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1. A Standard Nomenclature for Referencing and Authentication of Pluripotent Stem Cells

Author

Andreas Kurtz, Stefanie Seltmann, Amos Bairoch, Marie-Sophie Bittner, Kevin Bruce, Amanda Capes-Davis, Laura Clarke, Jeremy M. Crook, Laurence Daheron, Johannes Dewender, Adam Faulconbridge, Wataru Fujibuchi, Alexander Gutteridge, Derek J. Hei, Yong-Ou Kim, Jung-Hyun Kim, Anja Kolb- Kokocinski, Fritz Lekschas, Geoffrey P. Lomax, Jeanne F. Loring, Tenneille Ludwig, Nancy Mah, Tohru Matsui, Robert Müller, Helen Parkinson, Michael Sheldon, Kelly Smith, Harald Stachelscheid, Glyn Stacey, Ian Streeter, Anna Veiga, and Ren-He Xu

Subjects
human pluripotent stem cells, cell line nomenclature, cell data referencing, cell line authentication, cell databases, stem cell registry, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

Unambiguous cell line authentication is essential to avoid loss of association between data and cells. The risk for loss of references increases with the rapidity that new human pluripotent stem cell (hPSC) lines are generated, exchanged, and implemented. Ideally, a single name should be used as a generally applied reference for each cell line to access and unify cell-related information across publications, cell banks, cell registries, and databases and to ensure scientific reproducibility. We discuss the needs and requirements for such a unique identifier and implement a standard nomenclature for hPSCs, which can be automatically generated and registered by the human pluripotent stem cell registry (hPSCreg). To avoid ambiguities in PSC-line referencing, we strongly urge publishers to demand registration and use of the standard name when publishing research based on hPSC lines.

Published
2018
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2. Clonality of circulating tumor cells in breast cancer brain metastasis patients

Author

Carlotta Riebensahm, Simon A. Joosse, Malte Mohme, Annkathrin Hanssen, Jakob Matschke, Yvonne Goy, Isabell Witzel, Katrin Lamszus, Jolanthe Kropidlowski, Cordula Petersen, Anja Kolb-Kokocinski, Sascha Sauer, Kerstin Borgmann, Markus Glatzel, Volkmar Müller, Manfred Westphal, Sabine Riethdorf, Klaus Pantel, and Harriet Wikman

Subjects
CTC, Breast cancer, Brain metastases, Clonality, CNA, NGS, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background The incidence of brain metastases in breast cancer (BCBM) patients is increasing. These patients have a very poor prognosis, and therefore, identification of blood-based biomarkers, such as circulating tumor cells (CTCs), and understanding the genomic heterogeneity could help to personalize treatment options. Methods Both EpCAM-dependent (CellSearch® System) and EpCAM-independent Ficoll-based density centrifugation methods were used to detect CTCs from 57 BCBM patients. DNA from individual CTCs and corresponding primary tumors and brain metastases were analyzed by next-generation sequencing (NGS) in order to evaluate copy number aberrations and single nucleotide variations (SNVs). Results CTCs were detected after EpCAM-dependent enrichment in 47.7% of the patients (≥ 5 CTCs/7.5 ml blood in 20.5%). The CTC count was associated with ERBB2 status (p = 0.029) of the primary tumor as well as with the prevalence of bone metastases (p = 0.021). EpCAM-independent enrichment revealed CTCs in 32.6% of the patients, especially among triple-negative breast cancer (TNBC) patients (70.0%). A positive CTC status after enrichment of either method was significantly associated with decreased overall survival time (p

Published
2019
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3. Deficient methylation and formylation of mt-tRNAMet wobble cytosine in a patient carrying mutations in NSUN3

Author

Lindsey Van Haute, Sabine Dietmann, Laura Kremer, Shobbir Hussain, Sarah F. Pearce, Christopher A. Powell, Joanna Rorbach, Rebecca Lantaff, Sandra Blanco, Sascha Sauer, Urania Kotzaeridou, Georg F. Hoffmann, Yasin Memari, Anja Kolb-Kokocinski, Richard Durbin, Johannes A. Mayr, Michaela Frye, Holger Prokisch, and Michal Minczuk

Subjects
Science
Abstract

The post-transcriptional 5-methylcytosine (m5C) modification occurs in a wide range of nuclear-encoded RNAs. Here the authors identify the mitochondrial tRNA-Met as a target for the m5C methyltransferase NSun3—found mutated in a mitochondrial disease patient—and link mitochondrial tRNA modifications with energy metabolism.

Published
2016
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4. Author response: Population-scale proteome variation in human induced pluripotent stem cells

Author

Helena Kilpinen, Rachel Denton, Francesco Paolo Casale, Ewan Birney, Laura Clarke, Christopher M. Kirton, Natalie Moens, Daniel D Seaton, Alex Alderton, Alejandro Brenes, Petr Danecek, Angus I. Lamond, Oliver Stegle, Dalila Bensaddek, Chukwuma A. Agu, Minal Patel, Angela Goncalves, Ian Streeter, Anja Kolb-Kokocinski, Peter W. Harrison, Marc Jan Bonder, Shane A. McCarthy, Philip L. Beales, Reena Halai, Bogdan Mirauta, Davide Denovi, Willem H. Ouwehand, Ruta Meleckyte, Sarah Harper, Andreas Leha, Richard Durbin, Fiona M. Watt, Yasin Memari, and Daniel J. Gaffney

Subjects
education.field_of_study, Variation (linguistics), Scale (ratio), Population, Proteome, Computational biology, Human Induced Pluripotent Stem Cells, Biology, education
Published
2020

5. A Standard Nomenclature for Referencing and Authentication of Pluripotent Stem Cells

Author

Ian Streeter, Stefanie Seltmann, Anja Kolb Kokocinski, Geoffrey P. Lomax, Jeanne F. Loring, Glyn Stacey, Harald Stachelscheid, Laurence Daheron, Kelly P. Smith, Tohru Matsui, K. Bruce, Adam Faulconbridge, Wataru Fujibuchi, Michael Sheldon, Robert Müller, Jung-Hyun Kim, Marie-Sophie Bittner, Derek J. Hei, Johannes Dewender, Laura Clarke, Yong-Ou Kim, Anna Veiga, Amos Marc Bairoch, Andreas Kurtz, Amanda Capes-Davis, Helen Parkinson, Fritz Lekschas, Tenneille Ludwig, Jeremy M. Crook, Ren-He Xu, Nancy Mah, and Alexander Gutteridge

Subjects
Pluripotent Stem Cells, 0301 basic medicine, Databases, Factual, Biology, Biochemistry, Unique identifier, 03 medical and health sciences, Terminology as Topic, Research based, Genetics, Humans, Registries, human pluripotent stem cells, ddc:576, cell line authentication, Induced pluripotent stem cell, lcsh:QH301-705.5, Nomenclature, Biological Specimen Banks, lcsh:R5-920, Authentication, Information retrieval, cell data referencing, Cell Biology, 030104 developmental biology, lcsh:Biology (General), Perspective, cell line nomenclature, lcsh:Medicine (General), stem cell registry, cell databases, Developmental Biology
Abstract

Unambiguous cell line authentication is essential to avoid loss of association between data and cells. The risk for loss of references increases with the rapidity that new human pluripotent stem cell (hPSC) lines are generated, exchanged, and implemented. Ideally, a single name should be used as a generally applied reference for each cell line to access and unify cell-related information across publications, cell banks, cell registries, and databases and to ensure scientific reproducibility. We discuss the needs and requirements for such a unique identifier and implement a standard nomenclature for hPSCs, which can be automatically generated and registered by the human pluripotent stem cell registry (hPSCreg). To avoid ambiguities in PSC-line referencing, we strongly urge publishers to demand registration and use of the standard name when publishing research based on hPSC lines., In this article Kurtz, Seltmann and colleagues propose a standard nomenclature and registry for human pluripotent stem cells. The nomenclature is based on fixed name elements and provides a unique identifier for PSC lines suitable for referencing over diverse data sources, registries, publications, and cell banks. Rigorous application is needed to reduce risks from misidentification and false referencing of lines and data.

Published
2018

6. Clonality of circulating tumor cells in breast cancer brain metastasis patients

Author

Cordula Petersen, Yvonne Goy, Annkathrin Hanssen, Jakob Matschke, Isabell Witzel, Harriet Wikman, Katrin Lamszus, Volkmar Müller, Sabine Riethdorf, Jolanthe Kropidlowski, Kerstin Borgmann, Anja Kolb-Kokocinski, Carlotta Riebensahm, Sascha Sauer, Malte Mohme, Klaus Pantel, Manfred Westphal, Markus Glatzel, and Simon A. Joosse

Subjects
Oncology, medicine.medical_specialty, Poor prognosis, DNA Copy Number Variations, Early Relapse, Breast Neoplasms, Cell Count, lcsh:RC254-282, 03 medical and health sciences, Breast cancer, 0302 clinical medicine, Circulating tumor cell, Surgical oncology, Internal medicine, Biomarkers, Tumor, medicine, Humans, Chromosome Aberrations, Brain Neoplasms, business.industry, Chromosomal aberrations, Incidence (epidemiology), Brain metastases, CNA, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Epithelial Cell Adhesion Molecule, Neoplastic Cells, Circulating, Prognosis, medicine.disease, CTC, Survival Analysis, Primary tumor, 3. Good health, NGS, 030220 oncology & carcinogenesis, Mutation, Female, Technology Platforms, business, Research Article, Clonality, Brain metastasis
Abstract

Background The incidence of brain metastases in breast cancer (BCBM) patients is increasing. These patients have a very poor prognosis, and therefore, identification of blood-based biomarkers, such as circulating tumor cells (CTCs), and understanding the genomic heterogeneity could help to personalize treatment options. Methods Both EpCAM-dependent (CellSearch® System) and EpCAM-independent Ficoll-based density centrifugation methods were used to detect CTCs from 57 BCBM patients. DNA from individual CTCs and corresponding primary tumors and brain metastases were analyzed by next-generation sequencing (NGS) in order to evaluate copy number aberrations and single nucleotide variations (SNVs). Results CTCs were detected after EpCAM-dependent enrichment in 47.7% of the patients (≥ 5 CTCs/7.5 ml blood in 20.5%). The CTC count was associated with ERBB2 status (p = 0.029) of the primary tumor as well as with the prevalence of bone metastases (p = 0.021). EpCAM-independent enrichment revealed CTCs in 32.6% of the patients, especially among triple-negative breast cancer (TNBC) patients (70.0%). A positive CTC status after enrichment of either method was significantly associated with decreased overall survival time (p

