Causes of Extreme Mitochondrial Mutation Rate Variation

项目总结 线粒体突变在人类中发生的频率非常高，是遗传和衰老的主要原因。 相关疾病。尽管长期以来，高突变率一直被认为是高强度的 发生在线粒体内的代谢活动，最近的证据对这一观点提出了质疑，创造了 该领域对线粒体突变的原因存在巨大的不确定性。与人类不同，有些人 真核生物的线粒体DNA突变率极低。回答以下问题： 一些生物能够保持较低的线粒体突变率有可能告诉我们 了解是什么导致它们在人类体内如此之高。然而，值得注意的是，几乎没有做出什么努力。 来解决真核遗传学的这个基本问题。拟议的研究将集中在开花上。 植物作为一个模型来理解线粒体突变率变化的机制。 植物中线粒体(和叶绿体)DNA替换率通常低于植物核。 基因组和数量级低于动物线粒体。然而，植物也表现出极端的 线粒体序列进化速率的波动，即使在关系密切的物种之间也是如此。取得的进展 对大多数植物物种中极低比率的机制的理解一直是 受制于研究罕见突变事件的固有技术困难。新技术的出现 利用深度测序和定量聚合酶链式反应技术直接测量稀有物质的方法 突变和量化DNA损伤率提供了一个令人兴奋的机会来克服这些历史性的 障碍。拟议的研究将把这些方法应用于野生型和突变型背景 模型被子植物拟南芥测试一套替代假说，与保真度有关 DNA聚合酶，重组修复机制的有效性，偏向基因转换的影响， 以及对植物细胞器中DNA损伤的暴露/敏感性。将对这两种植物进行分析 和分生组织，以区分简单积累在植物组织中的突变和 实际上是传给后代的。这项研究还将扩展到开花植物的相关物种 最近线粒体序列进化的速度有了很大的加快。这些 调查将阐明导致线粒体突变率差异的机制。 并为正在进行的关于氧化损伤作为人类诱变力量的作用的辩论提供信息 线粒体。

PROJECT SUMMARY Mitochondrial mutations occur at a very high rate in humans and are a major cause of inherited and age- related diseases. Although elevated mutation rates have long been considered a byproduct of the intense metabolic activity that occurs within mitochondria, recent evidence has called this view into question, creating enormous uncertainty in the field about the causes of mitochondrial mutations. In contrast to humans, some eukaryotes exhibit extremely low rates of mutation in their mitochondrial DNA. Answering the question of how some organisms are able to maintain low mitochondrial mutation rates has the potential to inform our understanding of what causes them to be so high in humans. Remarkably, however, little effort has been made to address this fundamental question of eukaryotic genetics. The proposed research will focus on flowering plants as a model for understanding the mechanisms responsible for variation in mitochondrial mutation rate. Rates of mitochondrial (and plastid) DNA substitutions in plants are generally lower than in plant nuclear genomes and orders of magnitude lower than in animal mitochondria. However, plants also exhibit extreme fluctuations in rates of mitochondrial sequence evolution even among closely related species. Progress in understanding the mechanisms responsible for the extremely low rates in most plant species has been impeded by the inherent technical difficulties in studying rare mutation events. The advent of new methodologies that leverage deep sequencing and quantitative PCR technologies to directly measure rare mutations and quantify rates of DNA damage presents an exciting opportunity to overcome these historical barriers. The proposed research will apply these methodologies to both wild-type and mutant backgrounds in the model angiosperm Arabidopsis thaliana to test a suite of alternative hypotheses, relating to the fidelity of DNA polymerases, the efficacy of recombinational repair mechanisms, the effects of biased gene conversion, and exposure/susceptibility to DNA damage in plant organelles. Analyses will be conducted on both vegetative and meristematic tissues to distinguish mutations that simply accumulate in plant tissues from those that are actually transmitted to offspring. The research will also be extended to related species of flowering plants in which there has been a recent and massive acceleration in rates of mitochondrial sequence evolution. These investigations will elucidate the mechanisms responsible for variation in mitochondrial mutation rates across eukaryotes and inform ongoing debates about the role of oxidative damage as a mutagenic force in human mitochondria.