Germline selection shapes human mitochondrial DNA diversity
Wei Wei(University of Cambridge), Salih Tuna(University of Cambridge), Michael J. Keogh(University of Cambridge), Katherine R. Smith(University of Cambridge), Katherine R. Smith(University of Cambridge), Timothy J. Aitman(Institute of Genetics and Cancer), Phil L. Beales(Great Ormond Street Hospital), David Bennett(John Radcliffe Hospital), Daniel P. Gale(University College London), Maria A. K. Bitner-Glindzicz(Great Ormond Street Hospital), Graeme C. Black(University of Manchester), Paul Brennan(Newcastle upon Tyne Hospitals NHS Foundation Trust), Perry Elliott(St Bartholomew's Hospital), Frances Flinter(St Thomas' Hospital), R. Andrés Floto(University of Cambridge), Henry Houlden(University College London), Melita Irving(Guy's and St Thomas' NHS Foundation Trust), Ania Koziell(King's College London), Eamonn R. Maher(University of Cambridge), Hugh S. Markus(University of Cambridge), Nicholas W. Morrell(University of Cambridge), William G. Newman(University of Manchester), Irene Roberts(John Radcliffe Hospital), John A. Sayer(Newcastle upon Tyne Hospitals NHS Foundation Trust), Kenneth G. C. Smith(University of Cambridge), Kenneth G. C. Smith(Moorfields Eye Hospital NHS Foundation Trust), Jenny C. Taylor(Moorfields Eye Hospital NHS Foundation Trust), Hugh Watkins(Centre for Human Genetics), Andrew R. Webster(Moorfields Eye Hospital NHS Foundation Trust), Andrew O.M. Wilkie(King's College London), Catherine Williamson(Imperial College Healthcare NHS Trust), NIHR BioResource–Rare Diseases, 100,000 Genomes Project–Rare Diseases Pilot, Sofie Ashford(University of Cambridge), Christopher J. Penkett(University of Cambridge), Kathleen Stirrups(University of Cambridge), Augusto Rendon(University of Cambridge), Willem H. Ouwehand(NHS Blood and Transplant), John R. Bradley(University of Cambridge), F. Lucy Raymond(University of Cambridge), Mark Caulfield(Queen Mary University of London), Ernest Turro(University of Cambridge), Patrick F. Chinnery(University of Cambridge), Aarnoud Huissoon, Abigail Crisp-Hihn, Adam Shaw, Adam J. Mead, Adam P. Levine, Adrian J. Thrasher, Agnieszka Bierżyńska, Ahamad Hassan, Ajith Kumar, Alba Sanchis‐Juan(Imperial College Healthcare NHS Trust), Alex Richter(Imperial College Healthcare NHS Trust), Allan Lawrie(Imperial College Healthcare NHS Trust), Amy Frary, Andrea H. Németh, Andrea Olschewski, Andreas C. Themistocleous, Andrew C. Browning, Andrew Mumford, Andrew M. Schaefer(University of Cambridge), Andrew Marshall, Andrew O.M. Wilkie(John Radcliffe Hospital), Andrew Peacock(University of Cambridge), Andrew R. Harper(University of Cambridge), Andrew R. Webster(Moorfields Eye Hospital NHS Foundation Trust), Andrew S.C. Rice, Angela Pyle, Ania Koziell(King's College London), Anna M. Drazyk, Anne M. Kelly, Annette Wagner, Anthony Attwood, Anthony De Soyza, Anthony M. Vandersteen, Anthony T. Moore, Anton Vonk Noordegraaf(University College London), Anupama Rao(University College London), Archana Herwadkar(University College London), Arjan C. Houweling, Arjune Sen(John Radcliffe Hospital), Augusto Rendon(University of Cambridge), Austen Worth(John Radcliffe Hospital), Barbara Girerd(John Radcliffe Hospital), Bella Madan(John Radcliffe Hospital), Brian T. Wilson(John Radcliffe Hospital), Carmen Bugarin Diz, Carmen Treacy, Carole Brewer, Carolyn Campbell, Carolyn M. Millar, Catherine Roughley, Catherine Titterton(University of Cambridge), Catherine Williamson(Imperial College Healthcare NHS Trust), Cecilia Compton, Cesare Danesino, Chantal Thys, Charaka Hadinnapola, Charu Deshpande, Cheng‐Hock Toh, Chris Van Geet, Christian Babbs, C. Geoffrey Woods, Christopher J. Penkett(University of Cambridge), Christopher D. Watt, Claire