Published
2019

7. Induction of Neural Crest Stem Cells From Bardet–Biedl Syndrome Patient Derived hiPSCs

Author

William B. Barrell, John N. Griffin, Jessica-Lily Harvey, HipSci Consortium, Davide Danovi, Philip Beales, Agamemnon E. Grigoriadis, Karen J. Liu, Richard Durbin, Daniel Gaffney, Chukwuma Agu, Alex Alderton, Shrada Amatya, Petr Danecek, Rachel Denton, Angela Goncalves, Reena Halai, Sarah Harper, Chris Kirton, Andrew Knights, Anja Kolb-Kokocinski, Andreas Leha, Shane McCarthy, Yasin Memari, Minal Patel, Ewan Birney, Oliver Stegle, Francesco Paolo Casale, Laura Clarke, Peter Harrison, Helena Kilpinen, Davis McCarthy, Ian Streeter, Fiona Watt, Davide Denovi, Ruta Meleckyte, Natalie Moens, Willem Ouwehand, Ludovic Vallier, Angus Lamond, and Dalila Bensaddek

Subjects
human induced pluripotent stem cells, hiPSCs, Bardet–Biedl Syndrome, neural crest, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, BBS, lcsh:RC321-571
Abstract

Neural crest cells arise in the embryo from the neural plate border and migrate throughout the body, giving rise to many different tissue types such as bones and cartilage of the face, smooth muscles, neurons, and melanocytes. While studied extensively in animal models, neural crest development and disease have been poorly described in humans due to the challenges in accessing embryonic tissues. In recent years, patient-derived human induced pluripotent stem cells (hiPSCs) have become easier to generate, and several streamlined protocols have enabled robust differentiation of hiPSCs to the neural crest lineage. Thus, a unique opportunity is offered for modeling neurocristopathies using patient specific stem cell lines. In this work, we make use of hiPSCs derived from patients affected by the Bardet–Biedl Syndrome (BBS) ciliopathy. BBS patients often exhibit subclinical craniofacial dysmorphisms that are likely to be associated with the neural crest-derived facial skeleton. We focus on hiPSCs carrying variants in the BBS10 gene, which encodes a protein forming part of a chaperonin-like complex associated with the cilium. Here, we establish a pipeline for profiling hiPSCs during differentiation toward the neural crest stem cell fate. This can be used to characterize the differentiation properties of the neural crest-like cells. Two different BBS10 mutant lines showed a reduction in expression of the characteristic neural crest gene expression profile. Further analysis of both BBS10 mutant lines highlighted the inability of these mutant lines to differentiate toward a neural crest fate, which was also characterized by a decreased WNT and BMP response. Altogether, our study suggests a requirement for wild-type BBS10 in human neural crest development. In the long term, approaches such as the one we describe will allow direct comparison of disease-specific cell lines. This will provide valuable insights into the relationships between genetic background and heterogeneity in cellular models. The possibility of integrating laboratory data with clinical phenotypes will move us toward precision medicine approaches.

Published
2019

8. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Author

Kathleen M. Gorman, Esther Meyer, Detelina Grozeva, Egidio Spinelli, Amy McTague, Alba Sanchis-Juan, Keren J. Carss, Emily Bryant, Adi Reich, Amy L. Schneider, Ronit M. Pressler, Michael A. Simpson, Geoff D. Debelle, Evangeline Wassmer, Jenny Morton, Diana Sieciechowicz, Eric Jan-Kamsteeg, Alex R. Paciorkowski, Mary D. King, J. Helen Cross, Annapurna Poduri, Heather C. Mefford, Ingrid E. Scheffer, Tobias B. Haack, Gary McCullagh, John J. Millichap, Gemma L. Carvill, Jill Clayton-Smith, Eamonn R. Maher, F. Lucy Raymond, Manju A. Kurian, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Siddharth Banka, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Saeed Al Turki, Carl Anderson, Richard Anney, Dinu Antony, Maria Soler Artigas, Muhammad Ayub, Senduran Balasubramaniam, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Ewan Birney, Douglas Blackwood, Martin Bobrow, Elena Bochukova, Patrick Bolton, Rebecca Bounds, Chris Boustred, Gerome Breen, Mattia Calissano, Keren Carss, Krishna Chatterjee, Lu Chen, Antonio Ciampi, Sebhattin Cirak, Peter Clapham, Gail Clement, Guy Coates, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Aaron Day-Williams, Ian N.M. Day, Thomas Down, Yuanping Du, Ian Dunham, Sarah Edkins, Peter Ellis, David Evans, Sadaf Faroogi, Ghazaleh Fatemifar, David R. Fitzpatrick, Paul Flicek, James Flyod, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Louise Gallagher, Matthias Geihs, Daniel Geschwind, Heather Griffin, Xueqin Guo, Xiaosen Guo, Hugh Gurling, Deborah Hart, Audrey Hendricks, Peter Holmans, Bryan Howie, Liren Huang, Tim Hubbard, Steve E. Humphries, Pirro Hysi, David K. Jackson, Yalda Jamshidi, Tian Jing, Chris Joyce, Jane Kaye, Thomas Keane, Julia Keogh, John Kemp, Karen Kennedy, Anja Kolb-Kokocinski, Genevieve Lachance, Cordelia Langford, Daniel Lawson, Irene Lee, Monkol Lek, Jieqin Liang, Hong Lin, Rui Li, Yingrui Li, Ryan Liu, Jouko Lönnqvist, Margarida Lopes, Valentina Iotchkova, Daniel MacArthur, Jonathan Marchini, John Maslen, Mangino Massimo, Iain Mathieson, Gaëlle Marenne, Peter McGuffin, Andrew McIntosh, Andrew G. McKechanie, Andrew McQuillin, Sarah Metrustry, Hannah Mitchison, Alireza Moayyeri, James Morris, Francesco Muntoni, Kate Northstone, Michael O'Donnovan, Alexandros Onoufriadis, Stephen O'Rahilly, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy R. Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, Olli Pietilainen, Vincent Plagnol, Lydia Quaye, Michael A. Quail, Karola Rehnström, Susan Ring, Graham R.S. Ritchie, Nicola Roberts, David B. Savage, Peter Scambler, Stephen Schiffels, Miriam Schmidts, Nadia Schoenmakers, Robert K. Semple, Eva Serra, Sally I. Sharp, So-Youn Shin, David Skuse, Kerrin Small, Lorraine Southam, Olivera Spasic-Boskovic, David St Clair, Jim Stalker, Elizabeth Stevens, Beate St Pourcian, Jianping Sun, Jaana Suvisaari, Ionna Tachmazidou, Martin D. Tobin, Ana Valdes, Margriet Van Kogelenberg, Peter M. Visscher, Louise V. Wain, James T.R. Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Elanor Wheeler, Tamieka Whyte, Hywel Williams, Kathleen A. Williamson, Crispian Wilson, Kim Wong, ChangJiang Xu, Jian Yang, Fend Zhang, Pingbo Zhang, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gavin Arno, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Jenny Carmichael, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Michel Michaelides, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Pediatric surgery, APH - Aging & Later Life, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and APH - Quality of Care

Subjects
0301 basic medicine, Male, Adolescent, Loss of Heterozygosity, Context (language use), Postnatal microcephaly, Neurotransmission, medicine.disease_cause, Bioinformatics, Synaptic Transmission, Loss of heterozygosity, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Calcium Channels, N-Type, Report, Genetics, medicine, Humans, Child, Genetics (clinical), Mutation, Dyskinesias, business.industry, Infant, medicine.disease, Hypotonia, Pedigree, 030104 developmental biology, Dyskinesia, Child, Preschool, Calcium, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

© 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.

Published
2018

9. Tyrosine kinase 2 is not limiting human antiviral type III interferon responses

Author

Petra Kaiser-Labusch, Julia Bank, Anja Kolb-Kokocinski, Sandra Ammann, Stephan Ehl, Sebastian Fuchs, Heymut Omran, and Christine Edelbusch

Subjects
0301 basic medicine, medicine.medical_treatment, Immunology, Eczema, Biology, Virus, Cell Line, Interferon-gamma, Mice, 03 medical and health sciences, Interferon, medicine, Animals, Humans, Immunology and Allergy, Receptors, Interleukin-10, Receptors, Cytokine, Child, Receptor, Skin, TYK2 Kinase, Interleukin-6, Monocyte, Immunoglobulin E, Interleukin-10, Killer Cells, Natural, 030104 developmental biology, medicine.anatomical_structure, Cytokine, Tyrosine kinase 2, Mutation, Disease Susceptibility, Interferons, Signal transduction, Cytokine receptor, Job Syndrome, Signal Transduction, medicine.drug
Abstract

Tyrosine kinase 2 (TYK2) associates with interferon (IFN) alpha receptor, IL-10 receptor (IL-10R) beta and other cytokine receptor subunits for signal transduction, in response to various cytokines, including type-I and type-III IFNs, IL-6, IL-10, IL-12 and IL-23. Data on TYK2 dependence on cytokine responses and in vivo consequences of TYK2 deficiency are inconsistent. We investigated a TYK2 deficient patient, presenting with eczema, skin abscesses, respiratory infections and IgE levels >1000 U/mL, without viral or mycobacterial infections and a corresponding cellular model to analyze the role of TYK2 in type-III IFN mediated responses and NK-cell function. We established a novel simple diagnostic monocyte assay to show that the mutation completely abolishes the IFN-α mediated antiviral response. It also partly reduces IL-10 but not IL-6 mediated signaling associated with reduced IL-10Rβ expression. However, we found almost normal type-III IFN signaling associated with minimal impairment of virus control in a TYK2 deficient human cell line. Contrary to observations in TYK2 deficient mice, NK-cell phenotype and function, including IL-12/IL-18 mediated responses, were normal in the patient. Thus, preserved type-III IFN responses and normal NK-cell function may contribute to antiviral protection in TYK2 deficiency leading to a surprisingly mild human phenotype.

