Host management of the mitochondrial genome

线粒体基因组的宿主管理

• 批准号: 9127455
• 负责人: PATRICK H O'FARRELL
• 金额: $ 42.2万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-19 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9127455
• 关键词: Aging; Bacterial Infections; Behavior; Breeding; Cell Nucleus; Complex; Conflict (Psychology); DNA; DNA Sequence; DNA-Directed DNA Polymerase; Development; Disadvantaged; Disease; Drosophila genus; Drosophila melanogaster; Educational process of instructing; Electron Transport; Energy Metabolism; Ensure; Equilibrium; Eukaryota; Event; Evolution; Female; Fertility; Gene-Modified; Genes; Genetic Recombination; Genome; Germ Cells; Germ Lines; Growth; Growth and Development function; Inheritance Patterns; Left; Life; Longevity; Maps; Measures; Metabolic Diseases; Metabolism; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Modeling; Molecular Genetics; Mutation; Nuclear; Oocytes; Oogenesis; Organelles; Organism; Pathway interactions; Phenotype; Population; Process; Production; Recombinants; Regulation; Replication Origin; Role; Seizures; Site; Spermatids; Spermatogenesis; Staging; Survivors; Techniques; Testing; Tissues; Work; base; bullying; egg; endonuclease; fly; gene product; interest; mitochondrial genome; neuronal cell body; programs; public health relevance; segregation; sperm cell; success; tool; transmission process

 DESCRIPTION (provided by applicant): Host management of the mitochondrial genome the small genome of the mitochondria has an influence out of proportion to its size. It is not just tha its few gene products are extremely important in energy metabolism. The apparent independence of the mitochondrial genome has required a complex "administrative" arrangement: the nucleus creates developmental programs that ensure the continued contribution of the mitochondrial genome to the host's needs. If the mitochondrial genome had free reign, it would evolve selfishly, enhance its replication to out compete its neighbors, and abandon production of electron transport functions, which do not naturally contribute to the replication or transmission of this genome. Nuclear "management" largely but not completely contains such unruly behaviors. This proposal explores the poorly understood regulatory interactions underlying the intergenomic relationship. For example, we found that mitochondrial DNA (mtDNA) is eliminated from mitochondria during spermatogenesis. This elimination enforces maternal-only inheritance, an inheritance pattern that limits mitochondrial genomes to a lineage. This limitation caps the evolutionary advantages of selfish behavior: for example, a super replicating genome might succeed within a lineage but it cannot spread to "infect" the whole breeding population. This proposal will examine the mechanism of this DNA elimination program and test the use of this DNA elimination pathway to control and limit mitochondrial genomes in somatic development. We will also use a bevy of new tools to study how different mitochondrial genomes within an organism compete for transmission, and how the nucleus oversees this competition. A specialized competition among mitochondrial genomes to populate the egg is important to the host. During this process, genomes functional in electron-transport out-replicate less functional genomes. This competition provides the purifying selection that eliminates mutations detrimental to the host. However, competition among mitochondrial genomes during growth and development is not based on function. During this stage, selfish interests dominate, and each mitochondrial genome strives to out-compete its neighbor, selecting for super replicating genomes. We created "heteroplasmic" lines with two mitochondrial genomes, one with a replicative advantage but functional deficit, and one with a functional edge but a replicative disadvantage. Retention of these two genomes depends on the strength of the selection in oogenesis versus selection during zygotic growth. We will examine the genetic changes in the mitochondrial genome and in the nuclear genome that influence this balance. This will identify the nuclear genes that modify competition to oversee the evolutionary directions taken by the mitochondrial genome, and the sites of their action on the mitochondrial genome. This approach will give us a molecular and genetic foothold on the mysterious processes controlling a central axis of regulation influencing metabolic disease, aging, metabolism and evolution.

 描述(申请人提供)：线粒体基因组的宿主管理线粒体的小基因组的影响与其大小不成比例。这不仅仅是因为它的几个基因产物在能量代谢中极其重要。线粒体基因组的明显独立性需要一个复杂的“行政”安排：细胞核创建发育程序，以确保线粒体基因组继续为宿主的需求做出贡献。如果线粒体基因组自由支配，它会自私地进化，增强复制以击败邻居，并放弃电子传输功能的产生，而电子传输功能自然不会对基因组的复制或传输做出贡献。核“管理”在很大程度上但不是完全包含了这种不守规矩的行为。这项建议探讨了基因组间关系背后鲜为人知的调控相互作用。例如，我们发现线粒体DNA(MtDNA)在精子发生过程中从线粒体中消除。这种消除强制只有母系遗传，这是一种将线粒体基因组限制在一个谱系的遗传模式。这一限制限制了自私行为的进化优势：例如，一个超级复制的基因组可能在一个谱系内成功，但它不能传播到“感染”整个繁殖种群。这项建议将研究这一DNA消除计划的机制，并测试这一DNA消除途径在体细胞发育中控制和限制线粒体基因组的使用。我们还将使用一系列新工具来研究有机体内不同的线粒体基因组如何竞争传递，以及核如何监督这种竞争。线粒体基因组之间的专门竞争以填充卵子对宿主来说很重要。在这一过程中，具有电子传输功能的基因组复制功能较少的基因组。这种竞争提供了纯净的选择，消除了对宿主有害的突变。然而，线粒体基因组在生长发育过程中的竞争并不是基于功能。在这个阶段，自私的利益占主导地位，每个线粒体基因组都在努力超越它的邻居，选择具有超级复制能力的基因组。我们创造了具有两个线粒体基因组的“异质”系，一个具有复制优势但功能缺陷，另一个具有功能优势但复制劣势。这两个基因组的保留取决于卵子发生过程中的选择与合子生长过程中的选择的强度。我们将研究影响这种平衡的线粒体基因组和核基因组中的遗传变化。这将确定改变竞争的核基因，以监督线粒体基因组采取的进化方向，以及它们对线粒体基因组的作用部位。这种方法将让我们在神秘的过程中获得分子和遗传的立足点，这些过程控制着影响代谢性疾病、衰老、新陈代谢和进化的中心轴。