Nuclear-Mitochondrial Fitness Interactions in Drosophila

描述（由申请人提供）：线粒体正常功能需要线粒体内循环基因组编码的37个基因和核染色体编码的1000多个基因协同表达。这种细胞内、基因组间的交流呈现了一个复杂的相互作用基因网络，这些基因对维持生命的能量生产至关重要。因为这些基因中的每一个在自然种群中都是可变的，每个基因之间的相互作用都可以通过个体之间的差异而改变。此外，线粒体是感知营养、氧气、细胞氧化还原状态和温度的许多信号通路的枢纽，使其对环境条件敏感。因此，这些相互作用呈现出一个复杂的系统，位于基因型和表型之间。第一个目标是通过生成和表型分析来自40个特征良好的近交系果蝇（果蝇遗传参考小组）的所有基因型对，以及来自D. melanogaster和D. simulans的6个测序mtdna，来解剖线粒体-核（mitonuclear）相互作用。这将为DGRP资源添加一个重要的mtDNA组件。该目的将分别量化代谢物谱和在替代饮食和氧气环境下对低氧应激的抵抗力。这将验证环境压力改变有丝核相互作用上位性成分的假设，并进一步验证mtDNA疾病状态在不传播mtDNA的男性中更常见的假设。第二个目标将确定特定的核转录本，其表达被mtDNA背景和这些相同的环境应激源（饮食成分或氧张力）改变。这将验证中心营养代谢和缺氧信号通路中的基因对mtDNA基因型唯一敏感的假设。在这两个目标中，所使用的mtDNA的谱系将用于mtDNA-表型关联的中立性测试，该测试允许将性状划分为mtDNA单倍型中不同类别的突变。由于大多数QTL和全基因组关联研究（GWAS）没有检测mtDNA或联合有丝核相互作用对表型的影响，因此提出的实验设计将直接解决这一缺陷，并可能确定GWAS中未发现的“缺失遗传性”成分。这项研究还将有助于了解与线粒体功能相关的特定途径，从而可能导致药物治疗。通过控制饮食或环境中的氧气水平，我们可以确定影响肥胖和对缺氧应激敏感性的核分裂相互作用的新作用。

DESCRIPTION (provided by applicant): Proper mitochondrial function requires the coordinated expression of 37 genes encoded in the circular genome inside the mitochondrion, and over 1000 genes encoded on nuclear chromosomes. This intracellular, intergenomic communication presents a complicated network of interacting genes that are critical for the energy production that sustains life. Because each of these genes is variable in natural populations, each gene-by-gene interaction can be altered by the variation among individuals. Moreover, the mitochondrion is a hub of many signaling pathways that sense nutrients, oxygen, redox state of the cell, and temperature making it sensitive to environmental conditions. As a result, these interactions present a complex system that lies between genotype and phenotype. The first Aim is to dissect this mitochondrial-nuclear (mitonuclear) interaction by generating and phenotyping all pairs of genotypes from 40 well-characterized inbred strains of Drosophila (the Drosophila Genetics Reference Panel), and 6 sequenced mtDNAs from D. melanogaster and D. simulans. This will add an important mtDNA component to the DGRP resource. This Aim will quantify metabolite profiles and resistance to hypoxic stress in alternative dietary and oxygen environments, respectively. This will test the hypothesis that environmental stress alters the epistatic component to mitonuclear interactions and further test the hypothesis that mtDNA disease states are more common in males, which do not transmit mtDNA. The second Aim will identify specific nuclear transcripts whose expression are altered by mtDNA background and these same environmental stressors (diet composition or oxygen tension). This will test the hypothesis that genes in the pathways of central nutrient metabolism and hypoxia signaling are uniquely sensitive to mtDNA genotype. In both Aims, the genealogy of the mtDNAs used will be used in a neutrality test of mtDNA-phenotype association that allows partitioning of traits to distinct classes of mutations in the mtDNA haplotypes. Because most QTL and genome wide association studies (GWAS) do not test for mtDNA or joint mitonuclear interaction effects on phenotype, the proposed experimental design will addresses this shortcoming directly, and may identify components of 'missing heritability' not identified in GWAS. The research will also contribute to knowledge of specific pathways relevant to mitochondrial function that may lead to pharmaceutical treatments. By manipulating diet or oxygen levels in the environment, we may identify novel roles for mitonuclear interactions affecting obesity and sensitivity to hypoxic stress. PUBLIC HEALTH RELEVANCE: Mitochondrial dysfunction is a leading cause of metabolic disease, affecting 1 in ~5000 individuals. Proper mitochondrial function requires coordinated expression of 37 genes in the mitochondrial genome (mtDNA) and more than 1000 genes in the nuclear genome, providing a large target for mutation. This project will dissect the joint contribution of mtDNA- and nuclear-encoded genes to metabolite levels and resistance to low oxygen. The first Aim will indentify genetic interactions between the two genomes that are sensitive to different levels of dietary carbohydrates and proteins, and to hypoxic stress, and the second Aim will identify genes whose expression are altered by mtDNA and dietary or oxygen stress. These experiments will provide information about the genetic basis of mitochondrial function for pathways related to obesity and the toxic effects of low oxygen, and could contribute to the development of mitochondrial replacement therapy or pharmaceuticals that compensate for reduced mitochondrial function.