Published
2016

10. DNAH11 Localization in the Proximal Region of Respiratory Cilia Defines Distinct Outer Dynein Arm Complexes

Author

Artem Shaposhnykov, Gerard W. Dougherty, Lea Bentur, Virginia Mirra, Julia Wallmeier, Martina Brueckner, Kavita Praveen, Heike Olbrich, Sara Kashef, Yasin Memari, Pekka Valmari, Heymut Omran, Claudius Werner, Mohammad Amin Kashef, Erica E. Davis, Bernd Dworniczak, Niki T. Loges, Christian Ruckert, Karsten Häffner, Johanna Raidt, Nicholas Katsanis, Micha Aviram, Gaia Pigino, Israel Amirav, Cordula Westermann, Anja Kolb-Kokocinski, Gyorgy Baktai, Tabea Menchen, Fardin Eghtedari, Judith A. Klinkenbusch, Rim Hjeij, Petra Pennekamp, and Richard Durbin

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, Mucociliary clearance, Clinical Biochemistry, Dynein, Context (language use), Biology, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Cilia, Lung, Molecular Biology, Original Research, Primary ciliary dyskinesia, Base Sequence, Kartagener Syndrome, Cilium, Homozygote, Dyneins, Axonemal Dyneins, Cell Biology, medicine.disease, Cell biology, Protein Transport, 030104 developmental biology, medicine.anatomical_structure, 030228 respiratory system, Mutation, Outer dynein arm
Abstract

Primary ciliary dyskinesia (PCD) is a recessively inherited disease that leads to chronic respiratory disorders owing to impaired mucociliary clearance. Conventional transmission electron microscopy (TEM) is a diagnostic standard to identify ultrastructural defects in respiratory cilia but is not useful in approximately 30% of PCD cases, which have normal ciliary ultrastructure. DNAH11 mutations are a common cause of PCD with normal ciliary ultrastructure and hyperkinetic ciliary beating, but its pathophysiology remains poorly understood. We therefore characterized DNAH11 in human respiratory cilia by immunofluorescence microscopy (IFM) in the context of PCD. We used whole-exome and targeted next-generation sequence analysis as well as Sanger sequencing to identify and confirm eight novel loss-of-function DNAH11 mutations. We designed and validated a monoclonal antibody specific to DNAH11 and performed high-resolution IFM of both control and PCD-affected human respiratory cells, as well as samples from green fluorescent protein (GFP)-left-right dynein mice, to determine the ciliary localization of DNAH11. IFM analysis demonstrated native DNAH11 localization in only the proximal region of wild-type human respiratory cilia and loss of DNAH11 in individuals with PCD with certain loss-of-function DNAH11 mutations. GFP-left-right dynein mice confirmed proximal DNAH11 localization in tracheal cilia. DNAH11 retained proximal localization in respiratory cilia of individuals with PCD with distinct ultrastructural defects, such as the absence of outer dynein arms (ODAs). TEM tomography detected a partial reduction of ODAs in DNAH11-deficient cilia. DNAH11 mutations result in a subtle ODA defect in only the proximal region of respiratory cilia, which is detectable by IFM and TEM tomography.

Published
2016

11. TTC25 Deficiency Results in Defects of the Outer Dynein Arm Docking Machinery and Primary Ciliary Dyskinesia with Left-Right Body Asymmetry Randomization

Author

Heymut Omran, Gerard W. Dougherty, Julia Wallmeier, John B. Wallingford, Heike Olbrich, Yasuko Asai, Chanjae Lee, Sascha Sauer, Yasin Memari, Kyosuke Shinohara, Petra Pennekamp, Matthias Griese, Johanna Raidt, Anja Kolb-Kokocinski, Tabea Menchen, Hidetaka Shiratori, Rim Hjeij, Christine Edelbusch, Richard Durbin, Claudius Werner, Hiroshi Hamada, Katsura Minegishi, Niki T. Loges, and Katsuyoshi Takaoka

Subjects
0301 basic medicine, Axoneme, Xenopus, Dynein, Fluorescent Antibody Technique, Genes, Recessive, Biology, Xenopus Proteins, 03 medical and health sciences, Mice, 0302 clinical medicine, Microscopy, Electron, Transmission, Report, medicine, Genetics, Animals, Humans, Exome, Genetics(clinical), Cilia, Genetics (clinical), Primary ciliary dyskinesia, Kartagener Syndrome, Cilium, Dyneins, Anatomy, Exons, medicine.disease, biology.organism_classification, Cell biology, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Outer dynein arm, NODAL, Carrier Proteins, Congenital disorder, Protein Binding
Abstract

Multiprotein complexes referred to as outer dynein arms (ODAs) develop the main mechanical force to generate the ciliary and flagellar beat. ODA defects are the most common cause of primary ciliary dyskinesia (PCD), a congenital disorder of ciliary beating, characterized by recurrent infections of the upper and lower airways, as well as by progressive lung failure and randomization of left-right body asymmetry. Using a whole-exome sequencing approach, we identified recessive loss-of-function mutations within TTC25 in three individuals from two unrelated families affected by PCD. Mice generated by CRISPR/Cas9 technology and carrying a deletion of exons 2 and 3 in Ttc25 presented with laterality defects. Consistently, we observed immotile nodal cilia and missing leftward flow via particle image velocimetry. Furthermore, transmission electron microscopy (TEM) analysis in TTC25-deficient mice revealed an absence of ODAs. Consistent with our findings in mice, we were able to show loss of the ciliary ODAs in humans via TEM and immunofluorescence (IF) analyses. Additionally, IF analyses revealed an absence of the ODA docking complex (ODA-DC), along with its known components CCDC114, CCDC151, and ARMC4. Co-immunoprecipitation revealed interaction between the ODA-DC component CCDC114 and TTC25. Thus, here we report TTC25 as a new member of the ODA-DC machinery in humans and mice.

Published
2016
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12. Deficient methylation and formylation of mt-tRNAMet wobble cytosine in a patient carrying mutations in NSUN3

Author

Laura S. Kremer, Georg F. Hoffmann, Richard Durbin, Sarah F. Pearce, Joanna Rorbach, Lindsey Van Haute, Michal Minczuk, Urania Kotzaeridou, Rebecca Lantaff, Sandra Blanco, Anja Kolb-Kokocinski, Michaela Frye, Christopher A. Powell, Shobbir Hussain, Johannes A. Mayr, Sabine Dietmann, Holger Prokisch, Sascha Sauer, Yasin Memari, Durbin, Richard [0000-0002-9130-1006], Prokisch, Holger [0000-0003-2379-6286], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Mitochondrial Diseases, Mitochondrial translation, Science, General Physics and Astronomy, Biology, Mitochondrion, MT-RNR1, Methylation, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, chemistry.chemical_compound, RNA, Transfer, Humans, ddc:610, Multidisciplinary, RNA, Methyltransferases, General Chemistry, Molecular biology, ddc, Mitochondria, 3. Good health, HEK293 Cells, 030104 developmental biology, Mitochondrial respiratory chain, Gene Expression Regulation, chemistry, Biochemistry, Mutation, Transfer RNA, Technology Platforms, Cytosine, HeLa Cells
Abstract

Epitranscriptome modifications are required for structure and function of RNA and defects in these pathways have been associated with human disease. Here we identify the RNA target for the previously uncharacterized 5-methylcytosine (m5C) methyltransferase NSun3 and link m5C RNA modifications with energy metabolism. Using whole-exome sequencing, we identified loss-of-function mutations in NSUN3 in a patient presenting with combined mitochondrial respiratory chain complex deficiency. Patient-derived fibroblasts exhibit severe defects in mitochondrial translation that can be rescued by exogenous expression of NSun3. We show that NSun3 is required for deposition of m5C at the anticodon loop in the mitochondrially encoded transfer RNA methionine (mt-tRNAMet). Further, we demonstrate that m5C deficiency in mt-tRNAMet results in the lack of 5-formylcytosine (f5C) at the same tRNA position. Our findings demonstrate that NSUN3 is necessary for efficient mitochondrial translation and reveal that f5C in human mitochondrial RNA is generated by oxidative processing of m5C., The post-transcriptional 5-methylcytosine (m5C) modification occurs in a wide range of nuclear-encoded RNAs. Here the authors identify the mitochondrial tRNA-Met as a target for the m5C methyltransferase NSun3—found mutated in a mitochondrial disease patient—and link mitochondrial tRNA modifications with energy metabolism.

