Mitonuclear genetics of complex traits in Drosophila

线粒体功能障碍是一种常见的疾病来源，影响约5000人中的1人。的 联合线粒体疾病基金会指出，“每30分钟就有一个孩子出生， 线粒体疾病”（www.umdf.org）。线粒体的生物学特性使得这些问题 非常复杂线粒体功能需要37个基因的协调表达 编码在线粒体内的线粒体DNA（mtDNA），以及超过1000个核编码基因 其产物必须被运送到线粒体中。线粒体DNA的高突变率和大的 核基因突变的目标，确保每个人都有一个独特的'线粒体核 基因型可以改变适应性在不同环境中的发展可以改变 基因型表达成年性状。因此，这些复杂性的来源是造成我们 了解线粒体疾病的遗传基础，更一般地说，遗传变异 线粒体在自然人群中的表现。 我们开发的果蝇模型提供了一个强大的遗传方法来剖析这一点。 复杂性我们已经将不同的mtDNA引入到受控的核遗传背景中， 确定了影响适应性特征和基因表达的遗传相互作用（“线粒体表位”）。我们 已经发现许多与线粒体遗传学有关的差异表达基因， 相互作用也表现出不同的表达在响应环境扰动。我们的工作 一种假说认为，线粒体整合了调节细胞内部 细胞和外部物理环境。 我们将探讨三个一般性问题。首先，什么样的信号通路是共享基因的基础 对线粒体基因型改变和物理环境改变的表达反应？这将是 通过配对线粒体基因型的基因表达和表观遗传实验， 环境压力源第二，哪些核基因调控mtDNA对表型的影响？这 将通过一组可变mtDNA的核基因组遗传筛选来解决。 第三，mtDNA突变对男性的影响是否大于女性？线粒体DNA的母系遗传 允许在雌性中直接选择，但阻止在雄性中选择。雄性特异性有害突变 会在人群中累积，这种现象被称为母亲的诅咒。这将得到解决 在一组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定量和医学领域的挑战有关。 遗传学这项研究的结果可能是关于遗传问题的信息， 鉴定用于线粒体替代疗法的合适供体。

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.