Mitochondrial Genomics: Inherited and acquired variants of nuclear and mitochondrial DNA in human health and disease
Mitochondrial disorders affect approximately 1 in 4300 of the population and cause progressive, incurable diseases that often result in premature death. The primary genetic defect affects either nuclear DNA or mitochondrial DNA (mtDNA), and ultimately leads to a biochemical defect of ATP synthesis. However, despite having the same basic biochemical basis, mitochondrial disorders have an enormously variable clinical presentation and disease course.
My laboratory aims to determine the major nuclear and mitochondrial genetic factors that modulate the clinical expression of mitochondrial disorders, thus explaining the variable phenotype. Specifically, we are working to (i) define the sub-cellular mechanism responsible for the mtDNA genetic bottleneck during female germ cell development (ii) characterise novel nuclear gene defects in patients with Mendelian mitochondrial disorders (iii) define critical nuclear-mtDNA interactions through the investigation of homoplasmic mtDNA diseases
These three laboratory research themes dove tail into a clinical translational research programme studying the natural history of mitochondrial disease, and developing new treatments through investigator-led experimental medicine studies and clinical trials in partnership with the pharmaceutical industry.
Biography
Personal Biography
Following a Bachelors degree in Neuroscience, Patrick Chinnery qualified in medicine in 1992 at Newcastle University. After three years of general medical training as a junior doctor in Newcastle Hospitals, Patrick studied for a PhD as a Wellcome Trust Clinical Research Training Fellow investigating the molecular basis of mitochondrial diseases. He then combined a Postdoctoral Research Fellowship from the Wellcome Trust with clinical training in neurology and genetics in Newcastle, and neurogenetics at Queen Square in London. Patrick was appointed Lecturer and then Senior Lecturer in Newcastle in 2002 before becoming Professor of Neurogenetics at Newcastle University in 2004. In 2003 he became a Wellcome Trust Senior Fellow in Clinical Science (renewed 2018 & 2013) and now holds a Wellcome Principal Research Fellowship (2018-). Patrick is a Fellow of the Academy of Medical Sciences (FMedSci, 2009), and an NIHR Senior Investigator (2010). In 2011 he was elected a Fellow of the American Neurological Association, and was awarded the Foulkes Foundation Medal by the Academy of Medical Sciences. He was Director of the NIHR Newcastle Biomedical Research Centre (2008-2015), and Director of the Institute of Genetic Medicine at Newcastle University (2010-2015). In 2015 he moved to the University of Cambridge as Professor of Neurology and Head of the Department of Clinical Neurosciences. Patrick jointly chairs the NIHR Rare Diseases Translational Research Collaboration (2012), and is the Executive Chair of the Medical Research Council (2024-). Patrick was elected Fellow of the Royal Society (FRS) in 2024.
Publications
Selected publications
Burr SP, Florian Klimm F, Glynos A, Malwina Prater M, Sendon P, Nash P, Powell CA, Simard M-L, Bonekamp NA, Charl J, Hector Diaz H, Bozhilova LV, Nie Y, Zhang H, Frison M, Falkenberg M, Jones N, Minczuk M, Stewart JB & Chinnery, PF. (2023)
Cell lineage specific mitochondrial resilience during mammalian organogenesis.
Cell 186, 1212-1229
Wei W, Schon K, Elgar G, Orioli A, Tanguy M, Giess A, Tischkowitz M, Caulfield M & Chinnery, PF. (2022)
Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes.
Nature 611, 105-114
Schon KR, Horvath R, Wei W, Calabrese C, Tucci A, Ibañez K, Ratnaike T, Pitceathly RDS, Bugiardini E, Quinlivan R, Hanna MG, Clement E, Ashton E, Sayer JA, Paul Brennan P, Josifova D, Izatt L, Fratter C, Nesbitt V, Timothy Barrett T, McMullen DJ, Smith S, Deshpande C, Smithson SF, Festenstein R, Canham N, Genomics England Research Consortium, Caulfield M, Houlden H, Rahman S, Neurology and Mitochondrial Disorders Genomics England Clinical Interpretation Partnership & Chinnery, PF. (2021)
Use of whole genome sequencing to determine the genetic basis of suspected mitochondrial disorders: a cohort study.
British Medical Journal 375, e066288
Cai N, Gomez-Duran A, Yonova-Doing E, Kundu K, Burgess AI, Golder ZJ, Calabrese C, Bonder MJ, Camacho M, Lawson RA, Li L, Williams-Gray CH, ICICLE-PD Study Group, Di Angelantonio E, Roberts DJ, Watkins NA, Ouwehand WH, Butterworth AS, Stewart ID, Pietzner M, Nick J. Wareham NJ, Langenberg C, Danesh J, Walter K, Rothwell PM, Howson JMH, Stegle O, Chinnery PF* & Soranzo N. (2021)
Mitochondrial DNA variants modulate proteostasis through N-formylmethionine.
Nature Medicine 27, 1564-1575
Yonova-Doing E, Calabrese C, Gomez-Duran A, Schon K, Wei W, Karthikeyan S, Chinnery PF* & Howson JMM (2021)
An atlas of mitochondrial DNA associations in UK Biobank.
Nature Genetics 53, 982-993
Wei W, Tuna S, Keogh MJ, Smith KR, Aitman TJ, Beales PL, Bennett DL, Gale DP, Bitner-Glindzicz MAK , Black GC, Brennan P, Elliott P, Flinter FA, Floto RA, Houlden H, Irving M, Koziell A, Maher ER, Markus HS, Morrell N, Newman WG, Roberts I, Sayer JA, Smith KGC, Taylor JC, Watkins H, Webster AR, Wilkie AO, Williamson C, on behalf of the NIHR BioResource - Rare Diseases and the 100,000 Genomes Project - Rare Diseases Pilot, Ashford S, Penkett CJ, Stirrups KE, Rendon A, Ouwehand WH, Bradley JR, Raymond FL, Caulfield M, Turro E & Chinnery PF (2019)
Germline selection shapes human mitochondrial DNA diversity.
Science 24, 6442