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Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.

Li J, Shi M, Ma Z, Zhao S, Euskirchen G, Ziskin J, Urban A, Hallmayer J, Snyder M - Mol. Syst. Biol. (2014)

Bottom Line: Expression of this module was dichotomized with a ubiquitously expressed subcomponent and another subcomponent preferentially expressed in the corpus callosum, which was significantly affected by our identified mutations in the network center.RNA-sequencing of the corpus callosum from patients with autism exhibited extensive gene mis-expression in this module, and our immunochemical analysis showed that the human corpus callosum is predominantly populated by oligodendrocyte cells.Our analysis delineates a natural network involved in autism, helps uncover novel candidate genes for this disease and improves our understanding of its molecular pathology.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Stanford Center for Genomics and Personalized Medicine Stanford University School of Medicine, Stanford, CA, USA.

No MeSH data available.


Related in: MedlinePlus

Expression analysis of the synaptic moduleDichotomized expression of the genes in module #13 across 295 brain sections. Relative abundance of each gene across the 295 brain sections was hierarchically clustered to reveal gene groups exhibiting similar expression patterns across tissues. Group 1 genes showed elevated expression in 175 regions (T1, e.g., corpus callosum) relative to other brain sections, and Group 2 genes showed high expression in 120 regions (T2, e.g., hippocampal regions) relative to other brain sections.RNA-sequencing of four different brain regions from a healthy subject. The brain regions include the Brodmann areas 9 (BA9), 40 (BA40), the amygdala (AMY) and the corpus callosum (CC), which revealed the same observation as from the microarray analyses. Group 1 (red) and 2 (blue) genes were compared with 1,000 randomly sampled genes (gray) from the transcriptome in each brain region. The raw FPKM values were normalized into the cumulative density functions based on kernel density estimation. The elevation of Group 2 genes across all brain regions and the greatest increase of Group 1 genes in the corpus callosum were all statistically significant (P < 1e-5, Wilcoxon rank-sum test).RNA-sequencing of the corpus callosum transcriptomes from six non-autistic individuals. FPKM quantifies the absolute expression of genes in each group. The two groups have similar expression in the corpus callosum (P > 0.5, Wilcoxon rank-sum test), which are all above the transcriptome background (P < 4.87e-6, Wilcoxon rank-sum test), suggesting that both sub-components are active in this tissue.
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fig03: Expression analysis of the synaptic moduleDichotomized expression of the genes in module #13 across 295 brain sections. Relative abundance of each gene across the 295 brain sections was hierarchically clustered to reveal gene groups exhibiting similar expression patterns across tissues. Group 1 genes showed elevated expression in 175 regions (T1, e.g., corpus callosum) relative to other brain sections, and Group 2 genes showed high expression in 120 regions (T2, e.g., hippocampal regions) relative to other brain sections.RNA-sequencing of four different brain regions from a healthy subject. The brain regions include the Brodmann areas 9 (BA9), 40 (BA40), the amygdala (AMY) and the corpus callosum (CC), which revealed the same observation as from the microarray analyses. Group 1 (red) and 2 (blue) genes were compared with 1,000 randomly sampled genes (gray) from the transcriptome in each brain region. The raw FPKM values were normalized into the cumulative density functions based on kernel density estimation. The elevation of Group 2 genes across all brain regions and the greatest increase of Group 1 genes in the corpus callosum were all statistically significant (P < 1e-5, Wilcoxon rank-sum test).RNA-sequencing of the corpus callosum transcriptomes from six non-autistic individuals. FPKM quantifies the absolute expression of genes in each group. The two groups have similar expression in the corpus callosum (P > 0.5, Wilcoxon rank-sum test), which are all above the transcriptome background (P < 4.87e-6, Wilcoxon rank-sum test), suggesting that both sub-components are active in this tissue.

Mentions: Most genes in module #13 were expressed across all brain sections (Supplementary Fig S8). However, hierarchical clustering of the normalized gene expression across brain sections revealed two distinct spatial patterns with some heterogeneity apparent in each (Fig3A, complete list in Supplementary Dataset S4). Group 1 had 56 of 119 total genes preferentially expressed in 175 regions (T1 regions in FigA), whereas the 63 genes of Group 2 had elevated expression in the other 120 brain regions (T2 regions in Fig3A). Group 1 genes were strongly expressed in sections associated with the corpus callosum (Fig3A, including LRP2 shown in Fig2A), which transfers motor, sensory and cognitive signals between the brain hemispheres. Group 2 genes (e.g., SHANK2 and SHANK3) were up-regulated in T2 regions, which encompassed neuron-rich regions, exemplified by the hippocampal formation, including CA 1/2/3/4 fields, subiculum and dentate gyrus. Tissue enrichment was derived from relative expression of individual genes across brain sections; closer examination of their absolute expression in each brain section relative to the transcriptome background revealed that Group 1 expression levels were at background levels across most tissue types, but peaked in the corpus callosum (Supplementary Fig S8). Group 2 genes were highly expressed across all tissues, albeit their expression levels were slightly depressed in the corpus callosum (Supplementary Fig S8). Thus, Group 2 genes were more ubiquitously expressed, and Group 1 genes were tissue specific in the corpus callosum, and the trend was evidenced by its increased tissue specificity index (P = 1.5e-4, Wilcoxon rank-sum test) and decreased expression breadth (P < 0.01, Wilcoxon rank-sum test, Supplementary Fig S9).


Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.