Published
2016

13. A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans

Author

Nicholas J. Timpson, Klaudia Walter, Josine L. Min, Ioanna Tachmazidou, Giovanni Malerba, So Youn Shin, Lu Chen, Marta Futema, Lorraine Southam, Valentina Iotchkova, Jie Huang, Yasin Memari, Shane McCarthy, Petr Danecek, Dawn Muddyman, Massimo Mangino, Cristina Menni, John R. B. Perry, Susan M. Ring, Amadou Gaye, George Dedoussis, Aliki Eleni Farmaki, Paul Burton, Philippa J. Talmud, Giovanni Gambaro, Tim D. Spector, George Davey Smith, Richard Durbin, J. Brent Richards, Steve E. Humphries, Eleftheria Zeggini, Nicole Soranzo, Saeed Al Turki, Carl Anderson, Richard Anney, Dinu Antony, Maria Soler Artigas, Muhammad Ayub, Senduran Balasubramaniam, Jeffrey C. Barrett, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Ewan Birney, Douglas Blackwood, Martin Bobrow, Elena Bochukova, Patrick Bolton, Rebecca Bounds, Chris Boustred, Gerome Breen, Mattia Calissano, Keren Carss, Krishna Chatterjee, Antonio Ciampi, Sebhattin Cirak, Peter Clapham, Gail Clement, Guy Coates, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Aaron Day Williams, Ian N. M. Day, Thomas Down, Yuanping Du, Ian Dunham, Sarah Edkins, Peter Ellis, David Evans, Sadaf Faroogi, Ghazaleh Fatemifar, David R. Fitzpatrick, Paul Flicek, James Flyod, A. Reghan Foley, Christopher S. Franklin, Louise Gallagher, Tom Gaunt, Matthias Geihs, Daniel Geschwind, Celia Greenwood, Heather Griffin, Detelina Grozeva, Xueqin Guo, Xiaosen Guo, Hugh Gurling, Deborah Hart, Audrey Hendricks, Peter Holmans, Bryan Howie, Liren Huang, Tim Hubbard, Matthew E. Hurles, Pirro Hysi, David K. Jackson, Yalda Jamshidi, Tian Jing, Chris Joyce, Jane Kaye, Thomas Keane, Julia Keogh, John Kemp, Karen Kennedy, Anja Kolb Kokocinski, Genevieve Lachance, Cordelia Langford, Daniel Lawson, Irene Lee, Monkol Lek, Jieqin Liang, Hong Lin, Rui Li, Yingrui Li, Ryan Liu, Jouko Lönnqvist, Margarida Lopes, Valentina Lotchkova, Daniel MacArthur, Jonathan Marchini, John Maslen, Mangino Massimo, Iain Mathieson, Gaëlle Marenne, Peter McGuffin, Andrew McIntosh, Andrew G. McKechanie, Andrew McQuillin, Sarah Metrustry, Josine Min, Hannah Mitchison, Alireza Moayyeri, James Morris, Francesco Muntoni, Kate Northstone, Michael O'Donnovan, Alexandros Onoufriadis, Stephen O'Rahilly, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy R. Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, John Perry, Olli Pietilainen, Vincent Plagnol, Lydia Quaye, Michael A. Quail, Lucy Raymond, Karola Rehnström, Brent Richards, Susan Ring, Graham R. S. Ritchie, Nicola Roberts, David B. Savage, Peter Scambler, Stephen Schiffels, Miriam Schmidts, Nadia Schoenmakers, Robert K. Semple, Eva Serra, Sally I. Sharp, Hasheem Shihab, David Skuse, Kerrin Small, Olivera Spasic Boskovic, Tim Spector, David St Clair, Jim Stalker, Elizabeth Stevens, Beate St Pourcian, Jianping Sun, Gabriela Surdulescu, Jaana Suvisaari, Ionna Tachmazidou, Nicholas Timpson, Martin D. Tobin, Ana Valdes, Margriet Van Kogelenberg, Parthiban Vijayarangakannan, Peter M. Visscher, Louise V. Wain, James T. R. Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Elanor Wheeler, Tamieka Whyte, Hywel Williams, Kathleen A. Williamson, Crispian Wilson, Scott G. Wilson, Kim Wong, ChangJiang Xu, Jian Yang, Fend Zhang, Pingbo Zhang, Hou Feng Zheng, COCCA, MASSIMILIANO, Nicholas J., Timpson, Klaudia, Walter, Josine L., Min, Ioanna, Tachmazidou, Giovanni, Malerba, So Youn, Shin, Lu, Chen, Marta, Futema, Lorraine, Southam, Valentina, Iotchkova, Cocca, Massimiliano, Jie, Huang, Yasin, Memari, Shane, Mccarthy, Petr, Danecek, Dawn, Muddyman, Massimo, Mangino, Cristina, Menni, John R. B., Perry, Susan M., Ring, Amadou, Gaye, George, Dedoussi, Aliki Eleni, Farmaki, Paul, Burton, Philippa J., Talmud, Giovanni, Gambaro, Tim D., Spector, George Davey, Smith, Richard, Durbin, J., Brent Richard, Steve E., Humphrie, Eleftheria, Zeggini, Nicole, Soranzo, Saeed Al, Turki, Carl, Anderson, Richard, Anney, Dinu, Antony, Maria Soler, Artiga, Muhammad, Ayub, Senduran, Balasubramaniam, Jeffrey C., Barrett, Inês, Barroso, Phil, Beale, Jamie, Bentham, Shoumo, Bhattacharya, Ewan, Birney, Douglas, Blackwood, Martin, Bobrow, Elena, Bochukova, Patrick, Bolton, Rebecca, Bound, Chris, Boustred, Gerome, Breen, Mattia, Calissano, Keren, Car, Krishna, Chatterjee, Antonio, Ciampi, Sebhattin, Cirak, Peter, Clapham, Gail, Clement, Guy, Coate, David, Collier, Catherine, Cosgrove, Tony, Cox, Nick, Craddock, Lucy, Crook, Sarah, Curran, David, Curti, Allan, Daly, Aaron Day, William, Ian N. M., Day, Thomas, Down, Yuanping, Du, Ian, Dunham, Sarah, Edkin, Peter, Elli, David, Evan, Sadaf, Faroogi, Ghazaleh, Fatemifar, David R., Fitzpatrick, Paul, Flicek, James, Flyod, A., Reghan Foley, Christopher S., Franklin, Louise, Gallagher, Tom, Gaunt, Matthias, Geih, Daniel, Geschwind, Celia, Greenwood, Heather, Griffin, Detelina, Grozeva, Xueqin, Guo, Xiaosen, Guo, Hugh, Gurling, Deborah, Hart, Audrey, Hendrick, Peter, Holman, Bryan, Howie, Liren, Huang, Tim, Hubbard, Matthew E., Hurle, Pirro, Hysi, David K., Jackson, Yalda, Jamshidi, Tian, Jing, Chris, Joyce, Jane, Kaye, Thomas, Keane, Julia, Keogh, John, Kemp, Karen, Kennedy, Anja Kolb, Kokocinski, Genevieve, Lachance, Cordelia, Langford, Daniel, Lawson, Irene, Lee, Monkol, Lek, Jieqin, Liang, Hong, Lin, Rui, Li, Yingrui, Li, Ryan, Liu, Jouko, Lönnqvist, Margarida, Lope, Valentina, Lotchkova, Daniel, Macarthur, Jonathan, Marchini, John, Maslen, Mangino, Massimo, Iain, Mathieson, Gaëlle, Marenne, Peter, Mcguffin, Andrew, Mcintosh, Andrew G., Mckechanie, Andrew, Mcquillin, Sarah, Metrustry, Josine, Min, Hannah, Mitchison, Alireza, Moayyeri, James, Morri, Francesco, Muntoni, Kate, Northstone, Michael, O'Donnovan, Alexandros, Onoufriadi, Stephen, O'Rahilly, Karim, Oualkacha, Michael J., Owen, Aarno, Palotie, Kalliope, Panoutsopoulou, Victoria, Parker, Jeremy R., Parr, Lavinia, Paternoster, Tiina, Paunio, Felicity, Payne, John, Perry, Olli, Pietilainen, Vincent, Plagnol, Lydia, Quaye, Michael A., Quail, Lucy, Raymond, Karola, Rehnström, Brent, Richard, Susan, Ring, Graham R. S., Ritchie, Nicola, Robert, David B., Savage, Peter, Scambler, Stephen, Schiffel, Miriam, Schmidt, Nadia, Schoenmaker, Robert K., Semple, Eva, Serra, Sally I., Sharp, Hasheem, Shihab, David, Skuse, Kerrin, Small, Olivera Spasic, Boskovic, Tim, Spector, David St, Clair, Jim, Stalker, Elizabeth, Steven, Beate St, Pourcian, Jianping, Sun, Gabriela, Surdulescu, Jaana, Suvisaari, Ionna, Tachmazidou, Nicholas, Timpson, Martin D., Tobin, Ana, Valde, Margriet Van, Kogelenberg, Parthiban, Vijayarangakannan, Peter M., Visscher, Louise V., Wain, James T. R., Walter, Guangbiao, Wang, Jun, Wang, Yu, Wang, Kirsten, Ward, Elanor, Wheeler, Tamieka, Whyte, Hywel, William, Kathleen A., Williamson, Crispian, Wilson, Scott G., Wilson, Kim, Wong, Changjiang, Xu, Jian, Yang, Fend, Zhang, Pingbo, Zhang, and Hou Feng, Zheng

Subjects
Very low-density lipoprotein, Population, vldl, apoc3, General Physics and Astronomy, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, rare mutations, Bioinformatics, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, genome-wide association study (GWAS), plasma lipids, 0302 clinical medicine, Polymorphism (computer science), Genetic variation, Settore MED/14 - NEFROLOGIA, Allele, education, Allele frequency, 030304 developmental biology, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, cholesterol, General Chemistry, Minor allele frequency
Abstract

The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ~0.25% (UK)) associated with plasma triglyceride (TG) levels (−1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10−8)) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (−1.0 s.d. (s.e.=0.173), P-value=7.32 × 10−9). This is consistent with an effect between 0.5 and 1.5 mmol l−1 dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale., Population-based genome sequencing provides an increasingly rich resource for the identification of low-frequency, large effect variants associated with clinically important phenotypes. Timpson et al. use UK10K data to identify a variant of the APOC3 gene strongly associated with plasma triglyceride levels.

Published
2014

14. Insights into hominid evolution from the gorilla genome sequence

Author

Paul Flicek, Yong Gu, David Neil Cooper, Tuuli Lappalainen, Nicholas I. Mundy, Petra C. Schwalie, Bryndis Yngvadottir, Peter D. Stenson, Michelle C Ward, Stephen H. Montgomery, Linda Vigilant, Matthew Mort, Katy Shaw, Julien Y. Dutheil, Lars Nørvang Andersen, Wesley C. Warren, Paul Heath, Emmanouil T. Dermitzakis, Edward V. Ball, Kathryn Beal, LaDeana W. Hillier, Tomas Marques-Bonet, Yali Xue, Javier Herrero, Richard K. Wilson, Emre Karakoc, Andreas Heger, Michael A. Quail, Yuan Chen, Daniel J. Turner, Kasper Munch, Anja Kolb-Kokocinski, Aylwyn Scally, Gregory E. Jordan, Pieter J. de Jong, Saba Sajjadian, Timothy D. O’Connor, Duncan T. Odom, Richard Durbin, Chris P. Ponting, Oliver A. Ryder, Andrew David Phillips, James C. Mullikin, Anthony Rogers, Javier Prado-Martinez, Stephen Meader, Jared T. Simpson, Gavin K. Laird, Chris Tyler-Smith, Shane A. McCarthy, Qasim Ayub, Can Alkan, Chris Clee, Mikkel H. Schierup, Weldon Whitener, Evan E. Eichler, Tina Graves, Asger Hobolth, Gerton Lunter, Stephen M. J. Searle, Ian Goodhead, Zemin Ning, Y. Amy Tang, Brenda J. Bradley, Dominic Schmidt, Stephen Fitzgerald, Nick Goldman, Jane Rogers, Baoli Zhu, Albert J. Vilella, Thomas Mailund, Scally, Aylwyn [0000-0002-0807-1167], McCarthy, Shane [0000-0002-2715-4187], Montgomery, Stephen [0000-0002-5474-5695], Mundy, Nicholas [0000-0002-5545-1517], Odom, Duncan [0000-0001-6201-5599], Apollo - University of Cambridge Repository, Wellcome Trust, European Molecular Biology Laboratory, University of Cambridge, Lundbeck Foundation, Academy of Finland, Emil Aaltonen Foundation, European Commission, European Research Council, Ministerio de Educación (España), Biotechnology and Biological Sciences Research Council (UK), Medical Research Council (UK), National Human Genome Research Institute (US), Danish Council for Independent Research, Swiss National Science Foundation, Louis Jeantet Foundation, EMBO, BIOBASE, National Science Foundation (US), Howard Hughes Medical Institute, Lappalainen, Tuuli Emilia, and Dermitzakis, Emmanouil

