Abstract
Autism is a complex disease whose etiology remains elusive. We integrated previously and newly generated data and developed a systems framework involving the interactome, gene expression and genome sequencing to identify a protein interaction module with members strongly enriched for autism candidate genes. Sequencing of 25 patients confirmed the involvement of this module in autism, which was subsequently validated using an independent cohort of over 500 patients. 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. Analysis of functional genomic data further revealed a significant involvement of this module in the development of oligodendrocyte cells in mouse brain. 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.
Highlights
Genetic studies of autism spectrum disorders (ASDs) in the past decade have implicated a large number of clinical mutations in more than 300 different human genes (Basu et al, 2009)
Most of our knowledge today about ASD genetics has been gained from genetic association or exome-sequencing analyses of large ASD patient cohorts, which allows us to begin to observe the molecular underpinnings of this disease
Since the retention of genetic mutations within a population is strongly driven by natural selection and population demographics (Hartl & Clark, 2007), mutations in genes critical for ASD are likely to be depleted by purifying selection or by population bottleneck, preventing the identification of ASD candidate genes only from mutational analyses
Summary
Genetic studies of autism spectrum disorders (ASDs) in the past decade have implicated a large number of clinical mutations in more than 300 different human genes (Basu et al, 2009). Gilmen et al constructed a network by connecting every pair of genes with any functional association, such as shared annotation terms, pathway memberships, interacting partners or coevolutionary patterns This association network was seeded with the genes previously found in ASD-associated de novo copy number variants (CNVs) followed by a search of their neighborhoods for sub-networks most enriched for these affected genes. Related studies were focused on a set of proteins potentially implicated in ASD and characterized their interacting partners to identify molecular pathways underlying ASD (Sakai et al, 2011; Corominas et al, 2014; Cristino et al, 2014) These approaches all started with a set of previously curated a 2014 The Authors.
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