Mutational and evolutionary impact of mitochondrial dysfunction

线粒体功能障碍的突变和进化影响

• 批准号: 8641387
• 负责人: DEE DENVER
• 金额: $ 27.88万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-10 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8641387
• 关键词: Achievement; Address; Affect; Age; Aging; Aging-Related Process; Alzheimer' s Disease; Animals; Biological Assay; Biological Phenomena; Biology; Caenorhabditis; Caenorhabditis elegans; Coupled; DNA Sequence Analysis; Disease; Employee Strikes; Environment; Enzymes; Equilibrium; Evolution; Functional disorder; Generations; Genetic; Genetic Variation; Genome; Germ-Line Mutation; Goals; Haplotypes; Health; Hereditary Disease; High-Throughput DNA Sequencing; Human; Human Genetics; Individual; Infection; Knowledge; Laboratories; Life; Longevity; Malignant Neoplasms; Microsporidia; Mitochondria; Mitochondrial DNA; Mitochondrial Myopathies; Modeling; Molecular; Mutation; Natural Immunity; Natural Selections; Nature; Nematoda; Nuclear; Parasite resistance; Parasites; Parkinson Disease; Play; Population; Population Sizes; Population Study; Process; Property; Reactive Oxygen Species; Relative (related person); Reporter; Reporter Genes; Research Project Grants; Resistance; Role; Sister; Somatic Cell; Somatic Mutation; Source; Study models; System; Technology; Testing; Transgenes; Variant; base; comparative; expectation; experience; fitness; genome-wide; innovation; insight; mitochondrial dysfunction; mitochondrial genome; mutant; novel; progenitor; public health relevance; theories

DESCRIPTION (provided by applicant): The main objective of the proposed research project is to provide knowledge on the mutational and evolutionary consequences of reactive oxygen species (ROS) that result from mitochondrial dysfunction. ROS are central players in a variety of human disorders and the aging process, but also play important protective roles in innate immunity against parasites. The main objective will be achieved using the model nematode Caenorhabditis elegans and its sister species C. briggsae. The first specific aim is to determine the impact of ROS on genome-wide germline mutation processes. This aim will be accomplished by first creating mutation-accumulation (MA) lines from C. elegans genetic mutants that experience higher or lower levels of ROS as compared to wild-type, and from C. briggsae strains that experience varying levels of ROS due variation in naturally-occurring mitochondrial genome deletions. The nuclear genomes of the resultant MA lines will be comprehensively analyzed for mutation using Solexa high-throughput DNA sequencing technology. The achievement of this aim will confirm or deny the widely held, but unproven hypothesis that ROS of mitochondrial origin cause elevated mutation rates in the nuclear genome. The second specific aim is to characterize the somatic mutation effects of ROS as a function of age. A simple yet powerful somatic mutation reporter transgene system will be employed to examine the mosaic somatic mutation process in the same C. elegans genetic backgrounds used for the first aim. Achievement of the second aim will provide essential knowledge on the role of ROS in somatic mutation accumulation, and novel insights into the extent to which germline and somatic mutation processes are coupled. The third specific aim is to identify the evolutionary causes of naturally- occurring mitochondrial genome deletions in C. briggsae. This aim will be accomplished by testing two opposing hypotheses: a first non-adaptive hypothesis that the deletions passively evolved due to weak natural selection associated with evolution in small populations, and a second adaptive hypothesis that ROS resulting from the deletions play a functional role in protecting nematodes against intracellular parasite infections. The first hypothesis will be tested using laboratory comparative population size studies involving C. briggsae of varying mitochondrial genome deletion levels; the second hypothesis will be tested using infection and competition assays involving Nematocida sp. 1, a newly discovered microsporidia parasite that infects C. briggsae in nature. Correlations between deletion levels and infection status will also be tested for in C. briggsae natural isolates. Achievement of the three aims will provide unprecedented knowledge on the effects of ROS on nuclear genome mutation processes, and the potential of a new paradigm for understanding the interplay between selection against the highly negative effects of ROS, and positive selection for ROS-induced resistance to parasites.

