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Human intellectual disability genes form conserved functional modules in Drosophila.

Oortveld MA, Keerthikumar S, Oti M, Nijhof B, Fernandes AC, Kochinke K, Castells-Nobau A, van Engelen E, Ellenkamp T, Eshuis L, Galy A, van Bokhoven H, Habermann B, Brunner HG, Zweier C, Verstreken P, Huynen MA, Schenck A - PLoS Genet. (2013)

Bottom Line: Novel links between ID genes successfully predicted that MYCN, PIGV and UPF3B regulate synapse development.Drosophila phenotype groups show, in addition to ID, significant phenotypic similarity also in humans, indicating that functional modules are conserved.The combined data indicate that ID disorders, despite their extreme genetic diversity, are caused by disruption of a limited number of highly connected functional modules.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.

ABSTRACT
Intellectual Disability (ID) disorders, defined by an IQ below 70, are genetically and phenotypically highly heterogeneous. Identification of common molecular pathways underlying these disorders is crucial for understanding the molecular basis of cognition and for the development of therapeutic intervention strategies. To systematically establish their functional connectivity, we used transgenic RNAi to target 270 ID gene orthologs in the Drosophila eye. Assessment of neuronal function in behavioral and electrophysiological assays and multiparametric morphological analysis identified phenotypes associated with knockdown of 180 ID gene orthologs. Most of these genotype-phenotype associations were novel. For example, we uncovered 16 genes that are required for basal neurotransmission and have not previously been implicated in this process in any system or organism. ID gene orthologs with morphological eye phenotypes, in contrast to genes without phenotypes, are relatively highly expressed in the human nervous system and are enriched for neuronal functions, suggesting that eye phenotyping can distinguish different classes of ID genes. Indeed, grouping genes by Drosophila phenotype uncovered 26 connected functional modules. Novel links between ID genes successfully predicted that MYCN, PIGV and UPF3B regulate synapse development. Drosophila phenotype groups show, in addition to ID, significant phenotypic similarity also in humans, indicating that functional modules are conserved. The combined data indicate that ID disorders, despite their extreme genetic diversity, are caused by disruption of a limited number of highly connected functional modules.

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ID modules, proof of predictive value and phenotype coherence across evolution.(A) Phenotype-based homotypic ID modules. PPIs from HRPD in black, PPIs from human Interologs in turquoise, co-isolated protein complexes in yellow and genetic interactions in green. A high resolution image of Figure 6A is provided as Figure S4. (B) Three examples of homotypic modules that predict novel connections and phenotypes. Dotted lines indicate additional support identified by targeted literature search (see Table S4). (C) The ‘long bristles’ genes MYCN, PIGV and UPF3B are required, as predicted, for normal synapse development of the Drosophila larval Neuromuscular junction (NMJ). Anti-dlg1 labelling in red. The synaptic area (µm2) was quantitatively assessed using an in house-developed Fiji macro. Panels show representative NMJs. Box plots show the quantitative MYCN, PIGV and UPF3B synaptic phenotypes, compared to their appropriate genetic background controls. ** p<0.01; *** p<0.001; two tailed T-test. All phenotypes are highly significant. (D) Phenotypic similarity of human disorders caused by genes in the same fly eye phenotype category. Red crosses indicate the mean within-group phenotype similarity score. Box plots display the distributions of 1000 random controls sampled from the full set of genes in HPO, with the box representing the 25%–75% interquartile range. Asterisks indicate significant within-group phenotype similarity. ** p<0.05; ** p<0.01; *** p<0.001. Eye morphology categories as indicated, whereby “fused” represents fused and partially fused ommatidia, “bristles, others” represents fewer, no and stubble bristles, and SEWDS represents small eye and wrinkled or dented surface. Note that genes associated with ERG defects, lethal, and NED-ID genes (no eye morphology phenotype) also show a high degree of phenotypic coherence in human.
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pgen-1003911-g006: ID modules, proof of predictive value and phenotype coherence across evolution.(A) Phenotype-based homotypic ID modules. PPIs from HRPD in black, PPIs from human Interologs in turquoise, co-isolated protein complexes in yellow and genetic interactions in green. A high resolution image of Figure 6A is provided as Figure S4. (B) Three examples of homotypic modules that predict novel connections and phenotypes. Dotted lines indicate additional support identified by targeted literature search (see Table S4). (C) The ‘long bristles’ genes MYCN, PIGV and UPF3B are required, as predicted, for normal synapse development of the Drosophila larval Neuromuscular junction (NMJ). Anti-dlg1 labelling in red. The synaptic area (µm2) was quantitatively assessed using an in house-developed Fiji macro. Panels show representative NMJs. Box plots show the quantitative MYCN, PIGV and UPF3B synaptic phenotypes, compared to their appropriate genetic background controls. ** p<0.01; *** p<0.001; two tailed T-test. All phenotypes are highly significant. (D) Phenotypic similarity of human disorders caused by genes in the same fly eye phenotype category. Red crosses indicate the mean within-group phenotype similarity score. Box plots display the distributions of 1000 random controls sampled from the full set of genes in HPO, with the box representing the 25%–75% interquartile range. Asterisks indicate significant within-group phenotype similarity. ** p<0.05; ** p<0.01; *** p<0.001. Eye morphology categories as indicated, whereby “fused” represents fused and partially fused ommatidia, “bristles, others” represents fewer, no and stubble bristles, and SEWDS represents small eye and wrinkled or dented surface. Note that genes associated with ERG defects, lethal, and NED-ID genes (no eye morphology phenotype) also show a high degree of phenotypic coherence in human.

