Sex-biased gene expression in the developing brain: implications for autism spectrum disorders.

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Autism spectrum disorders affect significantly more males than females. Understanding sex differences in normal human brain development may provide insight into the mechanism(s) underlying this disparity; however, studies of sex differences in brain development at the genomic level are lacking. Here, we report a re-analysis of sex-specific gene expression from a recent large transcriptomic study of normal human brain development, to determine whether sex-biased genes relate to specific mechanistic processes. We discovered that male-biased genes are enriched for the processes of extracellular matrix formation/glycoproteins, immune response, chromatin, and cell cytoskeleton. We highlight that these pathways have been repeatedly implicated in autism and demonstrate that autism candidate genes are also enriched for these pathways. We propose that the overlap of these male-specific brain transcriptional modules with the same pathways in autism spectrum disorders may partially explain the increased incidence of autism in males

Expression Profiling of Autism Candidate Genes during Human Brain Development Implicates Central Immune Signaling Pathways

The Autism Spectrum Disorders (ASD) represent a clinically heterogeneous set of conditions with strong hereditary components. Despite substantial efforts to uncover the genetic basis of ASD, the genomic etiology appears complex and a clear understanding of the molecular mechanisms underlying Autism remains elusive. We hypothesized that focusing gene interaction networks on ASD-implicated genes that are highly expressed in the developing brain may reveal core mechanisms that are otherwise obscured by the genomic heterogeneity of the disorder. Here we report an in silico study of the gene expression profile from ASD-implicated genes in the unaffected developing human brain. By implementing a biologically relevant approach, we identified a subset of highly expressed ASD-candidate genes from which interactome networks were derived. Strikingly, immune signaling through NFκB, Tnf, and Jnk was central to ASD networks at multiple levels of our analysis, and cell-type specific expression suggested glia—in addition to neurons—deserve consideration. This work provides integrated genomic evidence that ASD-implicated genes may converge on central cytokine signaling pathways

Co-expression Network Analysis of the Developing Human Brain Implicates Synaptogenesis and Mitochondrial Function as Central Mechanisms in Autism

We analyzed the spatial-temporal co-expression relationships of 455 genes previously implicated in Autism spectrum disorder (ASD) using the BrainSpan transcriptome atlas. Understanding how the heterogenous set of ASD-related genes contribute to normal brain development helps identifying cellular/molecular processes which are commonly disrupted in ASD. First, we discovered modules among ASD candidates with biologically relevant temporal co-expression dynamics. These modules were related to the processes of synaptogenesis, apoptosis, and the neurotransmitter y-aminobutyric acid (GABA). Second, we created a transcriptome-wide co-expression network to discover significant Molecular Interaction Modules, and demonstrated that ASD candidate genes are enriched in modules related to the processes of synaptogenesis, mitochondrial function, protein translation, and ubiquitination. Finally, we identified hub genes within the ASD-enriched Molecular Interaction Modules, which may serve as additional ASD candidate genes, potential biomarkers, or therapeutic targets

Co-expression Network Analysis of the Developing Human Brain Implicates Synaptogenesis and Mitochondrial Function as Central Mechanisms in Autism

We analyzed the spatial-temporal co-expression relationships of 455 genes previously implicated in Autism spectrum disorder (ASD) using the BrainSpan transcriptome atlas. Understanding how the heterogenous set of ASD-related genes contribute to normal brain development helps identifying cellular/molecular processes which are commonly disrupted in ASD. First, we discovered modules among ASD candidates with biologically relevant temporal co-expression dynamics. These modules were related to the processes of synaptogenesis, apoptosis, and the neurotransmitter y-aminobutyric acid (GABA). Second, we created a transcriptome-wide co-expression network to discover significant Molecular Interaction Modules, and demonstrated that ASD candidate genes are enriched in modules related to the processes of synaptogenesis, mitochondrial function, protein translation, and ubiquitination. Finally, we identified hub genes within the ASD-enriched Molecular Interaction Modules, which may serve as additional ASD candidate genes, potential biomarkers, or therapeutic targets.Pattern Recognition and Bioinformatic

Functional genomics analysis of Phelan-McDermid syndrome 22q13 region during human neurodevelopment

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by varying degrees of intellectual disability, severely delayed language development and specific facial features, and is caused by a deletion within chromosome 22q13.3. SHANK3, which is located at the terminal end of this region, has been repeatedly implicated in other neurodevelopmental disorders and deletion of this gene specifically is thought to cause much of the neurologic symptoms characteristic of PMS. However, it is still unclear to what extent SHANK3 deletions contribute to the PMS phenotype, and what other genes nearby are causal to the neurologic disease. In an effort to better understand the functional landscape of the PMS region during normal neurodevelopment, we assessed RNA-sequencing (RNA-seq) expression data collected from post-mortem brain tissue from developmentally normal subjects over the course of prenatal to adolescent age and analyzed expression changes of 65 genes on 22q13. We found that the majority of genes within this region were expressed in the brain, with ATNX10, MLC1, MAPK8IP2, and SULT4A1 having the highest overall expression. Analysis of the temporal profiles of the highest expressed genes revealed a trend towards peak expression during the early post-natal period, followed by a drop in expression later in development. Spatial analysis revealed significant region specific differences in the expression of SHANK3, MAPK8IP2, and SULT4A1. Region specific expression over time revealed a consistently unique gene expression profile within the cerebellum, providing evidence for a distinct developmental program within this region. Exon-specific expression of SHANK3 showed higher expression within exons contributing to known brain specific functional isoforms. Overall, we provide an updated roadmap of the PMS region, implicating several genes and time periods as important during neurodevelopment, with the hope that this information can help us better understand the phenotypic heterogeneity of PMS.Pattern Recognition and Bioinformatic