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Shared Pathways Among Autism Candidate Genes Determined by Co-expression Network Analysis of the Developing Human Brain Transcriptome.

Mahfouz A, Ziats MN, Rennert OM, Lelieveldt BP, Reinders MJ - J. Mol. Neurosci. (2015)

Bottom Line: Autism spectrum disorder (ASD) is a neurodevelopmental syndrome known to have a significant but complex genetic etiology.Furthermore, we also constructed co-expression networks from the entire transcriptome and found that ASD candidate genes were enriched in modules related to mitochondrial function, protein translation, and ubiquitination.Overall, our multi-dimensional co-expression analysis of ASD candidate genes in the normal developing human brain suggests the heterogeneous set of ASD candidates share transcriptional networks related to synapse formation and elimination, protein turnover, and mitochondrial function.

View Article: PubMed Central - PubMed

Affiliation: Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands. a.mahfouz@tudelft.nl.

ABSTRACT
Autism spectrum disorder (ASD) is a neurodevelopmental syndrome known to have a significant but complex genetic etiology. Hundreds of diverse genes have been implicated in ASD; yet understanding how many genes, each with disparate function, can all be linked to a single clinical phenotype remains unclear. We hypothesized that understanding functional relationships between autism candidate genes during normal human brain development may provide convergent mechanistic insight into the genetic heterogeneity of ASD. We analyzed the co-expression relationships of 455 genes previously implicated in autism using the BrainSpan human transcriptome database, across 16 anatomical brain regions spanning prenatal life through adulthood. We discovered modules of ASD candidate genes with biologically relevant temporal co-expression dynamics, which were enriched for functional ontologies related to synaptogenesis, apoptosis, and GABA-ergic neurons. Furthermore, we also constructed co-expression networks from the entire transcriptome and found that ASD candidate genes were enriched in modules related to mitochondrial function, protein translation, and ubiquitination. Hub genes central to these ASD-enriched modules were further identified, and their functions supported these ontological findings. Overall, our multi-dimensional co-expression analysis of ASD candidate genes in the normal developing human brain suggests the heterogeneous set of ASD candidates share transcriptional networks related to synapse formation and elimination, protein turnover, and mitochondrial function.

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Hub genes of ASD modules. Each of the four ASD-enriched modules is presented with the degree-sorted circle layout of cytoscape, with the nodes’ size and color reflect the level of connectivity within the network. The bigger the node, the more connections it has. For clarity, edges with correlation values smaller than 0.9 are removed. a Top-connected genes of the magenta module. b Top-connected genes of the brown module. c Top-connected genes of the orange module. d Top-connected genes of the purple module
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Fig6: Hub genes of ASD modules. Each of the four ASD-enriched modules is presented with the degree-sorted circle layout of cytoscape, with the nodes’ size and color reflect the level of connectivity within the network. The bigger the node, the more connections it has. For clarity, edges with correlation values smaller than 0.9 are removed. a Top-connected genes of the magenta module. b Top-connected genes of the brown module. c Top-connected genes of the orange module. d Top-connected genes of the purple module

Mentions: An alternative approach to annotate the function of each ASD-enriched module is to analyze the genes with the strongest correlations within each module. It has been shown that within an interaction network, genes with the most connections to other genes, termed hub genes, are informative for the network as a whole, and are potential high-yield therapeutic targets (Barabási et al. 2011). The strongest correlations within a module were explored using Cytoscape v2.8 (Smoot et al. 2011). First, each ASD-enriched module (magenta, brown, orange, and purple) was imported as a graph with genes acting as nodes and pair-wise correlations between genes representing edges between the nodes. Figure 6 shows a subset of the connected nodes within each graph.Fig. 6


Shared Pathways Among Autism Candidate Genes Determined by Co-expression Network Analysis of the Developing Human Brain Transcriptome.

Mahfouz A, Ziats MN, Rennert OM, Lelieveldt BP, Reinders MJ - J. Mol. Neurosci. (2015)

Hub genes of ASD modules. Each of the four ASD-enriched modules is presented with the degree-sorted circle layout of cytoscape, with the nodes’ size and color reflect the level of connectivity within the network. The bigger the node, the more connections it has. For clarity, edges with correlation values smaller than 0.9 are removed. a Top-connected genes of the magenta module. b Top-connected genes of the brown module. c Top-connected genes of the orange module. d Top-connected genes of the purple module
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4644211&req=5

Fig6: Hub genes of ASD modules. Each of the four ASD-enriched modules is presented with the degree-sorted circle layout of cytoscape, with the nodes’ size and color reflect the level of connectivity within the network. The bigger the node, the more connections it has. For clarity, edges with correlation values smaller than 0.9 are removed. a Top-connected genes of the magenta module. b Top-connected genes of the brown module. c Top-connected genes of the orange module. d Top-connected genes of the purple module
Mentions: An alternative approach to annotate the function of each ASD-enriched module is to analyze the genes with the strongest correlations within each module. It has been shown that within an interaction network, genes with the most connections to other genes, termed hub genes, are informative for the network as a whole, and are potential high-yield therapeutic targets (Barabási et al. 2011). The strongest correlations within a module were explored using Cytoscape v2.8 (Smoot et al. 2011). First, each ASD-enriched module (magenta, brown, orange, and purple) was imported as a graph with genes acting as nodes and pair-wise correlations between genes representing edges between the nodes. Figure 6 shows a subset of the connected nodes within each graph.Fig. 6

Bottom Line: Autism spectrum disorder (ASD) is a neurodevelopmental syndrome known to have a significant but complex genetic etiology.Furthermore, we also constructed co-expression networks from the entire transcriptome and found that ASD candidate genes were enriched in modules related to mitochondrial function, protein translation, and ubiquitination.Overall, our multi-dimensional co-expression analysis of ASD candidate genes in the normal developing human brain suggests the heterogeneous set of ASD candidates share transcriptional networks related to synapse formation and elimination, protein turnover, and mitochondrial function.

View Article: PubMed Central - PubMed

Affiliation: Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands. a.mahfouz@tudelft.nl.

ABSTRACT
Autism spectrum disorder (ASD) is a neurodevelopmental syndrome known to have a significant but complex genetic etiology. Hundreds of diverse genes have been implicated in ASD; yet understanding how many genes, each with disparate function, can all be linked to a single clinical phenotype remains unclear. We hypothesized that understanding functional relationships between autism candidate genes during normal human brain development may provide convergent mechanistic insight into the genetic heterogeneity of ASD. We analyzed the co-expression relationships of 455 genes previously implicated in autism using the BrainSpan human transcriptome database, across 16 anatomical brain regions spanning prenatal life through adulthood. We discovered modules of ASD candidate genes with biologically relevant temporal co-expression dynamics, which were enriched for functional ontologies related to synaptogenesis, apoptosis, and GABA-ergic neurons. Furthermore, we also constructed co-expression networks from the entire transcriptome and found that ASD candidate genes were enriched in modules related to mitochondrial function, protein translation, and ubiquitination. Hub genes central to these ASD-enriched modules were further identified, and their functions supported these ontological findings. Overall, our multi-dimensional co-expression analysis of ASD candidate genes in the normal developing human brain suggests the heterogeneous set of ASD candidates share transcriptional networks related to synapse formation and elimination, protein turnover, and mitochondrial function.

Show MeSH
Related in: MedlinePlus