Genetic modules for autism

Abstract

Autism spectrum disorder (ASD) is genetically heterogeneous, with most ASD-associated variants accounting for very few cases. Michael Snyder and colleagues used a systems biology approach to identify common pathways dysregulated in ASD (Mol. Syst. Biol. 10, 774, 2014). Highly interacting modules were extracted from a protein interaction network. Two modules were significantly enriched for known ASD susceptibility genes, and one contained multiple genes involved in synaptic transmission. Whole-exome or whole-genome sequencing of 25 ASD and 5 control brains, followed by comparison to the 1000 Genomes Project database, identified 38 genes in this module that were significantly affected by rare, coding variants in individuals with ASD, 28 of which had not been previously linked to ASD. Expression analysis of all genes in the module found that they clustered into two groups, one preferentially expressed in the corpus callosum and the other more ubiquitously expressed. The corpus callosum is involved in communication between the brain hemispheres. The authors generated RNA sequencing data from the corpus callosum of six individuals with ASD and matched controls and found that the expression levels of genes in the module were significantly altered in ASD cases. This association did not hold for synaptic genes or ASD-associated genes in general. BL Written by Tiago Faial, Brooke LaFlamme, Emily Niemitz & Kyle Vogan Microexons on the brain Coregulated alternative splicing events involved in developmental and disease processes are largely uncharacterized. Manuel Irimia, Benjamin Blencowe and colleagues developed a computational pipeline to sys-tematically identify all alternative splicing events, including the use of microexons, in RNA sequencing data to better understand which biologi-cal processes are affected by specific alternative splicing programs (Cell 159, 1511–1523, 2014). The pipeline was applied to data from over 50 tissue and cell types in human and mouse and was designed to detect microexons—exons less than 27 nt in length—which are often missed in genome annotations. The authors found a group of ~2,500 neural-regu-lated splicing events and an enrichment of microexons among neural-specific alternative exons. Moreover, most microexon inclusion events were neural specific and highly conserved between humans and mice. Through analysis of publicly available RNA sequencing data, the authors found that the splicing factor nSR100 (SRRM4) was responsible for the regulation of most alternatively spliced microexons. They experimentally demonstrated that microexon regulation is switched on late during neural differentiation and that microexons likely function to enhance specific protein-protein interactions when spliced in. Finally, the authors found that 30% of alternatively spliced microexons were misregulated in the brains of some individuals with autism spectrum disorder (ASD), and the inclusion of neural-regulated microexons was correlated with nSR100 expression levels across all individuals with ASD analyzed. BL Zebrafish mutants versus morphants