描述（由申请人提供）： 拟议研究项目的主要目标是提供有关线粒体功能障碍导致的活性氧（ROS）突变和进化后果的知识。 ROS 在多种人类疾病和衰老过程中发挥着重要作用，而且在针对寄生虫的先天免疫中也发挥着重要的保护作用。主要目标将通过模型线虫秀丽隐杆线虫及其姐妹种 C. briggsae 来实现。第一个具体目标是确定 ROS 对全基因组种系突变过程的影响。这一目标将通过首先从线虫基因突变体中创建突变积累（MA）系来实现，这些突变体与野生型相比具有更高或更低水平的ROS，以及由于自然发生的线粒体基因组缺失的变化而经历不同水平ROS的C.briggsae菌株。将使用 Solexa 高通量 DNA 测序技术对所得 MA 系的核基因组进行全面突变分析。这一目标的实现将证实或否定广泛持有但未经证实的假设，即线粒体来源的 ROS 会导致核基因组突变率升高。第二个具体目标是将 ROS 的体细胞突变效应描述为年龄的函数。将采用简单而强大的体细胞突变报告基因转基因系统来检查用于第一个目标的相同秀丽隐杆线虫遗传背景中的嵌合体细胞突变过程。第二个目标的实现将为 ROS 在体细胞突变积累中的作用提供必要的知识，并为种系和体细胞突变过程的耦合程度提供新的见解。第三个具体目标是确定 C. briggsae 中自然发生的线粒体基因组缺失的进化原因。这一目标将通过测试两个相反的假设来实现：第一个非适应性假设，即缺失是由于与小群体进化相关的自然选择较弱而被动进化的；第二个适应性假设，即缺失产生的ROS在保护线虫免受细胞内寄生虫感染方面发挥功能性作用。第一个假设将通过实验室比较种群规模研究进行检验，该研究涉及不同线粒体基因组缺失水平的 C. briggsae；第二个假设将使用涉及杀线虫的感染和竞争测定进行测试。 1，一种新发现的微孢子虫寄生虫，可感染自然界中的 C. briggsae。还将在 C. briggsae 天然分离株中测试缺失水平和感染状态之间的相关性。这三个目标的实现将为 ROS 对核基因组突变过程的影响提供前所未有的知识，并为理解 ROS 的高度负面影响的选择与 ROS 诱导的寄生虫抗性的正选择之间的相互作用提供新范式的潜力。

项目成果

Selfish Mitochondrial DNA Proliferates and Diversifies in Small, but not Large, Experimental Populations of Caenorhabditis briggsae.

• DOI: 10.1093/gbe/evv116
• 发表时间: 2015-06-24
• 期刊: Genome biology and evolution
• 影响因子: 3.3
• 作者: Phillips WS;Coleman-Hulbert AL;Weiss ES;Howe DK;Ping S;Wernick RI;Estes S;Denver DR
• 通讯作者: Denver DR

Mitochondrial DNA Variation and Selfish Propagation Following Experimental Bottlenecking in Two Distantly Related Caenorhabditis briggsae Isolates

• DOI: 10.3390/genes11010077
• 发表时间: 2020-01
• 期刊: Genes
• 影响因子: 3.5
• 作者: Josiah T. Wagner;D. Howe;Suzanne Estes;D. Denver

Paternal Mitochondrial Transmission in Intra-Species Caenorhabditis briggsae Hybrids.

• DOI: 10.1093/molbev/msw192
• 发表时间: 2016-12
• 期刊: Molecular biology and evolution
• 影响因子: 10.7
• 作者: Ross JA;Howe DK;Coleman-Hulbert A;Denver DR;Estes S
• 通讯作者: Estes S

Natural variation in life history and aging phenotypes is associated with mitochondrial DNA deletion frequency in Caenorhabditis briggsae.

• DOI: 10.1186/1471-2148-11-11
• 发表时间: 2011-01-12
• 期刊: BMC evolutionary biology
• 影响因子: 3.4
• 作者: Estes S;Coleman-Hulbert AL;Hicks KA;de Haan G;Martha SR;Knapp JB;Smith SW;Stein KC;Denver DR
• 通讯作者: Denver DR

Natural variation in Caenorhabditis briggsae mitochondrial form and function suggests a novel model of organelle dynamics.

• DOI: 10.1016/j.mito.2012.12.006
• 发表时间: 2013-01
• 期刊: MITOCHONDRION
• 影响因子: 4.4
• 作者: Hicks, Kiley A.;Denver, Dee R.;Estes, Suzanne
• 通讯作者: Estes, Suzanne