Host management of the mitochondrial genome

线粒体基因组的宿主管理

基本信息

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
项目类别：
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

项目摘要

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，这不仅仅是其少数基因产物在能量代谢中极其重要。线粒体基因组需要复杂的“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统治，它就会自私地进化，增强其复制以超越其竞争。邻居,例如，核“管理”很大程度上但不完全包含这种不守规矩的行为。，我们发现线粒体 DNA (mtDNA) 在精子发生过程中从线粒体中消除，这种消除强制了母系遗传，这种遗传模式将线粒体基因组限制在一个谱系中。这种限制限制了自私行为的进化优势：例如，超级遗传。复制基因组可能会在一个谱系中成功，但它不能传播以“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。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播，以及细胞核如何监督这种竞争，以填充卵子。在此过程中，基因组非常重要。功能于这种竞争提供了消除宿主突变的纯化选择，但在生长和发育过程中，线粒体基因组之间的竞争并不是基于功能。线粒体基因组努力超越其邻居，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不足，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。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，这种方法将为我们提供控制影响代谢疾病、衰老、新陈代谢和进化的调节中心轴的神秘过程的分子和遗传立足点。。