The role of retrotransposons in autism spectrum disorders

逆转录转座子在自闭症谱系障碍中的作用

• 批准号: 8046942
• 负责人: HAIG H. KAZAZIAN
• 金额: $ 207.86万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046942
• 关键词: Address; Affect; Applications Grants; Area; Asses; Autistic Disorder; Base Sequence; Biological Assay; Brain; Cell Line; Child; Copy Number Polymorphism; Cultured Cells; Custom; Data; Data Analyses; Databases; Detection; Etiology; Event; Finding by Cause; Frequencies; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genome; Genomics; Genotype; Haploidy; Human; Human Genome; Individual; Introns; Laboratories; Live Birth; Location; Mammals; Minority; Monozygotic Twinning; Monozygotic twins; Nature; Neurologic; Parents; Patients; Phenotype; Play; Population; Predisposition; Process; Recording of previous events; Recurrence; Retrotransposition; Retrotransposon; Role; Sampling; Sensitivity and Specificity; Single Nucleotide Polymorphism; Source; Staging; Techniques; Technology; Twin Multiple Birth; Universities; Utah; Variant; abstracting; autism spectrum disorder; base; cohort; design; disorder control; genome wide association study; genome-wide; high throughput technology; member; next generation; offspring; proband; response; success

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.

描述（由申请人提供）：此申请响应RFA编号RFA-OD-10-005，并介绍主题区域1：应用基因组学和其他高通量技术。返回座子是哺乳动物中个体间基因组变异的通常被忽视的来源。人类基因组中这种变异的主要驱动力是线1（L1）逆转录座，其存在于〜500,000份中，分布在一系列的亚家族中，每个拷贝在进化史上的某个时候都活跃。当前活跃的亚家族被称为L1HS（用于人类特异性）或L1-TA（用于抄录的A组），每个单倍体基因组约有1000个成员组成，其中一小部分是积极动员的。我们已经开发了一种技术，可以通过高通量测序定位具有良好特异性和敏感性的逆转录座插入，并一直使用它来从各个个体中找到人类特异性的L1和SVA（另一个人逆转录）插入。同时，犹他大学的林恩·乔德（Lynn Jorde）实验室已经开发了一种基于下一代测序的方法，可以在全基因组范围内识别ALU插入。此外，我们处于开发一个珠阵列平台的第一阶段，用于高通量检测已知的逆转录子插入多态性（RIPS），以便使用RIPS作为SNPS和CNVS的替代标记进行关联研究。在我们的赠款应用中，我们将建议使用这些技术来研究Line-1和Alu反转座是否在自闭症疾病的遗传敏感性（ASDS）中起作用。这项研究将遵循3个目的：1。使用我们的测序技术，所有（低频和高频）L1和ALU多态性与ASD的关联，在有限的三重量表中，由父母和受影响的证据组成，2。研究Somatic de Novo L1和Alu插入的ASD患者基因组中的ASD患者基因组的插入率，并通过差异化的ASD患者基因组中的差异和3个差异化。使用基于阵列的方法来筛选许多个体（RIP-GWAS）的高频逆转座子多态性（RIP-GWAS）。 公共卫生相关性：自闭症谱系障碍（ASD）是影响美国大部分儿童人群的主要神经系统疾病（166个活产）。迄今为止，已经使用单核苷酸多态性和拷贝数变化来探索其病因的主要遗传成分，并成功地发现了少数ASD病例的原因。在这里，我们建议在搜索ASD病因中添加另一种形式的基因组变异，逆转录座诱导的多态性（RIP）。

项目成果

Pathogenic orphan transduction created by a nonreference LINE-1 retrotransposon.

• DOI: 10.1002/humu.21663
• 发表时间: 2012-02
• 期刊: HUMAN MUTATION
• 影响因子: 3.9
• 作者: Solyom, Szilvia;Ewing, Adam D.;Hancks, Dustin C.;Takeshima, Yasuhiro;Awano, Hiroyuki;Matsuo, Masafumi;Kazazian, Haig H., Jr.
• 通讯作者: Kazazian, Haig H., Jr.