Causes and consequences of microbe-mediated asexuality

项目摘要 有性生殖进化于10亿多年前，在真核生物出现后不久。性 理论上是创造遗传变异、适应新环境和适应新环境的一个重要方面， 从基因库中去除不利的性状。尽管如此，许多真核生物已经恢复到无性 生殖策略。重要的是，这种向无性生殖的转变会产生巨大的进化影响： 我们经常看到这方面的例子，如侵入性、致病性和抗药性生物体的迅速传播。 不幸的是，这种转变由于其缺乏可操作性而非常难以机械地询问。 实验的易处理性和事实上，许多恢复到无性恋是相当古老的。然而，节肢动物 富含最近获得的垂直遗传微生物（例如，沃尔巴克氏体、立克次体和Cardinium）， 将它们的节肢动物宿主转化为无性繁殖所谓的“孤雌生殖诱导”已经被 在这些细菌中多次重新发明，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操纵这些最近无性繁殖的谱系， 定义了无性繁殖的细胞生物学。此外，由于有许多独立的 过渡到微生物介导的无性恋，谱系将慢慢经历性功能的丧失，我们可以 用这个系统来追踪失去性生活的基因组和机制后果。我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生物体和基因组联系起来， 后果该提案描述了我的实验室在未来五年的研究目标， 包括：（1）机械表征介导无性繁殖的细菌蛋白，（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）使用正向遗传学绘制失去性行为的基因组后果。特别是，我们的创意 跨学科研究计划整合了基因组方法（例如，比较基因组测序 基因组学，数量性状基因座作图），非模式生物的分子方法， 易处理的模型系统（例如，酵母，果蝇）。我们将在最近发现的第一个 无性诱导细菌效应蛋白，以广泛定义微生物如何进化到操纵 有丝分裂和减数分裂，并从结果中解开生殖开关的原因。此外 对于繁殖的广泛意义，这些系统提供了新的机会来理解基本的 细胞生物学的各个方面是许多人类健康相关过程的基础。例如，有丝分裂的缺陷 是某些退行性疾病和癌症的典型特征，倍性的变化显著有助于 真菌致病机理和耐药性。我们专注于改变生殖和细胞的新机制 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.