. The nature of the interactions/regulations between proteins/molecules are shown with different edge types (see in-figure legend). The ASD-associated network (Figure 2) identifies several deletion/duplication pathway cascades, for example the MAPK3 pathway (see Discussion for additional examples). Here, deletions of the MAPK3 pathway components (i.e. SYNGAP1, SHANK2, KRAS, MAPK3, PAK2, and CREBBP) and duplications of their negative regulators (i.e. FMR1, GDI1, ARHGDIA, CAMK2B, and CAMKK2) found in autistic patients identify converging effects on the MAPK pathway, specifically reduced CREB-dependent transcription [9], [62], [63], [64]. CREB-dependent transcription has been implicated in neuroadaptation [20]. In addition, increased NO* production leads to the inhibition of MAPK1/3 activity [65], which fits well with the observed CNV duplications of both NOS1 and DLG4, the latter gene promoting recruitment of NOS1[66]. Similarly, duplication of PRKG1, which is up-regulated by NO* and expresses a product that inhibits IP3 production, is predicted to reduced activation of the calcium-releasing IP3-receptor ITPR1[67], which is in turn found to be deleted.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3675007&req=5

pgen-1003523-g003: Distinct duplications and deletions of genes whose proteins interact within the ASD-associated network perturb pathways in the same direction.Genes duplicated within ASD dn CNVs are indicated with green upwards arrows while those deleted are denoted by blue downwards arrows. Previously identified ASD-Implicated genes found to be disrupted in autism patients are denoted with red downwards arrows. The nature of the interactions/regulations between proteins/molecules are shown with different edge types (see in-figure legend). The ASD-associated network (Figure 2) identifies several deletion/duplication pathway cascades, for example the MAPK3 pathway (see Discussion for additional examples). Here, deletions of the MAPK3 pathway components (i.e. SYNGAP1, SHANK2, KRAS, MAPK3, PAK2, and CREBBP) and duplications of their negative regulators (i.e. FMR1, GDI1, ARHGDIA, CAMK2B, and CAMKK2) found in autistic patients identify converging effects on the MAPK pathway, specifically reduced CREB-dependent transcription [9], [62], [63], [64]. CREB-dependent transcription has been implicated in neuroadaptation [20]. In addition, increased NO* production leads to the inhibition of MAPK1/3 activity [65], which fits well with the observed CNV duplications of both NOS1 and DLG4, the latter gene promoting recruitment of NOS1[66]. Similarly, duplication of PRKG1, which is up-regulated by NO* and expresses a product that inhibits IP3 production, is predicted to reduced activation of the calcium-releasing IP3-receptor ITPR1[67], which is in turn found to be deleted.
Mentions: Of the 203 CNV genes identified through the synaptic mouse phenotype associations and the ASD-associated network, 110 (54%) are found only in duplications while 91 (45%) are only in deletions. We next investigated how the two directions – duplications or deletions – of copy number change might reflect common or divergent aetiologies. To achieve this we analysed the GO biological process annotations assigned to duplicated and, separately, to deleted genes for significantly over-represented terms (Table S6). While many of the over-represented annotation terms are shared between the deleted and duplicated gene sets, we noted a striking difference: The deleted candidate genes are significantly enriched only in genes that are positive regulators of biological processes (GO:0048518, 35/82 annotated genes, 2.4-fold enrichment, BH-adjusted p = 3×10−4) while, conversely, an enrichment of genes that are negative regulators of biological processes is only observed amongst the duplicated candidate gene set (GO:0048519, 34/105 annotated genes, 2-fold enrichment, BH-adjusted p = 0.006; Table 3). Each of the 4 CNV set's candidate genes contribute to each of these enrichments with many sets nominally significant individually (Table S7). Furthermore, reclassifying the partially duplicated, and therefore likely-disrupted, genes as deletions enhances these enrichments further (Table S8). These enrichments are complementary and thus immediately suggest a convergent model of action in which the duplication of negative regulator genes or the deletion of positive regulator genes both act to perturb a common target process and affect the same outcome. The unusually frequent deletions of positive regulators and duplications of negative regulators enable specific and biologically-meaningful interpretations of the ASD-associated network (see Figure 3 and Discussion).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: MRC Functional Genomics Unit, University of Oxford, Department of Physiology, Anatomy, and Genetics, Oxford, United Kingdom.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus