Ribosomal DNA copy number: a novel genetic factor associated with body mass index in humans?

肥胖率在过去30年里飙升，在英国和全球都是一个严重的公共卫生问题。虽然高卡路里饮食和久坐不动的生活方式等因素是导致这种增长的原因，但基因也在个体对环境的反应中发挥着重要作用。除了罕见症状外，体重调节受到许多基因的影响，每个基因的影响相对较小。在过去的15年里，人们已经做出了广泛的努力来确定这些基因，但目前，体重的很大一部分遗传力尚未确定。我们之前的工作已经确定了我们的DNA的一部分(称为核糖体DNA或rDNA)对饮食暴露做出反应。RDNA包含制造制造蛋白质的分子机器的关键部件的说明。这些基因在大多数人类遗传学研究中都被忽视了，因为在理解它们在DNA中的组织方面存在技术问题。重要的是，我们有许多这些基因的拷贝(~100-600)，拷贝的数量因个体而异。在此基础上，我们研究了rDNA是否可能导致肥胖风险。在导致这一提议的工作中，我们发现肥胖个体的rDNA基因拷贝较少。在这里，我们希望在更大的人群(约50万受试者)中验证这一发现，使用的资源既有遗传数据，也有体重、身高、体脂量等测量数据。这将使我们能够验证一个人拥有的rDNA拷贝数是一个以前未知的有助于体重调节的遗传因素，以确定这与其他易感遗传因素以及与体重调节和一些与肥胖相关的健康状况的其他测量有何关系。我们还将对喂食导致肥胖的饮食的小鼠的组织进行类似的分析-这是一个了解特定基因如何发挥作用来控制体重的常见模型。总之，拟议的工作将导致理解rDNA拷贝数在体重调节中的作用。这将使我们能够利用这一点，连同已知的肥胖遗传风险，建立一个更准确的工具，能够评估一个人的体重增加的遗传倾向。这样的工具使临床医生能够识别有疾病风险的个人，并进行干预以防止疾病的发生。此外，我们将验证rDNA对遗传风险的贡献是否代表了一种以前未知的途径。结合建立小鼠模型有效性的工作，这将为未来的工作铺平道路，以了解这如何有助于体重调节。除了提高我们对与肥胖有关的人类生物学的理解外，这也可能朝着开发新型治疗剂的方向发展。

Obesity rates have skyrocketed in the last three decades and represent a serious public health problem in the United Kingdom and globally. Although factors such as calorie dense diets and more sedentary lifestyles are responsible for this increase, genes also play a significant role in how an individual responds to their environment. With the exception of rare syndromes, regulation of body weight is under the influence of many genes, each with a relatively small effect. Over the last 15 years, there have been extensive efforts to identify such genes, but currently, a large proportion of heritability of body weight is yet to be identified. Our previous work has identified a part of our DNA (known as ribosomal DNA or rDNA) to respond to dietary exposures. rDNA contains instructions for making key components of the molecular machines that make proteins. These genes have been overlooked in most studies of human genetics due to technical issues with understanding their organisation within the DNA. Importantly, we have many copies of these genes (~100-600) and the number of copies varies across individuals. Building on this, we looked at whether rDNA may be contributing to obesity risk. In the work leading to this proposal, we identified that obese individuals had less copies of the rDNA genes. Here, we wish to verify this finding in a much larger population (~half a million subjects) using a resource that has both genetic data as well as measurements of weight, height, amount of body fat, among others. This will allow us to validate that the number of copies of rDNA an individual has is a previously unknown genetic factor contributing to body weight regulation, to identify how this relates to other predisposing genetic factors and also to other measurements that are associated with body weight regulation and some of the health conditions associated with obesity. We will also perform a similar analysis on tissues from mice that have been fed diets that cause obesity-this is a common model for understanding how specific genes function to control body weight. Together the proposed work will result in understanding the role of rDNA copy number in body weight regulation. This will allow us to use this, together with what is already known about genetic risk for obesity to build a more accurate tool to be able to assess an individual's genetic predisposition towards weight gain. Such tools allow clinicians to identify individuals at risk of a disease and intervene to prevent the disease occurring. In addition, we will verify whether the contribution of rDNA to genetic risk represents a previously unknown pathway. In combination with the work to establish the validity of the mouse model, this will pave the way to future work to understand how this contributes to body weight regulation. Besides improving our understanding of human biology in relation to obesity, this could also progress towards the development of novel therapeutic agents.