The role of retrotransposons in autism spectrum disorders

描述（由申请人提供）：本申请是对RFA编号RFA-OD-10-005的响应，并涉及主题领域1：应用基因组学和其他高通量技术。反转录转座子是哺乳动物个体间基因组变异的一个经常被忽视的来源。人类基因组中这种变异的主要驱动力是LINE-1（L1）逆转录转座，它存在于约50万个拷贝中，分布在一系列亚家族中，每个亚家族在进化历史的某个时刻都是活跃的。目前活跃的亚家族被称为L1 H（人类特异性）或L1-Ta（转录组a），每个单倍体基因组由约1000个成员组成，其中一小部分是活跃的。我们开发了一种通过高通量测序以良好的特异性和灵敏度定位反转录转座子插入的技术，并已使用该技术从不同个体中发现人类特异性L1和SVA（另一种人类反转录转座子）插入。与此同时，犹他州大学的林恩乔德实验室开发了一种类似的下一代测序方法，以在全基因组范围内识别Alu插入。此外，我们正在开发一种用于高通量检测已知反转录转座子插入多态性（RIPs）的珠阵列平台的第一阶段，以便使用RIPs作为SNP和CNVs的替代标记进行关联研究。在我们的资助申请中，我们将建议使用这些技术来研究LINE-1和Alu反转录转座是否在自闭症谱系障碍（ASD）的遗传易感性中发挥作用。本研究将遵循三个目标：1。所有（低和高频率）L1和Alu多态性与ASD的关联使用我们的测序技术在有限数量的三人组，包括父母和受影响的先证者，2。研究ASD患者基因组中的体细胞从头L1和Alu插入率，通过对不一致的单卵双胞胎的研究确定;中高频反转录转座子多态性与ASD的相关性，使用基于阵列的方法筛选许多个体（RIP-GWAS）。 公共卫生相关性：自闭症谱系障碍（ASD）是影响大部分美国儿童人口（1/166活产）的主要神经系统疾病。到目前为止，预测其病因的主要遗传成分已被探索使用单核苷酸多态性和拷贝数变异，成功地找到了一小部分ASD病例的原因。在这里，我们建议增加另一种形式的基因组变异，反转录转座子诱导的多态性（RIPs），寻找ASD的病因。

DESCRIPTION (provided by applicant): This application is in response to RFA number RFA-OD-10-005 and addresses thematic area 1: Applying genomics and other high throughput technologies. Retrotransposons are an often-overlooked source of inter-individual genomic variation in mammals. The primary driver of this variation in the human genome is the LINE-1 (L1) retrotransposition, which exists in ~500,000 copies spread across a succession of subfamilies each of which was active at some point in evolutionary history. The currently active subfamily is known as either L1Hs (for Human-specific) or L1-Ta (for Transcribed group a) and consists of some ~1000 members per haploid genome, a small subset of which are actively mobilized. We have developed a technique to locate retrotransposon insertions with good specificity and sensitivity by high-throughput sequencing, and have been using it to find human-specific L1 and SVA (another human retrotransposon) insertions from various individuals. In parallel, the laboratory of Lynn Jorde at the University of Utah has developed a similar next-generation sequencing-based approach to identify Alu insertions on a genome-wide scale. Additionally, we are in the first stages of developing a bead-array platform for the high-throughput detection of known retrotransposon insertion polymorphisms (RIPs) in order to perform an association study using RIPs as an alternate marker to SNPs and CNVs. In our grant application, we will propose to use these technologies to study whether LINE-1 and Alu retrotransposition plays a role in the genetic susceptibility to autism-spectrum disorders (ASDs). This study will follow 3 aims: 1. The association of all (low and high frequency) L1 and Alu polymorphisms with ASDs using our sequencing technique in a limited number of trios consisting of the parents and affected proband, 2. Studying the rate of somatic de novo L1 and Alu insertion in ASD patient genomes, ascertained through the study of discordant monozygotic twins, and 3. The association of moderate- to high-frequency retrotransposon polymorphisms with ASDs using an array-based approach to screen many individuals (RIP-GWAS). PUBLIC HEALTH RELEVANCE: Autism spectrum disorders (ASD) are major neurological conditions affecting a large proportion of the US population of children (1 in 166 live births). To date, the predicted major genetic component of their etiology has been explored using single nucleotide polymorphisms and copy number variations with success in finding the cause of a small minority of ASD cases. Here we propose to add another form of genome variation, retrotransposon-induced polymorphisms (RIPs), to the search for ASD etiology.