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（由申请人提供）：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。不仅仅是它的少数基因产物在能量代谢中极其重要。线粒体基因组明显的独立性需要复杂的“管理”安排：细胞核创建发育程序，确保线粒体基因组持续满足宿主的需求。如果线粒体基因组有自由支配权，它将自私地进化，增强其复制以超越其邻居，并放弃电子传输功能的产生，而电子传输功能自然不会有助于该基因组的复制或传输。核“管理”很大程度上但不完全包含这种不守规矩的行为。该提案探讨了基因组间关系背后的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。这种消除强制执行纯母系遗传，这是一种将线粒体基因组限制为谱系的遗传模式。这种限制限制了自私行为的进化优势：例如，超级复制基因组可能会在一个谱系中取得成功，但它无法传播以“感染”整个繁殖群体。该提案将研究这种 DNA 消除程序的机制，并测试使用这种 DNA 消除途径来控制和限制体细胞发育中的线粒体基因组。我们还将使用一系列新工具来研究生物体内不同的线粒体基因组如何竞争传输，以及细胞核如何监督这种竞争。线粒体基因组之间为了填充卵而进行的专门竞争对于宿主来说非常重要。在此过程中，具有电子传输功能的基因组复制功能较弱的基因组。这种竞争提供了纯化选择，消除了对宿主有害的突变。然而，生长和发育过程中线粒体基因组之间的竞争并不是基于功能。在此阶段，自私利益占主导地位，每个线粒体基因组都努力超越其邻居，选择超级复制基因组。我们创建了具有两种线粒体基因组的“异质”系，一种具有复制优势但功能缺陷，另一种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。我们将检查线粒体基因组和核基因组中影响这种平衡的遗传变化。这将识别改变竞争的核基因，以监督线粒体基因组的进化方向，以及它们在线粒体基因组上的作用位点。这种方法将为我们在控制影响代谢疾病、衰老、新陈代谢和进化的调节中心轴的神秘过程提供分子和遗传立足点。