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: 8628088
• 负责人: Scott E Devine
• 金额: $ 30.9万
• 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/8628088
• 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）： 项目概要 转座遗传元件 (TE) 占据人类基因组的 44%。人类的 TE（例如 L1 元件）在“跳入”基因时可能会导致疾病，并且已在人类中记录了数十种导致疾病的 TE 插入。人们普遍认为 TE 动员主要发生在人类种系中。然而，最近的一些证据表明人类 L1 元件也在体细胞中转座。至少在两种类型的人类肿瘤中观察到体细胞 L1 插入，表明这种插入可能会产生疾病状态，包括癌症。在本提案中，我们将检查人类种系与体细胞 L1 动员的相对水平。在目标 1 中，我们将使用我们最近开发的转座子测序技术来检查从健康美国人获得的组织组中的 L1 插入。通过研究同一个体多个组织中 L1 的动员，我们将确定健康美国人中种系与体细胞 L1 插入的相对丰度。我们还将寻找 L1 动员的 RNA 残留机制的证据，该机制在小鼠中产生嵌合体细胞插入，也可能在人类中产生此类插入。在目标 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肿瘤的形成。我们的实验室最近发现 L1 在人类肺部肿瘤中被高频率地动员，我们怀疑一些新的 L1 插入促进了肿瘤的发生。我们将在目标 2 中直接检验这一假设。我们还将确定体细胞 L1 动员是否发生在其他肿瘤类型中。在目标 3 中，我们将研究在人类体内产生新的 L1 插入的源元素。我们将确定源元件拷贝数是否影响人类的 L1 突变和癌症风险。最后，我们将检验人类肺癌中源元素受甲基化控制的假设。总之，这些研究将极大地扩展我们对人类 L1 突变的认识，并将为 L1 突变如何影响人类健康提供重要的新见解。