Subjects
0106 biological sciences, Transcription, Genetic, Gorilla, 01 natural sciences, Genome, ddc:576.5, Phylogeny, Pongo/genetics, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, Genomics, Eastern gorilla, 3. Good health, Genetic Variation/genetics, Proteins/genetics, Female, Pan troglodytes, Genetic Speciation, Population, Molecular Sequence Data, Biology, 010603 evolutionary biology, Article, Evolution, Molecular, 03 medical and health sciences, Western lowland gorilla, Species Specificity, biology.animal, Animals, Humans, Gorilla gorilla/genetics, Pan troglodytes/genetics, education, Gene, 030304 developmental biology, Gorilla gorilla, Pongo, Genetic Variation, Proteins, biology.organism_classification, Macaca mulatta, Macaca mulatta/genetics, Population bottleneck, Gene Expression Regulation, Evolutionary biology, Genome/genetics, Sequence Alignment
Abstract

Scally, A. et al., Gorillas are humans' closest living relatives after chimpanzees, and are of comparable importance for the study of human origins and evolution. Here we present the assembly and analysis of a genome sequence for the western lowland gorilla, and compare the whole genomes of all extant great ape genera. We propose a synthesis of genetic and fossil evidence consistent with placing the human-chimpanzee and human-chimpanzee-gorilla speciation events at approximately 6 and 10 million years ago. In 30% of the genome, gorilla is closer to human or chimpanzee than the latter are to each other; this is rarer around coding genes, indicating pervasive selection throughout great ape evolution, and has functional consequences in gene expression. A comparison of protein coding genes reveals approximately 500 genes showing accelerated evolution on each of the gorilla, human and chimpanzee lineages, and evidence for parallel acceleration, particularly of genes involved in hearing. We also compare the western and eastern gorilla species, estimating an average sequence divergence time 1.75 million years ago, but with evidence for more recent genetic exchange and a population bottleneck in the eastern species. The use of the genome sequence in these and future analyses will promote a deeper understanding of great ape biology and evolution. © 2012 Macmillan Publishers Limited. All rights reserved., This research was supported in part by Wellcome Trust grants WT062023(toJ.H.,K.B.,S.F.,A.J.V.,P.F.),WT089066(toR.D.),WT077192(toR.D.,S.M., A.K.-K., J.T.S., W.W.), WT077009 (to Y.X., B.Y., Q.A., Y.C., C.T.-S.), WT077198 (to G.K.L.) and 075491/Z/04 (to G.L.); EMBL grants (to P.C.S., P.F.); scholarships from the Gates Cambridge Trust (to G.E.J. and T.D.O’C.); an MRC Special Fellowship in Biomedical Informatics (toA.S.);funding from the Lundbeck Foundation(toA.H.);the Academy of Finland and the Emil Aaltonen Foundation(toT.L.);a Marie Curie fellowship(toT.M.-B.); the European Community’s Seventh Framework Programme (FP7/2007-2013)/ ERC Starting Grant(StG_20091118)(toT.M.-B.);an FPI grant from the Spanish Ministry of Education (BES-2010-032251) (to J.P.-M.); a BBSRC Doctoral Training Grant (to S.H.M.); grants from the UK Medical Research Council (to A.H., S.M., C.P.P.); the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health(to J.C.M.);the Danish Council for Independent Research, Natural Sciences,grant no.09-062535(toK.M.,M.H.S.);a Commonwealth Scholarship (to M.C.W.); the Swiss National Science Foundation, Louis Jeantet Foundation (to E.T.D.); an ERC Starting Grant and an EMBO Young Investigator Award, Hutchinson Whampoa (to D.T.O.); NHGRI support (to W.C.W.); support from BIOBASE GmbH (to E.V.B., P.D.S., M.M., A.D.P., K.S., D.N.C.); US National Science Foundation grant DGE-0739133(toW.W.);NHGRIU54HG003079(toR.K.W.);NIHgrantHG002385(to E.E.E). E.E.E. is an investigator of the Howard Hughes Medical Institute.

Published
2016

15. Common genetic variation drives molecular heterogeneity in human IPSCs

Author

Daniel J. Gaffney, Helena Kilpinen, Angela Goncalves, Ian Streeter, Ludovic Vallier, Sendu Bala, Philip L. Beales, Christopher M. Kirton, Francesco Paolo Casale, Reena Halai, Nathalie Moens, Adam Faulconbridge, Davis J. McCarthy, Laura Clarke, Peter W. Harrison, Alex Alderton, Shane A. McCarthy, Anja Kolb-Kokocinski, Filipa A.C. Soares, Willem H. Ouwehand, Minal Patel, Petr Danacek, Sarah Harper, Andreas Leha, Richard Durbin, Ruta Meleckyte, Davide Danovi, Dalila Bensaddek, Sofie Ashford, Ewan Birney, Rachel Nelson, Oliver J. Culley, Vackar Afzal, Oliver Stegle, Chukwuma A. Agu, Angus I. Lamond, Fiona M. Watt, and Yasin Memari

Subjects
0303 health sciences, Genomics, Computational biology, Biology, Molecular heterogeneity, Phenotype, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Genetic variation, Induced pluripotent stem cell, Reprogramming, Genotyping, 030304 developmental biology
Abstract

Induced pluripotent stem cell (iPSC) technology has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterisation of many existing iPSC lines limits their potential use for research and therapy. Here, we describe the systematic generation, genotyping and phenotyping of 522 open access human iPSCs derived from 189 healthy male and female individuals as part of the Human Induced Pluripotent Stem Cells Initiative (HipSci:http://www.hipsci.org). Our study provides a comprehensive picture of the major sources of genetic and phenotypic variation in iPSCs and establishes their suitability for use in genetic studies of complex human traits and cancer. Using a combination of genomewide analyses we find that 5-25% of the variation in different iPSC phenotypes, including differentiation capacity and cellular morphology, arises from differences betweenindividuals. We also assess the phenotypic effects of rare, genomic copy number mutations that are recurrently seen following iPSC reprogramming and present an initial map of common regulatory variants affecting the transcriptome of pluripotent cells in humans.

Published
2016

16. Common genetic variation drives molecular heterogeneity in human iPSCs

Author

Willem H. Ouwehand, Ruta Meleckyte, Sarah Harper, Andreas Leha, Richard Durbin, Daniel J. Gaffney, Helena Kilpinen, Philip L. Beales, Peter W. Harrison, Chukwuma A. Agu, A. White, Reena Halai, Angela Goncalves, Ian Streeter, Adam Faulconbridge, Sendu Bala, Davis J. McCarthy, Shane A. McCarthy, Minal Patel, Petr Danacek, Dalila Bensaddek, Francesco Paolo Casale, Annie Kathuria, Laura Clarke, Rachel Nelson, Yasin Memari, Filipa A.C. Soares, Alex Alderton, Anja Kolb-Kokocinski, Sharad R. Patel, Davide Danovi, Sofie Ashford, Oliver J. Culley, Christopher M. Kirton, Vackar Afzal, Kaur Alasoo, Nathalie Moens, Angus I. Lamond, Oliver Stegle, Ewan Birney, Alice L. Mann, Ludovic Vallier, Fiona M. Watt, McCarthy, Shane [0000-0002-2715-4187], Ouwehand, Willem [0000-0002-7744-1790], Vallier, Ludovic [0000-0002-3848-2602], Durbin, Richard [0000-0002-9130-1006], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Quality Control, DNA Copy Number Variations, Genotype, Induced Pluripotent Stem Cells, Quantitative Trait Loci, Genome-wide association study, Quantitative trait locus, Biology, Article, Transcriptome, 03 medical and health sciences, Genetic variation, Humans, Induced pluripotent stem cell, Genotyping, Cells, Cultured, Genetics, Multidisciplinary, Genetic Variation, Cellular Reprogramming, Phenotype, 3. Good health, 030104 developmental biology, Gene Expression Regulation, Organ Specificity, DNA methylation
Abstract

Technology utilizing human induced pluripotent stem cells (iPS cells) has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterization of many existing iPS cell lines limits their potential use for research and therapy. Here we describe the systematic generation, genotyping and phenotyping of 711 iPS cell lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative. Our study outlines the major sources of genetic and phenotypic variation in iPS cells and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 5-46% of the variation in different iPS cell phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of genomic copy-number alterations that are repeatedly observed in iPS cells. In addition, we present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells.

Published
2016

17. Whole-exome sequencing in an isolated population from the Dalmatian island of Vis

Author

Ana Jerončić, Harry Campbell, Ivana Kolcic, Graham R. S. Ritchie, Eleftheria Zeggini, Igor Rudan, Dominik Glodzik, Yasin Memari, Caroline Hayward, Angela Matchan, Vesna Boraska Perica, Richard Durbin, Ozren Polasek, Audrey E. Hendricks, Anja Kolb-Kokocinski, Veronique Vitart, and Alan F. Wright

Subjects
0301 basic medicine, dbSNP, Reproductive Isolation, Croatia, Population, Population genetics, 030105 genetics & heredity, Biology, Runs of Homozygosity, Polymorphism, Single Nucleotide, Article, Evolution, Molecular, 03 medical and health sciences, Gene Frequency, Genetics, Humans, Exome, education, Allele frequency, Genetics (clinical), Exome sequencing, Islands, education.field_of_study, Human genetics, 030104 developmental biology, Mutation, exome, sequence, isolated
Abstract

We have whole-exome sequenced 176 individuals from the isolated population of the island of Vis in Croatia in order to describe exonic variation architecture. We found 290 577 single nucleotide variants (SNVs), 65% of which are singletons, low frequency or rare variants. A total of 25 430 (9%) SNVs are novel, previously not catalogued in NHLBI GO Exome Sequencing Project, UK10K-Generation Scotland, 1000Genomes Project, ExAC or NCBI Reference Assembly dbSNP. The majority of these variants (76%) are singletons. Comparable to data obtained from UK10K-Generation Scotland that were sequenced and analysed using the same protocols, we detected an enrichment of potentially damaging variants (non-synonymous and loss-of-function) in the low frequency and common variant categories. On average 115 (range 93-140) genotypes with loss-of-function variants, 23 (15-34) of which were homozygous, were identified per person. The landscape of loss- of-function variants across an exome revealed that variants mainly accumulated in genes on the xenobiotic-related pathways, of which majority coded for enzymes. The frequency of loss-of-function variants was additionally increased in Vis runs of homozygosity regions where variants mainly affected signalling pathways. This work confirms the isolate status of Vis population by means of whole-exome sequence and reveals the pattern of loss-of- function mutations, which resembles the trails of adaptive evolution that were found in other species. By cataloguing the exomic variants and describing the allelic structure of the Vis population, this study will serve as a valuable resource for future genetic studies of human diseases, population genetics and evolution in this population.