Li J, Shi M, Ma Z, Zhao S, Euskirchen G, Ziskin J, Urban A, Hallmayer J, Snyder M - Mol. Syst. Biol. (2014)

Expression analysis of the synaptic moduleDichotomized expression of the genes in module #13 across 295 brain sections. Relative abundance of each gene across the 295 brain sections was hierarchically clustered to reveal gene groups exhibiting similar expression patterns across tissues. Group 1 genes showed elevated expression in 175 regions (T1, e.g., corpus callosum) relative to other brain sections, and Group 2 genes showed high expression in 120 regions (T2, e.g., hippocampal regions) relative to other brain sections.RNA-sequencing of four different brain regions from a healthy subject. The brain regions include the Brodmann areas 9 (BA9), 40 (BA40), the amygdala (AMY) and the corpus callosum (CC), which revealed the same observation as from the microarray analyses. Group 1 (red) and 2 (blue) genes were compared with 1,000 randomly sampled genes (gray) from the transcriptome in each brain region. The raw FPKM values were normalized into the cumulative density functions based on kernel density estimation. The elevation of Group 2 genes across all brain regions and the greatest increase of Group 1 genes in the corpus callosum were all statistically significant (P < 1e-5, Wilcoxon rank-sum test).RNA-sequencing of the corpus callosum transcriptomes from six non-autistic individuals. FPKM quantifies the absolute expression of genes in each group. The two groups have similar expression in the corpus callosum (P > 0.5, Wilcoxon rank-sum test), which are all above the transcriptome background (P < 4.87e-6, Wilcoxon rank-sum test), suggesting that both sub-components are active in this tissue.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4300495&req=5

fig03: Expression analysis of the synaptic moduleDichotomized expression of the genes in module #13 across 295 brain sections. Relative abundance of each gene across the 295 brain sections was hierarchically clustered to reveal gene groups exhibiting similar expression patterns across tissues. Group 1 genes showed elevated expression in 175 regions (T1, e.g., corpus callosum) relative to other brain sections, and Group 2 genes showed high expression in 120 regions (T2, e.g., hippocampal regions) relative to other brain sections.RNA-sequencing of four different brain regions from a healthy subject. The brain regions include the Brodmann areas 9 (BA9), 40 (BA40), the amygdala (AMY) and the corpus callosum (CC), which revealed the same observation as from the microarray analyses. Group 1 (red) and 2 (blue) genes were compared with 1,000 randomly sampled genes (gray) from the transcriptome in each brain region. The raw FPKM values were normalized into the cumulative density functions based on kernel density estimation. The elevation of Group 2 genes across all brain regions and the greatest increase of Group 1 genes in the corpus callosum were all statistically significant (P < 1e-5, Wilcoxon rank-sum test).RNA-sequencing of the corpus callosum transcriptomes from six non-autistic individuals. FPKM quantifies the absolute expression of genes in each group. The two groups have similar expression in the corpus callosum (P > 0.5, Wilcoxon rank-sum test), which are all above the transcriptome background (P < 4.87e-6, Wilcoxon rank-sum test), suggesting that both sub-components are active in this tissue.
Mentions: Most genes in module #13 were expressed across all brain sections (Supplementary Fig S8). However, hierarchical clustering of the normalized gene expression across brain sections revealed two distinct spatial patterns with some heterogeneity apparent in each (Fig3A, complete list in Supplementary Dataset S4). Group 1 had 56 of 119 total genes preferentially expressed in 175 regions (T1 regions in FigA), whereas the 63 genes of Group 2 had elevated expression in the other 120 brain regions (T2 regions in Fig3A). Group 1 genes were strongly expressed in sections associated with the corpus callosum (Fig3A, including LRP2 shown in Fig2A), which transfers motor, sensory and cognitive signals between the brain hemispheres. Group 2 genes (e.g., SHANK2 and SHANK3) were up-regulated in T2 regions, which encompassed neuron-rich regions, exemplified by the hippocampal formation, including CA 1/2/3/4 fields, subiculum and dentate gyrus. Tissue enrichment was derived from relative expression of individual genes across brain sections; closer examination of their absolute expression in each brain section relative to the transcriptome background revealed that Group 1 expression levels were at background levels across most tissue types, but peaked in the corpus callosum (Supplementary Fig S8). Group 2 genes were highly expressed across all tissues, albeit their expression levels were slightly depressed in the corpus callosum (Supplementary Fig S8). Thus, Group 2 genes were more ubiquitously expressed, and Group 1 genes were tissue specific in the corpus callosum, and the trend was evidenced by its increased tissue specificity index (P = 1.5e-4, Wilcoxon rank-sum test) and decreased expression breadth (P < 0.01, Wilcoxon rank-sum test, Supplementary Fig S9).

Bottom Line: Expression of this module was dichotomized with a ubiquitously expressed subcomponent and another subcomponent preferentially expressed in the corpus callosum, which was significantly affected by our identified mutations in the network center.RNA-sequencing of the corpus callosum from patients with autism exhibited extensive gene mis-expression in this module, and our immunochemical analysis showed that the human corpus callosum is predominantly populated by oligodendrocyte cells.Our analysis delineates a natural network involved in autism, helps uncover novel candidate genes for this disease and improves our understanding of its molecular pathology.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Stanford Center for Genomics and Personalized Medicine Stanford University School of Medicine, Stanford, CA, USA.

No MeSH data available.


Related in: MedlinePlus