Mentions: We next mapped the phenotype-based homotypic ID modules that are underlying the determined enrichments in connectivity among our phenotype categories (see Materials and Methods). In total, we identified 26 functionally coherent ID modules composed of 100 Drosophila ID genes and 200 homotypic connections (Figure 6A and its high resolution image provided as Figure S4). For the remaining 170 ID genes (63%), no homotypic connections were annotated.


Human intellectual disability genes form conserved functional modules in Drosophila.

Oortveld MA, Keerthikumar S, Oti M, Nijhof B, Fernandes AC, Kochinke K, Castells-Nobau A, van Engelen E, Ellenkamp T, Eshuis L, Galy A, van Bokhoven H, Habermann B, Brunner HG, Zweier C, Verstreken P, Huynen MA, Schenck A - PLoS Genet. (2013)

ID modules, proof of predictive value and phenotype coherence across evolution.(A) Phenotype-based homotypic ID modules. PPIs from HRPD in black, PPIs from human Interologs in turquoise, co-isolated protein complexes in yellow and genetic interactions in green. A high resolution image of Figure 6A is provided as Figure S4. (B) Three examples of homotypic modules that predict novel connections and phenotypes. Dotted lines indicate additional support identified by targeted literature search (see Table S4). (C) The ‘long bristles’ genes MYCN, PIGV and UPF3B are required, as predicted, for normal synapse development of the Drosophila larval Neuromuscular junction (NMJ). Anti-dlg1 labelling in red. The synaptic area (µm2) was quantitatively assessed using an in house-developed Fiji macro. Panels show representative NMJs. Box plots show the quantitative MYCN, PIGV and UPF3B synaptic phenotypes, compared to their appropriate genetic background controls. ** p<0.01; *** p<0.001; two tailed T-test. All phenotypes are highly significant. (D) Phenotypic similarity of human disorders caused by genes in the same fly eye phenotype category. Red crosses indicate the mean within-group phenotype similarity score. Box plots display the distributions of 1000 random controls sampled from the full set of genes in HPO, with the box representing the 25%–75% interquartile range. Asterisks indicate significant within-group phenotype similarity. ** p<0.05; ** p<0.01; *** p<0.001. Eye morphology categories as indicated, whereby “fused” represents fused and partially fused ommatidia, “bristles, others” represents fewer, no and stubble bristles, and SEWDS represents small eye and wrinkled or dented surface. Note that genes associated with ERG defects, lethal, and NED-ID genes (no eye morphology phenotype) also show a high degree of phenotypic coherence in human.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814316&req=5