Published
2016

18. A Runx1-Smad6 Rheostat Controls Runx1 Activity during Embryonic Hematopoiesis

Author

Katrin Ottersbach, Sarah Kinston, Berthold Göttgens, Stéphanie G. I. Polderdijk, Anja Kolb-Kokocinski, Mary E. Janes, Marella F. T. R. de Bruijn, Nicola K. Wilson, Niv Pencovich, Kathy Knezevic, Thomas Bee, John E. Pimanda, and Yoram Groner

Subjects
Smad6 Protein, Molecular Sequence Data, Mice, Transgenic, SMAD, Regulatory Sequences, Nucleic Acid, Biology, Mice, chemistry.chemical_compound, hemic and lymphatic diseases, Chlorocebus aethiops, Animals, Humans, Molecular Biology, Transcription factor, Base Sequence, GATA2, Gene Expression Regulation, Developmental, Articles, Cell Biology, Embryo, Mammalian, Hematopoietic Stem Cells, Hematopoiesis, Haematopoiesis, RUNX1, chemistry, Proteasome, FLI1, COS Cells, Core Binding Factor Alpha 2 Subunit, embryonic structures, Cancer research, Stem cell, K562 Cells
Abstract

The oncogenic transcription factor Runx1 is required for the specification of definitive hematopoietic stem cells (HSC) in the developing embryo. The activity of this master regulator is tightly controlled during development. The transcription factors that upregulate the expression of Runx1 also upregulate the expression of Smad6, the inhibitory Smad, which controls Runx1 activity by targeting it to the proteasome. Here we show that Runx1, in conjunction with Fli1, Gata2, and Scl, directly regulates the expression of Smad6 in the aorta-gonad-mesonephros (AGM) region in the developing embryo, where HSCs originate. Runx1 regulates Smad6 activity via a novel upstream enhancer, and Runx1 null embryos show reduced Smad6 transcripts in the yolk-sac and c-Kit-positive fetal liver cells. By directly regulating the expression of Smad6, Runx1 sets up a functional rheostat to control its own activity. The perturbation of this rheostat, using a proteasomal inhibitor, results in an increase in Runx1 and Smad6 levels that can be directly attributed to increased Runx1 binding to tissue-specific regulatory elements of these genes. Taken together, we describe a scenario in which a key hematopoietic transcription factor controls its own expression levels by transcriptionally controlling its controller.

Published
2011

19. Purging of deleterious variants due to drift and founder effect in Italian populations with extended autozygosity

Author

Massimiliano Cocca, Marc Pybus, Pier Francesco Palamara, Erik Garrison, Michela Traglia, Cinzia F Sala, Sheila Ulivi, Yasin Memari, Anja Kolb-Kokocinski, Shane McCarthy, Richard Durbin, Paolo Gasparini, Daniela Toniolo, Nicole Soranzo, and Vincenza Colonna

Subjects
Genetics, 0303 health sciences, 03 medical and health sciences, Natural selection, 030305 genetics & heredity, Genotype, Consanguinity, 1000 Genomes Project, Biology, Inbreeding, Consanguineous Marriage, 030304 developmental biology, Deleterious alleles
Abstract

Purging through inbreeding occurs when consanguineous marriages increases the rate at which deleterious alleles are present in a homozygous state. In this study we carried out low-read depth (4-10x) whole-genome sequencing in 568 individuals from three Italian founder populations, and compared it to data from other Italian and European populations from the 1000 Genomes Project. We show extended consanguinity and depletion of homozygous genotypes at potentially detrimental sites in the founder populations compared to outbred populations. However these patterns are not compatible with the hypothesis of consanguinity driving the purging of highly deleterious mutations according to simulations. Therefore we conclude that genetic drift and the founder effect should be responsible for the observed purging of deleterious variants.

Published
2015

20. Immunofluorescence Analysis and Diagnosis of Primary Ciliary Dyskinesia with Radial Spoke Defects

Author

Kim G. Nielsen, Adrien Frommer, Julia Wallmeier, Martine Jaspers, David Shoseyov, Karsten Haeffner, June K. Marthin, Claudius Werner, Rim Hjeij, Heike Olbrich, Israel Amirav, Heymut Omran, Richard Durbin, Johanna Raidt, Sandra Cindric, Nael Elias, Sascha Sauer, Yasin Memari, Anja Kolb-Kokocinski, Niki T. Loges, Jörg Große-Onnebrink, Christine Edelbusch, Charlotte Jahnke, Eitan Kerem, and Mieke Boon

Subjects
Pulmonary and Respiratory Medicine, Adult, Male, Adolescent, Clinical Biochemistry, DNA Mutational Analysis, Mutation, Missense, Biology, Immunofluorescence, Young Adult, medicine, otorhinolaryngologic diseases, Missense mutation, Humans, Child, Fluorescent Antibody Technique, Indirect, Molecular Biology, Gene, Primary ciliary dyskinesia, Original Research, Genetics, medicine.diagnostic_test, Genetic heterogeneity, Kartagener Syndrome, Cilium, Proteins, Cell Biology, medicine.disease, DNA-Binding Proteins, Situs inversus, Cytoskeletal Proteins, Child, Preschool, Female, Protein Multimerization
Abstract

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder caused by several distinct defects in genes responsible for ciliary beating, leading to defective mucociliary clearance often associated with randomization of left/right body asymmetry. Individuals with PCD caused by defective radial spoke (RS) heads are difficult to diagnose owing to lack of gross ultrastructural defects and absence of situs inversus. Thus far, most mutations identified in human radial spoke genes (RSPH) are loss-of-function mutations, and missense variants have been rarely described. We studied the consequences of different RSPH9, RSPH4A, and RSPH1 mutations on the assembly of the RS complex to improve diagnostics in PCD. We report 21 individuals with PCD (16 families) with biallelic mutations in RSPH9, RSPH4A, and RSPH1, including seven novel mutations comprising missense variants, and performed high-resolution immunofluorescence analysis of human respiratory cilia. Missense variants are frequent genetic defects in PCD with RS defects. Absence of RSPH4A due to mutations in RSPH4A results in deficient axonemal assembly of the RS head components RSPH1 and RSPH9. RSPH1 mutant cilia, lacking RSPH1, fail to assemble RSPH9, whereas RSPH9 mutations result in axonemal absence of RSPH9, but do not affect the assembly of the other head proteins, RSPH1 and RSPH4A. Interestingly, our results were identical in individuals carrying loss-of-function mutations, missense variants, or one amino acid deletion. Immunofluorescence analysis can improve diagnosis of PCD in patients with loss-of-function mutations as well as missense variants. RSPH4A is the core protein of the RS head.

Published
2015

21. Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement

Author

Georg F. Hoffmann, Charlotte L. Alston, André Schaller, Richard J. Rodenburg, Holger Prokisch, Yoshihito Kishita, Markus Schuelke, Sascha Sauer, Yasin Memari, Thomas Meitinger, Regina Trollmann, Urania Kotzaeridou, Kei Murayama, Wolfgang Sperl, Thomas Wieland, Stefan Kölker, Saikat Santra, Tobias B. Haack, Hartmut Engels, Gudrun Schottmann, Boriana Büchner, Yasushi Okazaki, Johannes A. Mayr, Masakazu Kohda, Christopher B. Jackson, Yoshimi Tokuzawa, Jean-Marc Nuoffer, Richard Durbin, Beate Albrecht, Peter Freisinger, Robert W. Taylor, Ramona Bolognini, Dagmar Hahn, Tim M. Strom, Dagmar Wieczorek, Oswald Hasselmann, Laura S. Kremer, Kirsten Cremer, Elisabeth Graf, Akira Ohtake, Maaike de Vries, Anja Kolb-Kokocinski, Alexander M. Zink, Thomas Klopstock, and Seila Eggimann

Subjects
medicine.medical_specialty, Encephalopathy, Medizin, 610 Medicine & health, Biology, Compound heterozygosity, Atrophy, Valine, Internal medicine, ECHS1, 540 Chemistry, medicine, ddc:610, Fibroblast, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Research Articles, Catabolism, General Neuroscience, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Metabolism, medicine.disease, 3. Good health, ddc, medicine.anatomical_structure, Endocrinology, Biochemistry, 570 Life sciences, biology, Neurology (clinical), Technology Platforms
Abstract

OBJECTIVE: Short-chain enoyl-CoA hydratase (ECHS1) is a multifunctional mitochondrial matrix enzyme that is involved in the oxidation of fatty acids and essential amino acids such as valine. Here, we describe the broad phenotypic spectrum and pathobiochemistry of individuals with autosomal-recessive ECHS1 deficiency. METHODS: Using exome sequencing, we identified ten unrelated individuals carrying compound heterozygous or homozygous mutations in ECHS1. Functional investigations in patient-derived fibroblast cell lines included immunoblotting, enzyme activity measurement, and a palmitate loading assay. RESULTS: Patients showed a heterogeneous phenotype with disease onset in the first year of life and course ranging from neonatal death to survival into adulthood. The most prominent clinical features were encephalopathy (10/10), deafness (9/9), epilepsy (6/9), optic atrophy (6/10), and cardiomyopathy (4/10). Serum lactate was elevated and brain magnetic resonance imaging showed white matter changes or a Leigh-like pattern resembling disorders of mitochondrial energy metabolism. Analysis of patients' fibroblast cell lines (6/10) provided further evidence for the pathogenicity of the respective mutations by showing reduced ECHS1 protein levels and reduced 2-enoyl-CoA hydratase activity. While serum acylcarnitine profiles were largely normal, invitro palmitate loading of patient fibroblasts revealed increased butyrylcarnitine, unmasking the functional defect in mitochondrial β-oxidation of short-chain fatty acids. Urinary excretion of 2-methyl-2,3-dihydroxybutyrate - a potential derivative of acryloyl-CoA in the valine catabolic pathway - was significantly increased, indicating impaired valine oxidation. INTERPRETATION: In conclusion, we define the phenotypic spectrum of a new syndrome caused by ECHS1 deficiency. We speculate that both the β-oxidation defect and the block in l-valine metabolism, with accumulation of toxic methacrylyl-CoA and acryloyl-CoA, contribute to the disorder that may be amenable to metabolic treatment approaches.