Harris(University of Cambridge), Claire Lentaigne(Centre for Human Genetics), Claire Palles, Claire Searle(Unité de recherche sur les maladies cardiovasculaires et métaboliques), Clarissa Pilkington, Colin Church(St Thomas' Hospital), Courtney E. French, Crina Samarghitean, D. Mark Layton, D. Gareth Evans(Newcastle upon Tyne Hospitals NHS Foundation Trust), Damian Smedley, Daniel Greene, Daniel J. Hart, Daniel P. Gale(University of Manchester), David G. Kiely, David Gosal, David Allsup, David Bennett(John Radcliffe Hospital), David Montani, David Parry, David Thomas, Deborah Ruddy, Deborah Whitehorn, Detelina Grozeva, Detlef Böckenhauer, Dinakantha Kumararatne, Dragana Josifova(University College London), Eamonn R. Maher(University of Cambridge), Edwin Wong, Eleanor Dewhurst, Eleni Louka, Elizabeth Colby(University of Cambridge), Elizabeth Ormondroyd(Centre for Human Genetics), Ellen Thomas, Emilia M. Swietlik, Emily Staples(University of Oxford), Emma Matthews, Emma R. Woodward, Ernest Turro(University of Cambridge), Eshika Haque, F. Lucy Raymond(University of Cambridge), Fengyuan Hu, Fiona Lalloo, Florent Soubrier, Floria Cheng, Frances Flinter(St Thomas' Hospital), Gábor Kovács, Gavin Arno(Centre for Human Genetics), Gavin Hudson(Centre for Human Genetics), Genevieve Sayer, Gerald Carr‐White, Gerry Coghlan, Gillian Evans, Graeme C. Black(Newcastle upon Tyne Hospitals NHS Foundation Trust), Grant Hayman, H. Terence Cook(University of Cambridge), Hana Alachkar(University of Cambridge), Hana Lango Allen(University of Cambridge), Hanadi Kazkaz(Centre for Human Genetics), Hannah Stark, Hanns–Ulrich Marschall, Harm Jan Bogaard, Heather Maxwell, Helen Baxendale, Helen Hanson, Henning Gall, Henry Houlden(University College London), Hilary Longhurst, Hiva Fassihi, Horst Olschewski, Hossein-Ardeschir Ghofrani, Hugh S. Markus(University of Cambridge), Hugh Watkins(Centre for Human Genetics), Ian Tomlinson(University of Cambridge), Ilenia Simeoni(University of Cambridge), Irene Roberts(University of Oxford), David Edgar, J. Simon R. Gibbs, James E. Thaventhiran, James Fox, James S. Ware(University of Cambridge), James W. Whitworth, Janine Collins, Jay Suntharalingam, Jennifer Jolley, Jennifer M. Martin, Jennifer O’Sullivan, Jenny C. Taylor(Centre for Human Genetics), Jenny Chambers, Jesmeen Maimaris, Jill Clayton‐Smith(University of Cambridge), Joanna Pepke‐Żaba(University of Cambridge), Jodie Graham, John A. Sayer(Newcastle upon Tyne Hospitals NHS Foundation Trust), John‐Paul Westwood, John Burn, John Davis, John Wharton, John Taylor(Centre for Human Genetics), Jonathan Hoffman, Jonathan Stephens, Julian Adlard, Julie von Ziegenweidt(Queen Mary University of London), Julie Wessels(Queen Mary University of London), Kai Ren Ong, Karen L. Edwards(Queen Mary University of London), Kate Downes, Kate Gibson, Kate Talks, Kate Thomson, Kathelijne Peerlinck, Katherine R. Smith(University of Cambridge), Katherine R. Smith(University of Cambridge), Katherine P. Yates, Kathleen Stirrups(University of Cambridge), Kathleen Freson, Katie Snape, Keith Gomez, Keith Sibson, Keith W. Muir, Ken Poole, Kenneth G. C. Smith(University of Cambridge), Kenneth G. C. Smith(Guy's and St Thomas' NHS Foundation Trust), Keren Carss(University of Cambridge), Kevin J. Marchbank(University of Cambridge), Kimberly Gilmour(University of Cambridge), Kirsty Harkness(University of Cambridge), Lara Abulhoul(University of Cambridge), Laura Scelsi(University of Cambridge), Leema Robert, Lorena Lorenzo, Louise Izatt, Lucy Side, Lucy R. Wedderburn, Luke Howard, Lynn Greenhalgh, Manali Chitre, Manju A. Kurian, Marc Humbert, Marc Tischkowitz(University of Cambridge), Maria A. K. Bitner-Glindzicz(University of Cambridge), Maria C. Estiú, Marie Erwood, Marie