Mitonuclear genetics of complex traits in Drosophila

果蝇复杂性状的线粒体核遗传学

基本信息

批准号：
10377905
负责人：
DAVID M RAND
金额：
$ 38.58万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10377905
关键词：
Address Adult Affect Age Biological Assay Biology Child Complex Complex Genetic Trait Development Disease Drosophila genus Ensure Environment Environmental Risk Factor Epigenetic Process Female Foundations Gene Expression Gene Mutation Genes Genetic Genetic Drift Genetic Screening Genetic Variation Genome Genomics Genotype Incidence Individual Joints Medical Genetics Metabolic Diseases Mitochondria Mitochondrial DNA Mitochondrial Diseases Mitochondrial Inheritance Modeling Mothers Mutation Nuclear Pathway interactions Performance Pharmacologic Substance Phenotype Physical environment Population Quantitative Genetics Replacement Therapy Research Signal Pathway Source base differential expression environmental stressor experimental study fitness gene expression variation genetic approach male mitochondrial DNA mutation mitochondrial dysfunction mitochondrial genome prevent response sex therapy development trait

项目摘要

Mitochondrial dysfunction is a common source of disease, affecting 1 in ~5000 individuals. The United Mitochondrial Disease Foundation states “every 30 minutes a child is born who will develop a mitochondrial disease by age 10” (www.umdf.org). The biology of mitochondria makes these problems tremendously complex. Mitochondrial function requires the coordinated expression of 37 genes encoded in mitochondrial DNA (mtDNA) inside mitochondria, and over 1000 nuclear-encoded genes whose products must be transported into mitochondria. The high mutation rate for mtDNA and the large target of nuclear genes for mutations ensures that every individual has a unique ‘mito-nuclear genotype’ that can alter fitness. Development in different environments can alter how different genotypes express adult traits. Thus, these sources of complexity are responsible for key gaps in our understanding of the genetic bases of mitochondrial disease, and more generally, the genetic variation for mitochondrial performance in natural populations. The Drosophila model we have developed provides a powerful genetic approach to dissect this complexity. We have introduced different mtDNAs into controlled nuclear genetic backgrounds and identified genetic interactions (‘mitonuclear epistases’) affecting fitness traits and gene expression. We have discovered that many of the genes with differential expression resulting from mitonuclear genetic interactions also show differential expression in response environmental perturbations. Our working hypothesis is that mitochondria integrate genetic pathways regulating changes in both the internal cellular, and external physical, environments. We will pursue three general questions. First, what signaling pathways underlie the shared gene expression responses to altered mitonuclear genotypes and altered physical environments? This will be addressed with gene expression and epigenetic experiments pairing mitonuclear genotypes and environmental stressors. Second, which nuclear genes regulate mtDNA effects on phenotypes? This will be addressed with genetic screens of the nuclear genome across a panel of variable mtDNAs. Third, do mtDNA mutations affect males more than females? The maternal inheritance of mtDNA allows direct selection in females but prevents selection in males. Male-specific deleterious mutations could accumulate in populations, a phenomenon known as Mother’s Curse. This will be addressed using sex-based phenotypic assays in a panel of mtDNA genotypes that span a range of genetic divergences. Each of these questions is relevant to current challenges in quantitative and medical genetics. The findings from this research could be informative regarding genetic questions in the identification of appropriate donors for mitochondrial replacement therapies.

线粒体功能障碍是疾病的常见来源，影响了约5000人。这联合线粒体疾病基金会指出：“一个孩子出生的每30分钟就会发展一个到10英寸时的线粒体疾病（www.umdf.org）。线粒体的生物学使这些问题非常复杂。线粒体功能需要37个基因的协调表达在线粒体内部的线粒体DNA（mtDNA）中编码，超过1000个核编码基因其产品必须运输到线粒体中。 mtDNA和大突变率核基因的突变靶标可确保每个人都有独特的麦托核基因型可以改变健身。在不同环境中的开发可以改变不同的基因型表达成人特征。那就是这些复杂性的来源是我们的关键差距了解线粒体疾病的遗传基础，更普遍地是遗传变异用于天然种群中的线粒体性能。我们开发的果蝇模型提供了一种强大的遗传方法来剖析此事复杂。我们已经将不同的mtdnas引入了受控的核遗传背景中，鉴定出影响适应性特征和基因表达的遗传相互作用（“线核Epistases”）。我们已经发现，许多具有差异表达的基因是由线核遗传引起的相互作用在响应环境扰动中还显示出差异表达。我们的工作假设是线粒体整合了调节两者内部变化的遗传途径蜂窝和外部物理环境。我们将提出三个一般问题。首先，什么信号通路是共享基因的基础表达对改变的有线核基因型和改变物理环境的反应？这将是与基因表达和表观遗传实验有关，将有线粒体基因型和环境压力源。第二，哪些核基因调节mtDNA对表型的影响？这将用核基因组的遗传筛选来解决一组可变MTDNA。第三，mtDNA突变比女性更影响男性？ mtDNA的母校遗传允许在女性中进行直接选择，但可以防止男性选择。男性特异性有害突变可以在人群中积累，这是一种被称为母亲的诅咒的现象。这将被解决在跨越一系列通用的mtDNA基因型中使用基于性别的表型测定分歧。这些问题中的每一个都与定量和医学方面的当前挑战有关遗传学。这项研究的发现可能有关遗传问题的信息确定适合线粒体替代疗法的供体。