Published
2015

22. A global reference for human genetic variation

Author

Colonna V. (1000 Genomes Project Consortium) Adam Auton, Gonçalo R Abecasis, David M Altshuler, Richard M Durbin, David R Bentley, Aravinda Chakravarti, Andrew G Clark, Peter Donnelly, Evan E Eichler, Paul Flicek, Stacey B Gabriel, Richard A Gibbs, Eric D Green, Matthew E Hurles, Bartha M Knoppers, Jan O Korbel, Eric S Lander, Charles Lee, Hans Lehrach, Elaine R Mardis, Gabor T Marth, Gil A McVean, Deborah A Nickerson, Jeanette P Schmidt, Stephen T Sherry, Jun Wang, Richard K Wilson, Eric Boerwinkle, Harsha Doddapaneni, Yi Han, Viktoriya Korchina, Christie Kovar, Sandra Lee, Donna Muzny, Jeffrey G Reid, Yiming Zhu, Yuqi Chang, Qiang Feng, Xiaodong Fang, Xiaosen Guo, Min Jian, Hui Jiang, Xin Jin, Tianming Lan, Guoqing Li, Jingxiang Li, Yingrui Li, Shengmao Liu, Xiao Liu, Yao Lu, Xuedi Ma, Meifang Tang, Bo Wang, Guangbiao Wang, Honglong Wu, Renhua Wu, Xun Xu, Ye Yin, Dandan Zhang, Wenwei Zhang, Jiao Zhao, Meiru Zhao, Xiaole Zheng, Namrata Gupta, Neda Gharani, Lorraine H Toji, Norman P Gerry, Alissa M Resch, Jonathan Barker, Laura Clarke, Laurent Gil, Sarah E Hunt, Gavin Kelman, Eugene Kulesha, Rasko Leinonen, William M McLaren, Rajesh Radhakrishnan, Asier Roa, Dmitriy Smirnov, Richard E Smith, Ian Streeter, Anja Thormann, Iliana Toneva, Brendan Vaughan, Xiangqun Zheng-Bradley, Russell Grocock, Sean Humphray, Terena James, Zoya Kingsbury, Ralf Sudbrak, Marcus W Albrecht, Vyacheslav S Amstislavskiy, Tatiana A Borodina, Matthias Lienhard, Florian Mertes, Marc Sultan, Bernd Timmermann, Marie-Laure Yaspo, Lucinda Fulton, Robert Fulton, Victor Ananiev, Zinaida Belaia, Dimitriy Beloslyudtsev, Nathan Bouk, Chao Chen, Deanna Church, Robert Cohen, Charles Cook, John Garner, Timothy Hefferon, Mikhail Kimelman, Chunlei Liu, John Lopez, Peter Meric, Chris O'Sullivan, Yuri Ostapchuk, Lon Phan, Sergiy Ponomarov, Valerie Schneider, Eugene Shekhtman, Karl Sirotkin, Douglas Slotta, Hua Zhang, Senduran Balasubramaniam, John Burton, Petr Danecek, Thomas M Keane, Anja Kolb-Kokocinski, Shane McCarthy, James Stalker, Michael Quail, Christopher J Davies, Jeremy Gollub, Teresa Webster, Brant Wong, Yiping Zhan, Adam Auton, Christopher L Campbell, Yu Kong, Anthony Marcketta, Fuli Yu, Lilian Antunes, Matthew Bainbridge, Aniko Sabo, Zhuoyi Huang, Lachlan J M Coin, Lin Fang, Qibin Li, Zhenyu Li, Haoxiang Lin, Binghang Liu, Ruibang Luo, Haojing Shao, Yinlong Xie, Chen Ye, Chang Yu, Fan Zhang, Hancheng Zheng, Hongmei Zhu, Can Alkan, Elif Dal, Fatma Kahveci, Erik P Garrison, Deniz Kural, Wan-Ping Lee, Wen Fung Leong, Michael Stromberg, Alistair N Ward, Jiantao Wu, Mengyao Zhang, Mark J Daly, Mark A DePristo, Robert E Handsaker, Eric Banks, Gaurav Bhatia, Guillermo Del Angel, Giulio Genovese, Heng Li, Seva Kashin, Steven A McCarroll, James C Nemesh, Ryan E Poplin, Seungtai C Yoon, Jayon Lihm, Vladimir Makarov, Srikanth Gottipati, Alon Keinan, Juan L Rodriguez-Flores, Tobias Rausch, Markus H Fritz, Adrian M Stütz, Kathryn Beal, Avik Datta, Javier Herrero, Graham R S Ritchie, Daniel Zerbino, Pardis C Sabeti, Ilya Shlyakhter, Stephen F Schaffner, Joseph Vitti, David N Cooper, Edward V Ball, Peter D Stenson, Bret Barnes, Markus Bauer, R Keira Cheetham, Anthony Cox, Michael Eberle, Scott Kahn, Lisa Murray, John Peden, Richard Shaw, Eimear E Kenny, Mark A Batzer, Miriam K Konkel, Jerilyn A Walker, Daniel G MacArthur, Monkol Lek, Ralf Herwig, Li Ding, Daniel C Koboldt, David Larson, Kai Ye, Simon Gravel, Anand Swaroop, Emily Chew, Tuuli Lappalainen, Yaniv Erlich, Melissa Gymrek, Thomas Frederick Willems, Jared T Simpson, Mark D Shriver, Jeffrey A Rosenfeld, Carlos D Bustamante, Stephen B Montgomery, Francisco M De La Vega, Jake K Byrnes, Andrew W Carroll, Marianne K DeGorter, Phil Lacroute, Brian K Maples, Alicia R Martin, Andres Moreno-Estrada, Suyash S Shringarpure, Fouad Zakharia, Eran Halperin, Yael Baran, Eliza Cerveira, Jaeho Hwang, Ankit Malhotra, Dariusz Plewczynski, Kamen Radew, Mallory Romanovitch, Chengsheng Zhang, Fiona C L Hyland, David W Craig, Alexis Christoforides, Nils Homer, Tyler Izatt, Ahmet A Kurdoglu, Shripad A Sinari, Kevin Squire, Chunlin Xiao, Jonathan Sebat, Danny Antaki, Madhusudan Gujral, Amina Noor, Kenny Ye, Esteban G Burchard, Ryan D Hernandez, Christopher R Gignoux, David Haussler, Sol J Katzman, W James Kent, Bryan Howie, Andres Ruiz-Linares, Emmanouil T Dermitzakis, Scott E Devine, Hyun Min Kang, Jeffrey M Kidd, Tom Blackwell, Sean Caron, Wei Chen, Sarah Emery, Lars Fritsche, Christian Fuchsberger, Goo Jun, Bingshan Li, Robert Lyons, Chris Scheller, Carlo Sidore, Shiya Song, Elzbieta Sliwerska, Daniel Taliun, Adrian Tan, Ryan Welch, Mary Kate Wing, Xiaowei Zhan, Philip Awadalla, Alan Hodgkinson, Yun Li, Xinghua Shi, Andrew Quitadamo, Gerton Lunter, Jonathan L Marchini, Simon Myers, Claire Churchhouse, Olivier Delaneau, Anjali Gupta-Hinch, Warren Kretzschmar, Zamin Iqbal, Iain Mathieson, Androniki Menelaou, Andy Rimmer, Dionysia K Xifara, Taras K Oleksyk, Yunxin Fu, Xiaoming Liu, Momiao Xiong, Lynn Jorde, David Witherspoon, Jinchuan Xing, Brian L Browning, Sharon R Browning, Fereydoun Hormozdiari, Peter H Sudmant, Ekta Khurana, Chris Tyler-Smith, Cornelis A Albers, Qasim Ayub, Yuan Chen, Vincenza Colonna, Luke Jostins, Klaudia Walter, Yali Xue, Mark B Gerstein, Alexej Abyzov, Suganthi Balasubramanian, Jieming Chen, Declan Clarke, Yao Fu, Arif O Harmanci, Mike Jin, Donghoon Lee, Jeremy Liu, Xinmeng Jasmine Mu, Jing Zhang, Yan Zhang, Chris Hartl, Khalid Shakir, Jeremiah Degenhardt, Sascha Meiers, Benjamin Raeder, Francesco Paolo Casale, Oliver Stegle, Eric-Wubbo Lameijer, Ira Hall, Vineet Bafna, Jacob Michaelson, Eugene J Gardner, Ryan E Mills, Gargi Dayama, Ken Chen, Xian Fan, Zechen Chong, Tenghui Chen, Mark J Chaisson, John Huddleston, Maika Malig, Bradley J Nelson, Nicholas F Parrish, Ben Blackburne, Sarah J Lindsay, Zemin Ning, Yujun Zhang, Hugo Lam, Cristina Sisu, Danny Challis, Uday S Evani, James Lu, Uma Nagaswamy, Jin Yu, Wangshen Li, Lukas Habegger, Haiyuan Yu, Fiona Cunningham, Ian Dunham, Kasper Lage, Jakob Berg Jespersen, Heiko Horn, Donghoon Kim, Rob Desalle, Apurva Narechania, Melissa A Wilson Sayres, Fernando L Mendez, G David Poznik, Peter A Underhill, Lachlan Coin, David Mittelman, Ruby Banerjee, Maria Cerezo, Thomas W Fitzgerald, Sandra Louzada, Andrea Massaia, Graham R Ritchie, Fengtang Yang, Divya Kalra, Walker Hale, Xu Dan, Kathleen C Barnes, Christine Beiswanger, Hongyu Cai, Hongzhi Cao, Brenna Henn, Danielle Jones, Jane S Kaye, Alastair Kent, Angeliki Kerasidou, Rasika Mathias, Pilar N Ossorio, Michael Parker, Charles N Rotimi, Charmaine D Royal, Karla Sandoval, Yeyang Su, Zhongming Tian, Sarah Tishkoff, Marc Via, Yuhong Wang, Huanming Yang, Ling Yang, Jiayong Zhu, Walter Bodmer, Gabriel Bedoya, Zhiming Cai, Yang Gao, Jiayou Chu, Leena Peltonen, Andres Garcia-Montero, Alberto Orfao, Julie Dutil, Juan C Martinez-Cruzado, Rasika A Mathias, Anselm Hennis, Harold Watson, Colin McKenzie, Firdausi Qadri, Regina LaRocque, Xiaoyan Deng, Danny Asogun, Onikepe Folarin, Christian Happi, Omonwunmi Omoniwa, Matt Stremlau, Ridhi Tariyal, Muminatou Jallow, Fatoumatta Sisay Joof, Tumani Corrah, Kirk Rockett, Dominic Kwiatkowski, Jaspal Kooner, Trân T?nh Hiên, Sarah J Dunstan, Nguyen Thuy Hang, Richard Fonnie, Robert Garry, Lansana Kanneh, Lina Moses, John Schieffelin, Donald S Grant, Carla Gallo, Giovanni Poletti, Danish Saleheen, Asif Rasheed, Lisa D Brooks, Adam L Felsenfeld, Jean E McEwen, Yekaterina Vaydylevich, Audrey Duncanson, Michael Dunn, Jeffery A Schloss, 1000 Genomes Project Consortium, Institute for Medical Engineering and Science, Broad Institute of MIT and Harvard, Lincoln Laboratory, Massachusetts Institute of Technology. Department of Biology, Gabriel, Stacey, Lander, Eric Steven, Daly, Mark J, Banks, Eric, Bhatia, Gaurav, Kashin, Seva, McCarroll, Steven A, Nemesh, James, Poplin, Ryan E., Sabeti, Pardis, Shlyakhter, Ilya, Schaffner, Stephen F, Vitti, Joseph, Gymrek, Melissa A, Hartler, Christina M., and Tariyal, Ridhi

