The Impact of Autism Specific Genomic Variations on microRNA Gene Expression Profile
Seno, Mohammad Mahdi
Hospital for Sick Children
Autism is a highly heritable but complex disorder that probably involves numerous genetic factors. While many genetic studies of autism seek abnormalities in protein-coding genes that result in dysfunctional proteins, it is also important to consider mutations that affect whether a normal gene is turned on or off in the first place. If it is inappropriately turned on or off (“expressed”), even a normal gene may contribute to autism's pathology. Gene expression can be controlled by microRNAs (miRNAs), which also lie within the genome but are not protein-coding; instead, miRNAs bind to and silence genes. Thus, abnormalities in miRNAs can lead to inappropriate gene expression and neural dysfunction. This project hypothesizes that miRNAs are as important as protein-coding genes in pathways of nervous system development that are involved in autism, and Dr. Scherer's post-doctoral fellow will look for miRNA abnormalities in a systematic way. Previous research in Dr.Scherer's lab has identified autism-associated mutations that are copy number variants (CNVs), and these variants can affect whether there is too much or too little of a particular genetic sequence, including miRNAs. The fellow will use these autism-associated CNVs as a starting point for looking for miRNAs abnormalities. The study will also include a screen of RNA samples prepared from a subset of carefully selected families (mother-father-offspring "trios") using both miRNA and gene expression arrays. Subsequently, he will use functional analyses to confirm the results. What this means for people with autism: This project can clarify the genetic basis of autism, and takes a novel approach by looking for autism-associated mutations in parts of the genome that do not code for proteins, but which are critical for controlling gene expression. Understanding gene regulation in autism will pinpoint the dysfunctional molecular pathways and suggest therapeutic targets.