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

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.

Large scale studies of how genetic variation contributes to complex phenotypes and disease have relied on either genotyping arrays, or whole-exome sequencing. These approaches do not provide information across the whole genome, especially repetitive regions, such as the ribosomal DNA (rDNA). The 45S rDNA genes exist as tandem arrays across multiple chromosomes in the human genome. They each code for three of the four ribosomal RNAs-critical components of the ribosome. Importantly, there is inter-individual variation in the number of rDNA genes an individual possesses (~100-600). We have recently gathered strong pilot data across two independent human cohorts that shows that rDNA copy number has a negative correlation with body mass index (BMI) and that obese individuals have a significantly lower rDNA CN. We would now like to replicate this finding in a very large cohort (UK Biobank) and also in archived tissues of inbred C57BL/6J mice that have been exposed to control or obesogenic diets. We aim to explore the association of rDNA copy number with BMI and other adiposity and metabolic traits in a sex- and ancestry- specific manner to identify the most strongly associated phenotype and other important covariates. We will also assess if there is any dependence between rDNA copy number and other known genetic risk factors that have been identified to date from genome-wide association studies. This will allow us to build a more accurate polygenic risk score for BMI/body weight regulation for identifying high risk individuals and promoting early intervention prior to the onset of obesity. In addition, if rDNA copy number is an independent genetic factor associated with body weight regulation, the establishment of a relevant model system will allow us in future to explore the mechanistic basis of the association in a developmental and tissue-specific manner utilising the mouse model we will assess.