pgen-1003911-g006: ID modules, proof of predictive value and phenotype coherence across evolution.(A) Phenotype-based homotypic ID modules. PPIs from HRPD in black, PPIs from human Interologs in turquoise, co-isolated protein complexes in yellow and genetic interactions in green. A high resolution image of Figure 6A is provided as Figure S4. (B) Three examples of homotypic modules that predict novel connections and phenotypes. Dotted lines indicate additional support identified by targeted literature search (see Table S4). (C) The ‘long bristles’ genes MYCN, PIGV and UPF3B are required, as predicted, for normal synapse development of the Drosophila larval Neuromuscular junction (NMJ). Anti-dlg1 labelling in red. The synaptic area (µm2) was quantitatively assessed using an in house-developed Fiji macro. Panels show representative NMJs. Box plots show the quantitative MYCN, PIGV and UPF3B synaptic phenotypes, compared to their appropriate genetic background controls. ** p<0.01; *** p<0.001; two tailed T-test. All phenotypes are highly significant. (D) Phenotypic similarity of human disorders caused by genes in the same fly eye phenotype category. Red crosses indicate the mean within-group phenotype similarity score. Box plots display the distributions of 1000 random controls sampled from the full set of genes in HPO, with the box representing the 25%–75% interquartile range. Asterisks indicate significant within-group phenotype similarity. ** p<0.05; ** p<0.01; *** p<0.001. Eye morphology categories as indicated, whereby “fused” represents fused and partially fused ommatidia, “bristles, others” represents fewer, no and stubble bristles, and SEWDS represents small eye and wrinkled or dented surface. Note that genes associated with ERG defects, lethal, and NED-ID genes (no eye morphology phenotype) also show a high degree of phenotypic coherence in human.
Mentions: We next mapped the phenotype-based homotypic ID modules that are underlying the determined enrichments in connectivity among our phenotype categories (see Materials and Methods). In total, we identified 26 functionally coherent ID modules composed of 100 Drosophila ID genes and 200 homotypic connections (Figure 6A and its high resolution image provided as Figure S4). For the remaining 170 ID genes (63%), no homotypic connections were annotated.

Bottom Line: Novel links between ID genes successfully predicted that MYCN, PIGV and UPF3B regulate synapse development.Drosophila phenotype groups show, in addition to ID, significant phenotypic similarity also in humans, indicating that functional modules are conserved.The combined data indicate that ID disorders, despite their extreme genetic diversity, are caused by disruption of a limited number of highly connected functional modules.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.

ABSTRACT
Intellectual Disability (ID) disorders, defined by an IQ below 70, are genetically and phenotypically highly heterogeneous. Identification of common molecular pathways underlying these disorders is crucial for understanding the molecular basis of cognition and for the development of therapeutic intervention strategies. To systematically establish their functional connectivity, we used transgenic RNAi to target 270 ID gene orthologs in the Drosophila eye. Assessment of neuronal function in behavioral and electrophysiological assays and multiparametric morphological analysis identified phenotypes associated with knockdown of 180 ID gene orthologs. Most of these genotype-phenotype associations were novel. For example, we uncovered 16 genes that are required for basal neurotransmission and have not previously been implicated in this process in any system or organism. ID gene orthologs with morphological eye phenotypes, in contrast to genes without phenotypes, are relatively highly expressed in the human nervous system and are enriched for neuronal functions, suggesting that eye phenotyping can distinguish different classes of ID genes. Indeed, grouping genes by Drosophila phenotype uncovered 26 connected functional modules. Novel links between ID genes successfully predicted that MYCN, PIGV and UPF3B regulate synapse development. Drosophila phenotype groups show, in addition to ID, significant phenotypic similarity also in humans, indicating that functional modules are conserved. The combined data indicate that ID disorders, despite their extreme genetic diversity, are caused by disruption of a limited number of highly connected functional modules.

Show MeSH
Related in: MedlinePlus