Evolution of piRNAs and germline transposon control in Drosophila

描述（由申请人提供）：转座因子（te）是一种自私的遗传实体，可以快速席卷整个群体，在真核生物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TE介导的染色体重排有关，TE介导的染色体重排在人群中反复发生。此外，TE的错误调节与肿瘤发生和肿瘤进展有关，表明TE抑制在癌症抵抗中起关键作用。由TE活性产生的有害突变对宿主的抑制具有很强的选择性。最近对Piwi相互作用RNA （piRNA）途径的研究取得了令人兴奋的发现，这些蛋白质与te衍生的小RNA （piRNAs）协同作用，在男性和女性种系中沉默te。piRNA通路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。利用果蝇模型系统，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)研究piRNA通路在黑腹d和模拟d种间杂交中的功能。在种间杂交中观察到的异常表型通常表明潜在生物过程或途径的快速进化成分。通过比较piRNA蛋白定位、piRNA池和种间杂交种和纯种之间的种系TE表达，我将揭示piRNA通路在功能上存在分歧的方面。2)研究了Aubergine（一种重要的piRNA通路蛋白）在D. melanogaster和D. simulans之间的适应性差异。我将采用异源转基因技术来区分作为正选择目标的piRNA蛋白茄子的特定功能。这种对茄子的定向分析将有助于阐明整个piRNA途径中适应性蛋白进化的选择力。拟议的研究将增强我们对自私转座因子如何受其宿主控制的理解。由于这些元素的活性直接与几种人类遗传疾病的起源、发病或进展有关，因此这些知识对于产生更有效的治疗和预防至关重要

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