Causes and consequences of microbe-mediated asexuality

项目摘要 有性生殖在10亿多年前进化，也就是真核生物出现后不久。性 被认为是创造遗传变异、适应新环境的重要方面，以及在 从基因库中去除不利的特征。尽管如此，许多真核生物还是恢复了无性 生殖策略。重要的是，这种向无性繁殖的转变具有巨大的进化影响： 我们在入侵、致病和耐药生物的快速传播中经常看到这样的例子。 不幸的是，众所周知，这样的过渡很难机械地进行审问，因为它们缺乏 实验上的可驯性和许多回归无性的事实都是相当古老的。然而，节肢动物 富含最近获得的垂直遗传微生物(例如，沃尔巴克氏菌、立克次体和卡迪纳菌) 将它们的节肢动物宿主转变为无性繁殖。所谓的“孤雌生殖诱导”一直是 在这些细菌中进行了多次改造，并依赖于影响宿主减数分裂的微生物机制 或有丝分裂来改变倍性。我们可以在实验室里机械地操纵这些最近的无性血统 定义无性繁殖的细胞生物学。此外，因为有许多独立的 过渡到微生物介导的无性行为，血统会慢慢丧失性功能，我们可以 使用这个系统来追踪失去性行为的基因组和机制后果。我的实验室的长期目标是 是将有丝分裂、减数分裂和生殖的机械过程与长期的有机体和基因组联系起来 后果。这份提案描述了我的实验室在未来五年的研究目标， 包括：(1)对介导无性繁殖的细菌蛋白质进行机械表征；(2) 在不同的细菌和生殖生物学中鉴定有丝分裂和减数分裂效应蛋白， 以及(3)使用正向遗传学来绘制失去性行为的基因组后果。具体来说，我们的创意 跨学科研究计划整合了基因组方法(例如，基因组测序、比较 基因组学，数量性状基因座定位)，非模式生物的分子方法，以及 易于处理的模型系统(例如，酵母、果蝇)。我们将在我们最近发现的第一个推定的 无性诱导细菌效应蛋白广泛定义微生物是如何进化来操纵的 有丝分裂和减数分裂，并将生殖开关的原因与后果分开。此外 对于生殖的广泛意义，这些系统提供了新的机会来理解基本的 许多与人类健康相关的过程所涉及的细胞生物学方面。例如，有丝分裂中的缺陷 是某些退行性疾病和癌症的典型特征，倍性的变化显著地有助于 真菌的发病机制及耐药性。我们对改变生殖和细胞的新机制的关注 该司将支持在一系列系统中开发新的治疗途径。

Project Summary Sexual reproduction evolved more than one billion years ago, shortly after the appearance of eukaryotes. Sex is theorized to be an important aspect of creating genetic variation, adapting to new environments, and in removing disadvantageous traits from the gene pool. Despite this, many eukaryotes have reverted to asexual reproductive strategies. Importantly, such transitions to asexual reproduction have huge evolutionary impacts: we see regular examples of this in the rapid spread of invasive, pathogenic, and drug-resistant organisms. Unfortunately, such transitions are notoriously difficult to mechanistically interrogate due to their lack of experimental tractability and the fact that many reversions to asexuality are quite ancient. However, arthropods are rich in recently acquired vertically inherited microbes (e.g., Wolbachia, Rickettsia, and Cardinium) that convert their arthropod hosts to asexual reproduction. So-called “parthenogenesis induction” has been reinvented multiple times across these bacteria and relies on microbial mechanisms for impacting host meiosis or mitosis to alter ploidy. We can manipulate these recently asexual lineages in the lab to mechanistically define the cell biology of asexual reproduction. Furthermore, because there are numerous independent transitions to microbe-mediated asexuality, and lineages will slowly undergo a loss of sexual function, we can use this system to track the genomic and mechanistic consequences of lost sex. The long-term goal of my lab is to link mechanistic processes of mitosis, meiosis, and reproduction to long-term organismal and genomic consequences. This proposal describes my lab’s research goals across the next five years, which include: (1) mechanistically characterizing bacterial proteins mediating asexual reproduction, (2) identifying mitotic- and meiotic- effector proteins across diverse bacteria and reproductive biologies, and (3) using forward genetics to map the genomic consequences of lost sex. Specifically, our creative interdisciplinary research plan integrates genomic approaches (e.g., genome sequencing, comparative genomics, quantitative trait loci mapping), molecular approaches in non-model organisms, and genetics in tractable model systems (e.g., yeast, Drosophila). We will build on our recent discovery of the first putative asexuality inducing bacterial effector proteins to broadly define how microbes have evolved to manipulate mitosis and meiosis, and disentangle the causes of reproductive switches from the consequences. In addition to the broad significance of reproduction, these systems afford new opportunities to understand fundamental aspects of cell biology that underly many human-health relevant processes. For example, defects in mitosis are typical of certain degenerative conditions and cancers, and changes in ploidy significantly contribute to fungal pathogenesis and drug resistance. Our focus on novel mechanisms for altering reproduction and cell division will support the development of new therapeutic avenues across a range of systems.