Mammalian ribosomal DNA as an epigenetic sensor of environmental stress

During the last decade, large-scale genome-wide association studies (GWASs) have made a significant contribution to our understanding of the genetic basis of a range of human phenotypes and diseases. However, in nearly every case, only a minor proportion of the genetic risk has been explained. One problem continues to be that these GWASs have looked only at the single copy portion of the genome i.e. unique regions of the genome such as protein coding genes. However, nearly 50% of our genomes are made up of ‘repetitive DNA’ – regions of the genome which are found in multiple copies at multiple sites within the genome. How genetic variation in the repetitive portion of the genome influences mammalian phenotypes is currently unknown.

Recently, the Rakyan lab (www.qmul.ac.uk/blizard/qmul-epigenetics-hub/research/core-groups/rakyan-lab and www.rakyanlab.com) showed that genetic variation within the ribosomal DNA (rDNA) – the DNA that codes for ribosomes that are the protein producing factories of our cells – impacts key phenotypes in the mouse (Holland et al., 2016, Science). However, this only happens when the mice were exposed to an adverse environment. Therefore, genetic variation within the rDNA is important and has phenotypic consequences, but only when exposed to stress. We propose that similar effects happen in humans, especially given how our environments have changed in the last 100 years, and could explain a significant part of the genetic predisposition that GWASs have been unable to find.

At present, very little is known about the functional impact of genetic variation that exists within human rDNA. The aim of the Rosetrees studentship will be to identify environmentally responsive rDNA variants in the human genome. Briefly, the work will involve exposing human cell lines to a stressor in vitro, then performing cutting edge molecular analyses that integrate genetic, epigenetic and expression studies (including third generation nanopore sequencing and bioinformatics) to identify which human genetic variant rDNA copies respond to stress. Specifically, it will allow us to understand how individual genetic variation, that is currently being overlooked, interacts with environmental stressors, and how that results in disease. This studentship is ideally suited to a candidate wishing to develop a research career that combines both wet lab and computational skills (previous experience in bioinformatics is not essential).

The candidates will work in a world-class epigenetics research environment provided by the QMUL Epigenetics Hub (http://www.blizard.qmul.ac.uk/epigenetics.html), along with exciting new cross-faculty QMUL initiatives in genomics and computational biology (http://www.qmul.ac.uk/lifesciences/).

Your application should consist of a CV, contact details of two academic referees, and you must also include a personal statement (1,000 words maximum) describing your suitability for this project.

Informal Enquiries are encouraged before the closing date and can be made to Prof Vardhman Rakyan ([Email Address Removed])