Nuclear-Mitochondrial Fitness Interactions in Drosophila

描述（由申请人提供）：适当的线粒体功能需要在线粒体内的环状基因组中编码的37个基因和在核染色体上编码的1000多个基因的协调表达。这种细胞内、基因组间的通讯呈现出一个复杂的相互作用的基因网络，这些基因对维持生命的能量产生至关重要。由于这些基因在自然群体中都是可变的，每个基因与基因的相互作用都可以通过个体之间的变异而改变。此外，细胞色素是许多信号通路的中心，这些信号通路感知营养物质、氧气、细胞的氧化还原状态和温度，使其对环境条件敏感。因此，这些相互作用呈现出一个介于基因型和表型之间的复杂系统。第一个目的是通过从40个特征良好的果蝇近交系（果蝇遗传学参考小组）和6个测序的果蝇mtDNA中产生所有基因型对并进行表型分析，来剖析这种线粒体-核（线粒体）相互作用。melanogaster和D.模拟。这将为DGRP资源增加一个重要的mtDNA成分。该目标将分别量化替代饮食和氧气环境中的代谢产物谱和对低氧应激的抵抗力。这将检验环境压力改变上位性成分与线粒体相互作用的假设，并进一步检验mtDNA疾病状态在男性中更常见的假设，因为男性不传播mtDNA。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因素（饮食组成或氧张力）改变。这将检验假设，在中央营养代谢和缺氧信号通路的基因是唯一敏感的mtDNA基因型。在这两个目标中，所用mtDNA的系谱将用于mtDNA-表型关联的中性检验，该中性检验允许将性状划分为mtDNA单倍型中不同的突变类别。由于大多数QTL和全基因组关联研究（GWAS）不测试mtDNA或联合线粒体相互作用对表型的影响，拟议的实验设计将直接解决这一缺陷，并可能识别GWAS中未识别的“缺失遗传力”的组成部分。该研究还将有助于了解与线粒体功能相关的特定途径，这些途径可能导致药物治疗。通过控制饮食或环境中的氧气水平，我们可以确定线粒体相互作用影响肥胖和对缺氧应激的敏感性的新作用。

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.