Evolution of piRNAs and germline transposon control in Drosophila

果蝇中 piRNA 的进化和种系转座子控制

• 批准号: 7804082
• 负责人: Erin S Kelleher
• 金额: $ 4.56万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7804082
• 关键词: Address; Aubergine; Biological Models; Biological Process; Chromosomal Rearrangement; Complement; Complex; Conflict (Psychology); DNA Transposable Elements; Drosophila genus; Elements; Evolution; Explosion; Female; Genetic; Genome; Hereditary Disease; Human; Human Genetics; Hybrids; Immune system; Knowledge; Malignant Neoplasms; Mediating; Modeling; Mutation; Pathway interactions; Phenotype; Population; Prevention; Proteins; RNA; Research; Resistance; Role; Small RNA; Transgenes; Transgenic Organisms; Virus; effective therapy; male; mutant; piRNA; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Transposable elements (TEs) are selfish genetic entities that can rapidly sweep through populations, reaching high copy-number in eukaryotic genomes. More than 50 human genetic diseases are associated with TE insertions, or TE-mediated chromosomal rearrangements that occur recurrently in human populations. Misregulation of TEs, furthermore, is associated with tumorigenesis and tumor progression, suggesting a critical role for TE suppression in cancer resistance. The deleterious mutations that arise from TE activity exert strong selection for suppression by the host. A recent explosion of research on the Piwi- interacting RNA (piRNA) pathway has made the exciting discovery that these proteins act in concert with TE-derived small RNAs (piRNAs) to silence TEs in male and female germlines. The piRNA pathway has a conserved function across metazoa, yet surprisingly many piRNA proteins are the direct targets of positive selection. Using the model system Drosophila, my proposed research will elucidate both the protein and RNA contributions to evolutionary changes in piRNA mediated TE suppression. Specifically, I will: 1) Examine piRNA pathway function in D. melanogaster and D. simulans interspecific hybrids. Aberrant phenotypes observed in interspecific hybrids frequently indicate rapidly evolving components of the underlying biological process or pathway. By comparing piRNA protein localization, piRNA pools, and germline TE expression between interspecific hybrids and pure species, I will reveal aspects of the piRNA pathway that have diverged functionally. 2) Examine adaptive divergence of Aubergine, a critical piRNA pathway protein, between D. melanogaster and D. simulans. I will employ heterologous transgenics to distinguish specific functions of the piRNA protein Aubergine that have been targets of positive selection. This directed analysis of aubergine will help elucidate the selective force(s) that underlie adaptive protein evolution throughout the piRNA pathway. The proposed research will enhance our understanding of how selfish transposable elements are controlled by their hosts. Because activity of these elements contribute directly to the origin, onset, or progression of several human genetic diseases, this knowledge is critical to generating more effective treatment and prevention

描述（由申请人提供）：转座元件（TE）是自私的遗传实体，可以快速席卷整个群体，在真核基因组中达到高拷贝数。超过 50 种人类遗传疾病与 TE 插入或在人群中反复发生的 TE 介导的染色体重排有关。此外，TE 的失调与肿瘤发生和肿瘤进展相关，这表明 TE 抑制在癌症抵抗中发挥着关键作用。 TE 活性产生的有害突变对宿主的抑制产生强烈的选择作用。最近对 Piwi 相互作用 RNA (piRNA) 途径的大量研究取得了令人兴奋的发现，即这些蛋白质与 TE 衍生的小 RNA (piRNA) 协同作用，使雄性和雌性种系中的 TE 沉默。 piRNA 途径在后生动物中具有保守的功能，但令人惊讶的是许多 piRNA 蛋白是正选择的直接目标。使用果蝇模型系统，我提出的研究将阐明蛋白质和 RNA 对 piRNA 介导的 TE 抑制的进化变化的贡献。具体来说，我将： 1) 检查黑腹果蝇和拟果蝇种间杂种中的 piRNA 途径功能。在种间杂种中观察到的异常表型经常表明潜在生物过程或途径的快速进化组成部分。通过比较种间杂种和纯种之间的 piRNA 蛋白定位、piRNA 库和种系 TE 表达，我将揭示 piRNA 途径在功能上存在差异的方面。 2) 检查茄子（一种关键的 piRNA 途径蛋白）在黑腹果蝇和模拟果蝇之间的适应性分歧。我将采用异源转基因技术来区分 piRNA 蛋白茄子的特定功能，该蛋白已成为正向选择的目标。这种对茄子的定向分析将有助于阐明整个 piRNA 途径中适应性蛋白质进化的选择性力量。拟议的研究将增强我们对自私转座因子如何受宿主控制的理解。由于这些元素的活性直接影响几种人类遗传疾病的起源、发作或进展，因此这些知识对于产生更有效的治疗和预防至关重要