Scully, Mark Caulfield(Queen Mary University of London), Mark Gurnell, Mark I. McCarthy, Mark Toshner, Marta Bleda, Marta Vazquez‐Lopez(University of Cambridge), Martin R. Wilkins, Mary Mathias(University of Cambridge), Matthew A. Brown(Newcastle upon Tyne Hospitals NHS Foundation Trust), Matthew C. Sims(Newcastle upon Tyne Hospitals NHS Foundation Trust), Matthew Hall(Newcastle upon Tyne Hospitals NHS Foundation Trust), Matthew J. Daniels(Newcastle upon Tyne Hospitals NHS Foundation Trust), Matthew Buckland(Newcastle upon Tyne Hospitals NHS Foundation Trust), Matthew Traylor, Matthias Haimel, Maureen Cleary(St Bartholomew's Hospital), Mehul Dattani, Mélanie Eyries, Melanie Chan, Melanie N. Ekani, Melita Irving(Guy's and St Thomas' NHS Foundation Trust), Michael Laffan, Michael Gattens, Michael J. Browning, Michael Newnham, Michael A. Simpson, Michael Wright(University of Cambridge), Michel Michaelides, Michele P. Lambert, Moin A. Saleem, Moira Thomas, Monika Mozere, Munaza Ahmed, Naomi Clements Brod, Nathalie Kingston, Neil V. Shah, Neringa Jurkutė, Nichola Cooper, Nicholas W. Morrell(University of Cambridge), Nicola Curry, Nigel Burrows(University of Oxford), Nils Koelling, Noémi Roy, Olga Shamardina, Olivera Spasić-Bošković, Omid Sadeghi‐Alavijeh, Paolo Gresele, Patrick F. Chinnery(University of Cambridge), Patrick Yong, Patrick Yu‐Wai‐Man(University of Cambridge), Paul Lyons, Paul Aurora, Paul Brennan(Newcastle upon Tyne Hospitals NHS Foundation Trust), Paul A. Corris, Paul McAlinden, Paula Rayner-Matthews, Pavels Gordins, Perry Elliott(St Bartholomew's Hospital), Peter Dixon, Peter Kelleher, Peter W. Collins, Petros Syrris, Phil L. Beales(Great Ormond Street Hospital), Philip Ancliff, Philip G. Griffiths, Philip Twiss, Ping Yu, Quinten Waisfisz, R. Andrés Floto(University of Cambridge), R. Campbell Tait, Rachel Buchan, Rachel Linger, Rashid Kazmi, Ravishankar Sargur(University of Cambridge), Rémi Favier, Rhea Tan, Richard Antrobus, Richard Quinton, Richard H. Scott, Richard C. Trembath, Rita Horváth, Robert N. Sarkany, Robert Ross‐Russell, Robert V. MacKenzie Ross, Robin Condliffe, Roger James, Rosie Hague, Rutendo Mapeta, Ruth Armstrong, Ruth Casey, Sadia Noorani, Salih Tuna(University of Cambridge), Sally Johnson, Samantha Malka, Samya Obaji(Institute of Genetics and Cancer), Sara Boyce(Institute of Genetics and Cancer), Sarah Goddard, Sarah J. Rose, Sarah K. Westbury, Sarah Mangles, Sarju Mehta, Scott Hackett, Shahin Moledina, Shamima Rahman, Shehla Mohammed(University of Cambridge), Siddharth Banka, Simon Holden, Simon H. S. Pearce, Simon C. Satchell(NHS Blood and Transplant), Simon Staines(Imperial College Healthcare NHS Trust), Sinisa Savic(University of Manchester), Smita Y. Patel, Sofia Douzgou, Sofia Grigoriadou, Sofia Papadia, Sofie Ashford(University of Cambridge), Sol Schulman, Soo‐Mi Park, Sri V. V. Deevi, Stefan Ting Graf, Stephen Abbs, Stephen J. Wort, Stephen Jolles, Stephen D. Marks, Steven Okoli, Stuart A. Cook, Stuart Meacham, Suellen M. Walker, Susan Shapiro, Suthesh Sivapalaratnam, Taco W. Kuijpers, Tadbir K. Bariana, Tamam Bakchoul, Tamara Everington, Tara Renton, Teofila Bueser, Timothy Dent, Timothy J. Aitman(Institute of Genetics and Cancer), Tina Biss, Tina Dutt, Tom Fowler, Tom Vale, Tracy Lester, Trevor Cole, Vijeya Ganesan, William A. Sewell, Wei Wei(University of Cambridge), Wendy N. Erber, Werner Seeger, Wilf Kelsall, Willem H. Ouwehand(NHS Blood and Transplant), William Egner, William G. Newman(University of Manchester), William M. Hague, Yvette Wood
Cited by 251Open Access
Abstract
Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 mother-offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages.
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