Natural mutagenesis of human genomes by endogenous retrotransposons

内源逆转录转座子对人类基因组的自然突变

• 批准号: 8460004
• 负责人: Scott E Devine
• 金额: $ 29.94万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-16 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460004
• 关键词: American; Beryllium; Disease; Elements; Frequencies; Genes; Goals; Health; Human; Human Genome; Individual; Knowledge; L1 Elements; Laboratories; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Methylation; Mus; Mutagenesis; RNA; Relative (related person); Research Design; Retrotransposon; Somatic Cell; Source; Technology; Testing; Tissues; Tumor Tissue; cancer risk; genetic element; insight; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Project Summary Transposable genetic elements (TEs) occupy 44% of the human genome. Human TEs such as the L1 element can cause diseases when they "jump" into genes, and several dozen disease-causing TE insertions have been documented in humans. It has been widely assumed that TE mobilization occurs primarily in the human germline. However, several recent lines of evidence indicate that the human L1 element also transposes in somatic cells. Somatic L1 insertions have been observed in at least two types of human tumors, suggesting that such insertions may produce disease states, including cancers. In this proposal, we will examine the relative levels of germline vs. somatic L1 mobilization in humans. In Aim 1, we will use our recently developed transposon-seq technologies to examine L1 insertions in a tissue panel obtained from healthy Americans. By studying L1 mobilization in multiple tissues from the same individuals, we will establish the relative abundances of germline vs. somatic L1 insertions in healthy Americans. We also will seek evidence for the RNA carryover mechanism of L1 mobilization, which produces mosaic somatic insertions in mice and may also produce such insertions in humans. In Aim 2, we will examine normal/tumor tissue pairs to determine whether germline and somatic L1 insertions help to drive tumor formation in humans. Our laboratory recently found that L1 is mobilized at high frequencies in human lung tumors, and we suspect that some of the new L1 insertions fuel tumorigenesis. We will directly test this hypothesis in Aim 2. We also will determine whether somatic L1 mobilization occurs in other tumor types. In Aim 3, we will study source elements that produce new L1 insertions in humans. We will determine whether source element copy number influences L1 mutagenesis and cancer risk in humans. Finally, we will test the hypothesis that source elements are controlled by methylation in human lung cancers. Together, these studies will greatly expand our knowledge of L1 mutagenesis in humans and will provide major new insights on how L1 mutagenesis impacts human health.

描述（由申请人提供）： 项目摘要转座遗传因素（TES）占人类基因组的44％。当人类“跳入”基因时，诸如L1元素之类的人类TE可能会引起疾病，并且在人类中已经记录了几十个引起疾病的TE插入。人们普遍认为动员主要发生在人类种系中。然而，最近的几条证据表明，人L1元素也会在体细胞中转置。在至少两种类型的人类肿瘤中观察到了体细胞L1插入，这表明此类插入可能会产生包括癌症在内的疾病状态。在此提案中，我们将研究人类种系与体细胞L1动员的相对水平。在AIM 1中，我们将使用我们最近开发的转座式技术来检查从健康美国人获得的组织面板中的L1插入。通过研究来自同一个体的多个组织中的L1动员，我们将建立生殖线与健康美国人中的体细胞L1插入的相对丰度。我们还将寻求证据证明L1动员的RNA结转机制，该机制在小鼠中产生镶嵌物体细胞插入，也可能在人类中产生此类插入。在AIM 2中，我们将检查正常/肿瘤组织对，以确定种系和体细胞L1插入是否有助于驱动人类的肿瘤形成。我们的实验室最近发现，L1在人类肺部肿瘤的高频中动员，我们怀疑一些新的L1插入会促进肿瘤的发生。我们将在AIM 2中直接检验这一假设。我们还将确定在其他肿瘤类型中是否发生了体细胞L1动员。在AIM 3中，我们将研究在人类中产生新的L1插入的来源元素。我们将确定源元素拷贝数是否影响人类的L1诱变和癌症风险。最后，我们将检验以下假设：源元素是通过人肺癌中甲基化控制的。这些研究将大大扩展我们对人类L1诱变的了解，并将提供有关L1诱变如何影响人类健康的主要新见解。