Identification and functional characterisation of environmentally responsive rDNA variants in the human genome

Mammalian phenotypes are influenced by the interaction between genetics and environment. Understanding how these gene-environment interactions occur at the level of the cell is therefore crucial for elucidating the origins of mammalian phenotypes. Recently, my team found that providing mice with a reduced protein diet during early life results in reduced overall body size which is correlated with reduced activity of the ribosomal DNA (rDNA). The rDNA is an important part of the genome that codes for molecules required for protein synthesis, thereby permitting cell growth. The most surprising finding of our study was that the genetic sequence of the rDNA varied amongst individuals, thereby influencing any given individual's capacity to respond to stressful environments such as low protein diet. Related effects were also found in response to a high-fat diet. I hypothesize that similar effects occur in humans. That is, an individual's inherent capacity to respond to conditions of stress is influenced by the genetic make up of their rDNA. I would like to identify such human rDNA variants and understand how they function. The proposed work has the potential to yield new and important insights into how gene-environment interactions influence phenotypic and disease outcomes in humans.

Understanding the molecular basis of gene-environment interactions is crucial for defining the origins of mammalian phenotypes. Recently, my team reported that early-life protein restriction in mice induces a linear correlation between growth restriction and DNA methylation at ribosomal DNA (rDNA). The methylation dynamics were found to be restricted to rDNA copies associated with a specific genetic variant. Furthermore, the relative copy number of these environmentally- responsive variants showed inter-individual variation, thereby influencing the magnitude of growth restriction in any given individual. Related effects were also found in models of maternal high-fat or obesogenic diets. This represents a unique mammalian example of gene-environment induced epigenetic dynamics and associated phenotypic outcomes. I hypothesize that the human genome also harbors a combination of environmental stress-responsive and -unresponsive rDNA genetic variants. The combination of these variants will differ amongst individuals, thus influencing the inherent capacity to respond to conditions of extreme stress. I would like to identify such human rDNA variants and elucidate their functional consequence. The proposed work has the potential to yield new and important insights into how gene-environment interactions shape the epigenome and phenotypic outcomes, and potentially explain some of the currently 'missing' heritability for a range of human phenotypes and diseases.

Economic impact
Our proposed work is of a basic nature, and hence the main beneficiary of our specific research findings in the shorter term will be the international academic community. Understanding the molecular basis of gene-environment interactions in mammals is currently a key challenge of modern biology, and our results will be an important contribution, opening up new ways of thinking about such effects, and inshrining new avenues of research. We will disseminate our findings to scientists via attendance and organization of conferences, and scientific publications and to the general public through open days and events during national science week. Medium to longer term, our research has strong potential for developing strategies that aim to prevent or delay the onset of adult onset diseases. During the course of our project and beyond, we will liaise with the QMUL and Cambridge Research and Innovation departments to ensure that any potentially promising commercialization avenues are explored.

Societal impact
We will organise a range of key activities to engage non-academic audiences. The cornerstone of our approach will be the QMUL Epigenetics Hub. The QMUL Epigenetic hub was formed to promote interactions amongst the different research groups within Queen Mary University of London that investigate the role of epigenetic mechanisms in basic biological processes and disease pathogenesis. In addition, we aim to raise the profile of our work within QMUL and externally in the form of regular inter-lab meetings, public communication, and outreach activities. We recently hosted an event where Prof Nessa Carey presented a special lecture on Epigenetics to nearly 200 school children from the local community. This was followed by a dinner meet and greet with the scientists. Events like these are an excellent way of disseminating the findings from our project to the next generation of scientists.