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