A systems biology approach to unravel theunderlying functional modules of ASD

描述（由申请人提供）：自闭症谱系障碍（ASD）的患病率目前估计为150分之一，使其成为社会的主要负担。基因在自闭症的病因学中起着重要的作用，这一点已经得到了明确的确定，但之前的基因研究只成功地确定了少数几个强有力的候选基因。最近的技术创新为自闭症的遗传基础打开了一扇新的窗口。多个研究小组使用不同的方法来研究全基因组关联、拷贝数变异和单核苷酸多态性与自闭症的关联，结果表明，常见和罕见的变异都对自闭症的遗传易感性有贡献。为了进一步了解ASD的分子机制，在自闭症研究中开发和采用新的方法是至关重要的。在这里，我们建议从系统生物学的角度来研究自闭症，目的是确定与疾病相关的蛋白质网络和功能模块。为了实现这一目标，我们提出了一种整合的方法来构建自闭症蛋白-蛋白质相互作用网络，该网络包括自闭症风险基因、它们的脑表达剪接变体以及自闭症患者基因组缺失和重复断点中断的基因的突变转录本。具体目的如下。(1)利用我们最近开发的包含并行454 FLX测序和计算分析平台的高通量异构体发现管道，对自闭症候选基因的可选剪接异构体进行大规模发现；(2)鉴定和克隆自闭症患者基因组缺失和重复断点中断基因的突变转录本；(3)构建自闭症候选基因及其可选剪接变异体和突变转录物的相互作用组，确定自闭症相关的关键功能模块。这项研究的结果将对了解ASD背后的细胞通路做出重大贡献。

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.