A systems biology approach to unravel theunderlying functional modules of ASD

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DESCRIPTION (provided by applicant): The prevalence of autism spectrum disorders (ASD) is now estimated to be 1 in 150, making it a major burden to society. It has been clearly determined that genes play a major role in the etiology of autism, but previous genetic studies have succeeded in identifying only a few strong gene candidates. Recent technological innovations have opened a new window into the genetic basis of autism. Based on work by multiple groups using different approaches to examine genome-wide association, the association of copy number variants and single nucleotide polymorphisms with autism, it became evident that both common and rare variants are contributing to the genetic susceptibility to ASD. To make further progress in understanding molecular mechanisms of ASD, it is critical to develop and employ novel approaches in autism research. Here, we propose to investigate ASD from the systems biology perspective with the aim of defining the protein networks and functional modules that are relevant to the disease. To achieve this goal, we propose an integrative approach to build autism protein-protein interaction network that includes autism risk genes, their brain-expressed splice variants and mutant transcripts of the genes that are disrupted by the breakpoints of genomic deletions and duplications in autistic patients. The specific aims are as follows. (1) Perform a large-scale discovery of alternatively spliced isoforms of autism gene candidates using our recently developed high-throughput isoform discovery pipeline that incorporates parallel 454 FLX sequencing and computational analysis platforms; (2) Identify and clone mutant transcripts of the genes disrupted by the breakpoints of genomic deletions and duplications in autistic patients; (3) Build an interactome of autism candidate genes, their alternatively spliced variants and mutant transcripts to define key functional modules involved in ASD. The results of this study will make substantial contributions to knowledge of the cellular pathways that underlie ASD. PUBLIC HEALTH RELEVANCE: The results of this study will make substantial contributions to our knowledge of the causes of autism and of cognitive development. The discovery of specific pathways, networks and modules that functionally connect seemingly unrelated autism candidate genes is an important step towards understanding the molecular mechanism of ASD development. The final goal of this project is to define specific autism-relevant pathways and functional modules that could be targeted therapeutically.