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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：
10594405
负责人：
DAVID M RAND
金额：
$ 38.55万
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/10594405
关键词：
Address Adult Affect Age Biological Assay Biology Child Compensation 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 Epistasis Genetic Screening Genetic Variation Genome Genomics Genotype Incidence Individual Joints Medical Genetics Metabolic Diseases Mitochondria Mitochondrial DNA Mitochondrial Diseases 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 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.

线粒体功能障碍是一种常见的疾病来源，每5000人中就有一人受到影响。这个美国线粒体疾病基金会表示，每30分钟就有一个儿童出生，他们将发展为 10岁之前的线粒体疾病“(www.umdf.org)。线粒体的生物学造成了这些问题极其复杂。线粒体的功能需要37个基因的协调表达编码在线粒体内的线粒体DNA(MtDNA)，以及1000多个核编码基因其产物必须被运输到线粒体中。线粒体DNA的高突变率和大核基因突变的目标确保每个个体都有一个独特的‘有丝分裂核’ 可以改变健康状况的基因。不同环境中的发展可以改变不同基因类型表现出成人的特征。因此，这些复杂性的来源是我们的了解线粒体疾病的遗传基础，以及更广泛的遗传变异线粒体在自然种群中的表现。我们开发的果蝇模型提供了一种强大的遗传学方法来剖析这一点复杂性。我们已经将不同的mtDNA引入受控的核遗传背景和确定了影响适合度性状和基因表达的遗传交互作用(‘有丝分裂上位酶’)。我们已经发现许多差异表达的基因是由有丝分裂基因引起的相互作用在响应环境扰动时也表现出差异表达。我们的工作假说是线粒体整合了调节内部变化的遗传路径蜂窝和外部物理环境。我们将探讨三个一般性问题。首先，共有基因背后的信号通路是什么？对改变的有丝分裂核基因和改变的物理环境的表达反应？这将是基因表达和表观遗传学实验配对有丝分裂核基因和环境应激源。第二，哪些核基因调节mtDNA对表型的影响？这将通过对一组可变mtDNA的核基因组进行遗传筛选来解决。第三，线粒体DNA突变对男性的影响是否大于女性？线粒体DNA的母系遗传允许直接选择雌性，但禁止选择雄性。男性特有的有害突变可能会在人群中积累，这种现象被称为母亲的诅咒。这个问题将得到解决在一组跨越一系列基因的mtDNA基因型中使用基于性别的表型分析分歧。这些问题中的每一个都与当前量化和医学领域的挑战有关遗传学。这项研究的发现可能会对人类基因组中的遗传问题提供信息为线粒体替代疗法确定合适的供体。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

NUMTs Can Imitate Biparental Transmission of mtDNA-A Case in Drosophila melanogaster.

DOI：
10.3390/genes13061023
发表时间：
2022-06-06
期刊：
GENES
影响因子：
3.5
作者：
Parakatselaki, Maria-Eleni;Zhu, Chen-Tseh;Rand, David;Ladoukakis, Emmanuel D.
通讯作者：
Ladoukakis, Emmanuel D.

Mitochondria as environments for the nuclear genome in Drosophila: mitonuclear G×G×E.