About the Project
Mitochondrial diseases are a group of genetic disorders that range in severity from progressive muscle weakness in adults to neonatal death. A striking feature of mitochondrial diseases is their tissue specificity, which can affect any tissue at any stage of life. Mitochondria contain their own genome, called mitochondrial DNA (mtDNA), that is maintained independently of the nuclear genome. Patients with mitochondrial diseases frequently display deletions and duplications on individual mtDNAs, which are believed to result from errors of mtDNA replication. These mtDNA rearrangements can either occur spontaneously or result secondarily from mutations in genes required for replicating mtDNA.
The project will use an established mouse model of mitochondrial disease and ageing to map mtDNA rearrangements using cutting-edge sequencing technologies.
Mitochondrial DNA from mouse tissues will be analysed using Nanopore sequencing to determine how and where mtDNA rearrangements arise. This will be correlated both with the disease phenotypes seen in the mouse model and with the way in which mtDNA is replicated. This will provide valuable insights both into the tissue specificity of mitochondrial diseases as well as our understanding of the fundamental genetic process of mtDNA replication.
The project will involve training in Nanopore sequencing technology as well as the bioinformatic skills required for analysing the datasets produced. Training will also be provided in a range of molecular and genetic techniques, and the host institution provides training to all of its students in basic aspects of mitochondrial biology and medicine.
The project is based at the Wellcome Centre for Mitochondrial Research at Newcastle University. The Wellcome Centre brings together researchers working on fundamental, translational and clinical aspects of mitochondrial biology and disease in a vibrant and collaborative atmosphere. The Centre is equipped with state-of-the-art facilities and supports a lively community of PhD students.
Dr Tom Nicholls (https://www.ncl.ac.uk/medical-sciences/people/profile/thomasnicholls.html) established a research group in 2018 to study mitochondrial DNA replication and segregation, and its link to human mitochondrial diseases. Dr Jim Stewart (https://www.ncl.ac.uk/medical-sciences/people/profile/jimstewart.html) has recently moved to Newcastle and has made a series of important contributions to our understanding of mtDNA mutations in mitochondrial dysfunction and disease.
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 and how to apply can be found on our website:
Studentships commence: 1st October 2021
Trifunovic et al. (2004) Nature; 429(6990): 417-23.
Formenti et al. bioRxiv 2020.06.30.177956; doi: https://doi.org/10.1101/2020.06.30.177956
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