Adaptive protein evolution of_Drosophila_germline stem cell genes_bam_and_bgcn_

描述（由申请人提供）： 包括人类在内的动物在其性腺中含有少量细胞，称为生殖系干细胞（GSC）。这些细胞在动物的一生中对制造精子或卵子至关重要。决定一个分裂的干细胞更新为干细胞或分化，并在生殖细胞的早期分裂的调节是一些最关键的决定在发展。对果蝇（Drosophila melanogaster）这一过程的细胞信号的研究发现了许多相关的关键基因。在所有动物物种中适当调节这一过程的重要性将导致人们预测这些功能是高度保守的。然而，最近发现几种关键的GSC调节分子在果蝇的两个密切相关的物种中的适应性进化下迅速进化（D. melanogaster及其姊妹种D. simulans），但不是在几个其他密切相关的物种。与中性进化基因相比，这些适应性进化基因积累了非常显著的过量氨基酸变化。确定GSC基因进化的功能后果和驱动这些变化的进化力量对于理解GSC在正常发育过程中如何调节以及它们的失调如何导致不育，生殖系癌症和生殖隔离至关重要。该建议的重点是评估两个关键的GSC调节基因，bam和bgcn的功能后果和进化的力量，负责驱动高速率的蛋白质分歧。GSC调控基因的进化模式也将在其他果蝇物种中进行研究。已经提出了许多假说来解释驱动先前发现的其他生殖基因的快速蛋白质进化的进化机制。基于初步的功能和进化数据，本研究的重点在于验证一个假设，即调节生殖系内共生体的影响或防御生殖系内共生体的自然选择是bam和bgcn适应性进化的关键驱动力。这些研究提供了一个框架，以测试类似的选择性驱动的功能变化，在其他基因控制干细胞的命运决定在果蝇以及在其他生物体，包括人类，并了解进化的力量驱动这些进化的变化。 公共卫生相关性： 生殖系干细胞（GSC）可以说是动物繁殖所需的最基本的细胞类型，因为这些细胞在动物的整个生命中都保持生殖系，并产生继续形成精子或卵子的细胞。值得注意的是，几个关键的GSC调控基因在物种之间的蛋白质序列水平上发生了强烈的自然选择。我们提出的研究旨在确定GSC基因进化的功能后果，并测试生殖细胞内共生体冲突假说作为这些变化的关键进化驱动因素。

DESCRIPTION (provided by applicant): Animals including humans contain a small number of cells in their gonads called germline stem cells (GSCs). These cells are essential for making sperm or eggs throughout the lifetime of the animal. The decision for a dividing stem cell to renew as a stem cell or to differentiate, and the regulation of early divisions in the germline are some of the most critical decisions in development. Studies of the cellular signaling for this process in the fruit fly, Drosophila melanogaster, have discovered many of the key genes involved. The importance of proper regulation of this process in all animal species would lead one to predict that these functions are highly conserved. However, several of the key GSC regulatory molecules have recently been discovered to be rapidly evolving under adaptive evolution in two closely related species of Drosophila (D. melanogaster and its sibling species D. simulans) but not in several additional closely related species. These adaptively evolving genes have accumulated a highly significant excess of amino-acid changes compared to neutrally evolving genes. Identifying the functional consequences of GSC gene evolution and the evolutionary forces driving these changes is essential for understanding how GSCs are regulated during normal development and how their misregulation can lead to infertility, germline cancers, and reproductive isolation. This proposal focuses on evaluating both the functional consequences and the evolutionary forces responsible for driving high rates of protein divergence at two key GSC regulator genes, bam and bgcn. Evolutionary patterns of GSC regulatory genes will also be examined in other Drosophila species. Numerous hypotheses have been proposed to explain the evolutionary mechanisms driving the previously discovered rapid protein evolution of other reproductive genes. Based on preliminary functional and evolutionary data, this proposal focuses on testing the hypothesis that natural selection to modulate the effects of or defend against germline endosymbionts is a key driver of adaptive evolution of bam and bgcn. These studies provide a framework with which to test for similar selectively driven functional changes in other genes controlling stem cell fate decisions in Drosophila as well as in other organisms including humans, and for understanding the evolutionary forces driving these evolutionary changes. PUBLIC HEALTH RELEVANCE: Germline stem cells (GSCs) are arguably the most fundamental cell type required for animal reproduction because these cells both maintain the germline throughout the animal's life, and produce the cells that go on to form either sperm or eggs. Remarkably, several key GSC regulatory genes are under strong natural selection to change at the protein sequence level between species. Our proposed study is aimed at identifying the functional consequences of GSC gene evolution and to test the germline endosymbiont conflict hypothesis as a key evolutionary driver of these changes.