Causes of Extreme Mitochondrial Mutation Rate Variation

线粒体突变率极端变化的原因

• 批准号: 9980933
• 负责人: Daniel Benjamin Sloan
• 金额: $ 31.51万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-06 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980933
• 关键词: Acceleration; Address; Angiosperms; Animals; Arabidopsis; Base Pairing; Biological Assay; Biology; Candidate Disease Gene; Cells; Chemicals; DNA; DNA Damage; DNA Sequence; DNA biosynthesis; DNA-Directed DNA Polymerase; Diabetes Mellitus; Disease; Eukaryota; Event; Evolution; Exhibits; Gene Conversion; Gene Frequency; Genes; Genetic; Genome; Germ Lines; Human; Individual; Inherited; Investigation; Knowledge; Link; Maintenance; Malignant Neoplasms; Measurement; Measures; Metabolic; Metabolic Diseases; Methodology; Mismatch Repair; Mitochondria; Mitochondrial DNA; Modeling; Mouse-ear Cress; Mutation; Nerve Degeneration; Nuclear; Organelles; Organism; Pattern; Plants; Plastids; Point Mutation; Polymerase; Predisposition; Prevalence; Production; Reactive Oxygen Species; Recording of previous events; Research; Role; Series; Silene; Technology; Testing; Tissues; Uncertainty; Variant; age related; base; comparative; deep sequencing; innovation; interest; mitochondrial genome; mutant; offspring; oxidative damage; recombinational repair; repaired

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.

项目摘要 线粒体突变的发生率很高，是遗传和年龄的主要原因 相关疾病。尽管长期以来长期认为升高的突变率是强度的副产品 线粒体内发生的代谢活动，最近的证据使这种观点提出了质疑，创造了这种观点 关于线粒体突变原因的巨大不确定性。与人类形成鲜明对比的是 真核生物在线粒体DNA中表现出极低的突变速率。回答如何 有些生物可以保持低线粒体突变率有可能告知我们 了解导致他们在人类中如此高的原因。但是，很少努力 解决真核遗传学的基本问题。拟议的研究将集中于开花 植物是理解负责线粒体突变率变化的机制的模型。 植物中线粒体（和质体）DNA取代的速率通常低于植物核 基因组和数量级低于动物线粒体。但是，植物也表现出极端 线粒体序列进化速率的波动，即使在密切相关的物种之间也是如此。进步 了解大多数植物物种中极低率的机制已经是 在研究罕见突变事件时固有的技术困难阻碍了。新的到来 利用深度测序和定量PCR技术直接测量稀有的方法学 突变和量化DNA损伤的速率带来了一个令人兴奋的机会来克服这些历史 障碍。拟议的研究将将这些方法应用于野生型和突变背景 模型被子植物拟南芥测试了一套替代假设，与 DNA聚合酶，重组修复机制的疗效，偏见基因转化的作用， 以及对植物细胞器中DNA损伤的暴露/敏感性。分析将对两种营养 和分生组织，以区分简单地在植物组织中积聚的突变与 实际传输到后代。该研究还将扩展到相关的开花植物物种 线粒体序列演化的速率最近有一个巨大的加速度。这些 调查将阐明负责跨线粒体突变率变化的机制 真核生物并告知有关氧化损伤作为诱变力在人类中的作用的持续辩论 线粒体。