Background and hypotheses
Each of us has a genome. The genome is the same in every cell of our organism but its three-dimensional (3D) structure is different in every cell type. Genes, enhancers and other genomic regions interact with each other forming different networks in different cells.
These 3D genome networks are now available thanks to the recent development of chromosome capture techniques. We exploit graph theory computational approaches to analyse their properties, their sub-communities or fluxes of information, as we do with social networks.
Recent data suggest that genetic variants associated with inflammatory bowel disease (IBD) may be associated with microbial mishandling or aberrant/exaggerated responses to commensal or pathogenic microbes. However, a large fraction of these variants are in non-coding regions and remain unexplored. Here, we hypothesize that:
A) Many diseases with an immune component could be triggered by inappropriate host responses to commensal or pathogenic microbes.
B) Defective immune response in IBD patients can be linked to mutations in non-coding enhancers.
In this project, the student will investigate the role of microbes as “hidden influencers” of variation in these non-coding genomic sequences associated with IBD.
1. To identify communities of genes and non-coding enhancers activated in immune cells in response to microbes by integrating 3D genome networks and gene expression data from healthy donors and patients with microbial infections.
2. To develop Artificial Intelligence (AI) methods to uncover mechanistic associations between IBD-associated variants and enhancers that regulate the transcriptional response to pathogens/resident microbiota.
3. To explore the predictive value of these genomic regions in the onset and progression of the disease, opening new avenues for diagnosis and prevention.
Novelty and timeliness
Current technologies allow to map thousands of DNA interactions. However, we have little understanding about how this information is utilized by different immune cells in response to microbes. We propose a revolutionary analytical approach to fill this gap: modelling genome folding as a communication network of genetic elements.
We will develop and apply graph theory and AI methods to understand information processing in the 3D genome networks of immune cells, integrating gene expression data and genetic data. The primary supervisor (Daniel Rico) will provide training in quantitative skills (mathematics, statistics, computation, data analytics and informatics, machine learning and Artificial Intelligence). The other members of the supervisory team are experts in immunodeficiencies and infections (Sophie Hambleton), inflammatory bowel disease (Chris Lamb) and evolution of microbes (Robert Hirt), offering interdisciplinary training opportunities at the interface of computational and systems biology, microbiology and translational medicine.
More information about the supervisory team
Daniel Rico https://www.ncl.ac.uk/medical-sciences/people/profile/danielrico.html https://twitter.com/danielrico_bio
Chris Lamb https://www.ncl.ac.uk/medical-sciences/people/profile/christopherlamb.html https://twitter.com/drchrislamb
Robert Hirt https://www.ncl.ac.uk/medical-sciences/people/profile/roberthirt.html
Sophie Hambleton https://www.ncl.ac.uk/medical-sciences/people/profile/sophiehambleton.html
Benefits of being in the DiMeN DTP
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website: http://www.dimen.org.uk/