Identifying common and tissue-specific genetic drivers of fundamental biological processes taking place in human mitochondria

线粒体是‘细胞器’(可以被认为类似于人体的器官)，它们在细胞中扮演特定的角色，帮助细胞正常运作。线粒体主要负责产生化学“能量”，用于肌肉运动、呼吸和心脏功能等基本过程，但它们也参与大脑中的信号传输和产生身体热量等过程。由于线粒体在这些重要过程中的核心作用，功能不良的线粒体与帕金森氏症、糖尿病和癌症等一系列疾病有关，其中大脑等高能组织往往受到最严重的影响。因此，了解线粒体跨组织发生的生物过程对人类健康至关重要。除了提供生命蓝图的细胞核中存在的遗传物质(DNA)外，线粒体也有自己的DNA。这种遗传密码提供了创造蛋白质的信息，线粒体需要这些蛋白质来产生细胞能量。在利用这些蛋白质之前，线粒体DNA被转化为RNA(基因的表达)，然后以不同的方式进行处理，然后转化为蛋白质。将线粒体DNA转化为蛋白质的步骤是复杂的、多阶段的，而且在任何时候都依赖于核基因组中编码的基因。因此，核基因组和线粒体基因组之间有很强的联系：核基因组的突变已知会导致线粒体疾病。尽管我们对线粒体过程中涉及的核基因了解很多，但对影响线粒体功能的分子过程的各个阶段仍然缺乏了解，我们也缺乏健康个体携带的常见基因突变的目录，这些突变可以影响线粒体基因的表达水平和线粒体RNA的加工。在这项研究中，我们将使用新的技术来量化线粒体基因在大量个体和许多不同组织类型中的表达水平，从而为未来所有对比较健康和疾病个体的线粒体RNA水平感兴趣的研究创建一个参考框架。利用这些数据，我们将确定核基因组中与线粒体基因表达变异相关的遗传变异，并测试这种遗传变异是否只在某些组织中重要，或者它是否作用于整个人体。随后，我们将把我们确定的与线粒体基因表达相关的遗传变异与人类基因组的特征和注释数据库以及与疾病相关的突变目录进行比较。通过这种方式，我们将试图了解线粒体基因表达受到调控的机制，以及这些过程是否可以帮助研究人员了解疾病的根本原因。在健康个体中研究这些过程将使我们能够识别在线粒体正常功能中至关重要的基因，但也将创建一份目标基因(和突变)的清单，这些基因(和突变)可能在某些个体中功能失调，因此对疾病研究很重要。由于线粒体在心脏和大脑等高能组织中往往更重要，了解这些过程在不同组织中是否有所不同，将是推断对人类健康的潜在影响的关键。最后，这里发现的基因和基因突变可能会识别在衰老过程中重要的生物过程，因为功能不良的线粒体是衰老过程的一个标志，也可能突出与线粒体功能相关的核基因，这些基因对于在三亲胚胎的背景下进行研究是重要的。

Mitochondria are 'organelles' (which can be thought of as analogous to the organs of the human body) that perform specific roles in the cell to help it to function normally. Primarily mitochondria are responsible for generating chemical 'energy' that is used for fundamental processes like muscle movement, respiration and heart function, but they are also involved in processes like signal transmission in the brain and generating body heat. Due to their central role in these important processes, poor functioning mitochondria have been implicated in a wide range of diseases such as Parkinson's disease, diabetes and cancer, with high-energy tissues such as the brain often being the most affected. As a consequence, understanding the biological processes taking place in the mitochondria across tissues is key to human health.Alongside genetic material (DNA) that is present in the nucleus, which provides the blueprint for life, mitochondria also have their own DNA. This genetic code provides information to create proteins that are required for mitochondria to generate cellular energy. Before these proteins can be utilized, mitochondrial DNA is converted to RNA (expression of the gene), which is then processed in different ways before being translated into proteins. The steps converting mitochondrial DNA into proteins are complex, multi-staged and at all points rely on genes that are coded in the nuclear genome. As a result, there are strong relationships between the nuclear and mitochondrial genomes: mutations in the nuclear genome are known to cause mitochondrial disorders. Although we understand a great deal about the nuclear genes involved in mitochondrial processes, there is still a lack of understanding of all stages of the molecular processes influencing mitochondrial function, and we are lacking a catalogue of common genetic mutations carried by healthy individuals that can influence the levels of expression of mitochondrial genes and the processing of mitochondrial RNA. In this study we will use novel techniques to quantify the expression levels of mitochondrial genes across a large number of individuals and in many different tissue types, therefore creating a frame of reference for all future studies interested in comparing mitochondrial RNA levels in healthy and diseased individuals. Using this data we will then identify genetic variation in the nuclear genome that is associated with variation in mitochondrial gene expression and test whether this genetic variation is only important in certain tissues, or whether it acts across the entire human body. Following this, we will compare the genetic variation we identify as being associated with mitochondrial gene expression to databases of the features and annotations of the human genome, as well as catalogues of mutations linked to disease. In this way, we will attempt to understand the mechanisms by which mitochondrial gene expression is regulated and whether these processes may help researchers to understand the underlying causes of disease.Studying these processes in healthy individuals will allow us to identify genes that are important in the normal functioning of mitochondria, but will also create a list of target genes (and mutations) that may become dysfunctional in some individuals and are therefore important for the study of diseases. Since mitochondria tend to be more important in high-energy tissues such as the heart and brain, understanding if these processes vary in different tissues will be key to inferring the potential impacts on human health. Finally, genes and genetic mutations identified here may identify biological processes that are important in ageing, since poor functioning mitochondria are one hallmark of the ageing process, and could also highlight nuclear genes associated with mitochondrial function that are important to study in the context of three-parent embryos.