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）的患病率现在估计为1/150，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作用，这一点已经得到明确的确定，但以前的遗传学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户。基于多个小组使用不同方法研究全基因组关联、拷贝数变异和单核苷酸多态性与自闭症的关联的工作，很明显，常见和罕见变异都有助于ASD的遗传易感性。为了在理解ASD的分子机制方面取得进一步进展，在自闭症研究中开发和采用新的方法至关重要。在这里，我们建议从系统生物学的角度来研究ASD，目的是定义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质-蛋白质相互作用网络，该网络包括自闭症风险基因、其脑表达的剪接变体以及自闭症患者中被基因组缺失和重复的断点破坏的基因的突变转录本。具体目标如下。(1)使用我们最近开发的高通量异构体发现管道进行自闭症候选基因的选择性剪接异构体的大规模发现，该管道结合了并行的454 FLX测序和计算分析平台;（2）鉴定和克隆自闭症患者中被基因组缺失和重复的断点破坏的基因的突变体转录本;（3）构建自闭症候选基因、其选择性剪接变体和突变转录本的相互作用组，以确定参与ASD的关键功能模块。这项研究的结果将为ASD的细胞通路知识做出重大贡献。 公共卫生相关性：这项研究的结果将为我们了解自闭症和认知发展的原因做出重大贡献。发现功能上连接看似无关的自闭症候选基因的特定通路、网络和模块是理解ASD发展的分子机制的重要一步。该项目的最终目标是确定特定的自闭症相关通路和功能模块，可以有针对性的治疗。

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.