Subjects
demography, genetic association, genotype, Human genomics, Genome-wide association study, Review, SUSCEPTIBILITY, DISEASE, polymorphism, 0302 clinical medicine, quantitative trait locus, INDEL Mutation, genetics, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), MUTATION, Exome sequencing, 0303 health sciences, public health, Sequence analysis, High-Throughput Nucleotide Sequencing, standard, Genomics, Reference Standards, Physical Chromosome Mapping, 3. Good health, priority journal, Science & Technology - Other Topics, BAYES FACTORS, Molecular Developmental Biology, Genotype, Genetics, Medical, Quantitative Trait Loci, DNA sequence, rare disease, human genetics, information processing, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, POPULATION HISTORY, human genome, Humans, retroposon, Genetic variability, human, GENOME-WIDE ASSOCIATION, 1000 Genomes Project, Demography, Science & Technology, ancestry, disease predisposition, Genetic Variation, MACULAR DEGENERATION, major clinical study, gene linkage disequilibrium, purl.org/pe-repo/ocde/ford#3.01.02 [https], Genetics, Population, 030217 neurology & neurosurgery, haplotype, Internationality, VARIANT, Datasets as Topic, Human genetic variation, COMPLEMENT FACTOR-H, single nucleotide polymorphism, genetic variability, Exome, chromosome map, Genetics, Variant Call Format, Genome, Multidisciplinary, 1000 Genomes Project Consortium, international cooperation, Multidisciplinary Sciences, standards, Disease Susceptibility, medical genetics, General Science & Technology, Population, Computational biology, Biology, gene frequency, Polymorphism, Single Nucleotide, high throughput sequencing, Rare Diseases, promoter region, MD Multidisciplinary, Genetic variation, QH426, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genome, Human, population genetics, population structure, Sequence Analysis, DNA, gene structure, INDIVIDUALS, Haplotypes, Genome-Wide Association Study, purl.org/pe-repo/ocde/ford#1.06.07 [https]
Abstract

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies., Wellcome Trust (London, England) (Core Award 090532/Z/09/Z), Wellcome Trust (London, England) (Senior Investigator Award 095552/Z/11/Z ), Wellcome Trust (London, England) (WT095908), Wellcome Trust (London, England) (WT109497), Wellcome Trust (London, England) (WT098051), Wellcome Trust (London, England) (WT086084/Z/08/Z), Wellcome Trust (London, England) (WT100956/Z/13/Z ), Wellcome Trust (London, England) (WT097307), Wellcome Trust (London, England) (WT0855322/Z/08/Z ), Wellcome Trust (London, England) (WT090770/Z/09/Z ), Wellcome Trust (London, England) (Major Overseas program in Vietnam grant 089276/Z.09/Z), Medical Research Council (Great Britain) (grant G0801823), Biotechnology and Biological Sciences Research Council (Great Britain) (grant BB/I02593X/1), Biotechnology and Biological Sciences Research Council (Great Britain) (grant BB/I021213/1), Zhongguo ke xue ji shu qing bao yan jiu suo. Office of 863 Programme of China (2012AA02A201), National Basic Research Program of China (2011CB809201), National Basic Research Program of China (2011CB809202), National Basic Research Program of China (2011CB809203), National Natural Science Foundation of China (31161130357), Shenzhen Municipal Government of China (grant ZYC201105170397A), Canadian Institutes of Health Research (grant 136855), Quebec Ministry of Economic Development, Innovation, and Exports (PSR-SIIRI-195), Germany. Bundesministerium für Bildung und Forschung (0315428A), Germany. Bundesministerium für Bildung und Forschung (01GS08201), Germany. Bundesministerium für Bildung und Forschung (BMBF-EPITREAT grant 0316190A), Deutsche Forschungsgemeinschaft (Emmy Noether Grant KO4037/1-1), Beatriu de Pinos Program (2006 BP-A 10144), Beatriu de Pinos Program (2009 BP-B 00274), Spanish National Institute for Health (grant PRB2 IPT13/0001-ISCIII-SGEFI/FEDER), Japan Society for the Promotion of Science (fellowship number PE13075), Marie Curie Actions Career Integration (grant 303772), Fonds National Suisse del la Recherche, SNSF, Scientifique (31003A_130342), National Center for Biotechnology Information (U.S.) (U54HG3067), National Center for Biotechnology Information (U.S.) (U54HG3273), National Center for Biotechnology Information (U.S.) (U01HG5211), National Center for Biotechnology Information (U.S.) (U54HG3079), National Center for Biotechnology Information (U.S.) (R01HG2898), National Center for Biotechnology Information (U.S.) (R01HG2385), National Center for Biotechnology Information (U.S.) (RC2HG5552), National Center for Biotechnology Information (U.S.) (U01HG6513), National Center for Biotechnology Information (U.S.) (U01HG5214), National Center for Biotechnology Information (U.S.) (U01HG5715), National Center for Biotechnology Information (U.S.) (U01HG5718), National Center for Biotechnology Information (U.S.) (U01HG5728), National Center for Biotechnology Information (U.S.) (U41HG7635), National Center for Biotechnology Information (U.S.) (U41HG7497), National Center for Biotechnology Information (U.S.) (R01HG4960), National Center for Biotechnology Information (U.S.) (R01HG5701), National Center for Biotechnology Information (U.S.) (R01HG5214), National Center for Biotechnology Information (U.S.) (R01HG6855), National Center for Biotechnology Information (U.S.) (R01HG7068), National Center for Biotechnology Information (U.S.) (R01HG7644), National Center for Biotechnology Information (U.S.) (DP2OD6514), National Center for Biotechnology Information (U.S.) (DP5OD9154), National Center for Biotechnology Information (U.S.) (R01CA166661), National Center for Biotechnology Information (U.S.) (R01CA172652), National Center for Biotechnology Information (U.S.) (P01GM99568), National Center for Biotechnology Information (U.S.) (R01GM59290), National Center for Biotechnology Information (U.S.) (R01GM104390), National Center for Biotechnology Information (U.S.) (T32GM7790), National Center for Biotechnology Information (U.S.) (R01HL87699), National Center for Biotechnology Information (U.S.) (R01HL104608), National Center for Biotechnology Information (U.S.) (T32HL94284), National Center for Biotechnology Information (U.S.) (HHSN268201100040C), National Center for Biotechnology Information (U.S.) (HHSN272201000025C), Lundbeck Foundation (grant R170-2014-1039, Simons Foundation (SFARI award SF51), National Science Foundation (U.S.) (Research Fellowship DGE-1147470)

Published
2015

23. Mutations in the ribosomal protein gene RPL10 suggest a novel modulating disease mechanism for autism

Author

Sabine M. Klauck, R Wellenreuther, Anja Kolb-Kokocinski, Andreas G. Chiocchetti, Fritz Poustka, I Schupp, C Schuster, Annemarie Poustka, Lore Breitenbach-Koller, B Felder, and Gabriele Schmötzer

Subjects
Male, Ribosomal Proteins, Ribosomal Protein L10, Models, Neurological, Mutation, Missense, In situ hybridization, Biology, Hippocampus, Mice, Cellular and Molecular Neuroscience, Limbic system, Ribosomal protein, mental disorders, medicine, Animals, Humans, Missense mutation, Autistic Disorder, Molecular Biology, Gene, Genetics, Chromosomes, Human, X, Translation (biology), medicine.disease, Pedigree, Xq28, Psychiatry and Mental health, medicine.anatomical_structure, Amino Acid Substitution, Protein Biosynthesis, Mental Retardation, X-Linked, Autism, Female
Abstract

Autism has a strong genetic background with a higher frequency of affected males suggesting involvement of X-linked genes and possibly also other factors causing the unbalanced sex ratio in the etiology of the disorder. We have identified two missense mutations in the ribosomal protein gene RPL10 located in Xq28 in two independent families with autism. We have obtained evidence that the amino-acid substitutions L206M and H213Q at the C-terminal end of RPL10 confer hypomorphism with respect to the regulation of the translation process while keeping the basic translation functions intact. This suggests the contribution of a novel, possibly modulating aberrant cellular function operative in autism. Previously, we detected high expression of RPL10 by RNA in situ hybridization in mouse hippocampus, a constituent of the brain limbic system known to be afflicted in autism. Based on these findings, we present a model for autistic disorder where a change in translational function is suggested to impact on those cognitive functions that are mediated through the limbic system.

Published
2006

24. Erratum: Corrigendum: Common genetic variation drives molecular heterogeneity in human iPSCs

Author

Peter W. Harrison, Ludovic Vallier, Oliver Stegle, Christopher M. Kirton, Dalila Bensaddek, Davis J. McCarthy, Sendu Bala, Rachel Nelson, Davide Danovi, Willem H. Ouwehand, Nathalie Moens, Minal Patel, Philip L. Beales, Ruta Meleckyte, Alice L. Mann, Sofie Ashford, Reena Halai, Yasin Memari, Alex Alderton, Sharad R. Patel, Laura Clarke, Oliver J. Culley, Petr Danecek, Adam Faulconbridge, Sarah Harper, Daniel J. Gaffney, Helena Kilpinen, Angus I. Lamond, Angela Goncalves, Ian Streeter, Shane A. McCarthy, Andreas Leha, Richard Durbin, Vackar Afzal, Annie Kathuria, Francesco Paolo Casale, Anja Kolb-Kokocinski, Fiona M. Watt, Ewan Birney, Filipa A.C. Soares, A. White, Chukwuma A. Agu, and Kaur Alasoo

Subjects
0301 basic medicine, Genetics, 03 medical and health sciences, 030104 developmental biology, Multidisciplinary, Published Erratum, Biology, Molecular heterogeneity, Sentence, Genealogy
Abstract

Nature 546, 370–375 (2017); doi:10.1038/nature22403 In this Article, the authors Fiona M. Watt and Richard Durbin should also have been included as ‘jointly supervising’ authors, and authors Oliver Stegle and Daniel J. Gaffney should also have been noted as ‘equally contributing’ authors. In addition, the Author Contributions section should have included the sentence: ‘H.K. and A.G. contributed equally to this work; O.S. and D.J.G. contributed equally to this work’, as further clarification. The original Article has been corrected online.

Published
2017

25. Endoglin expression in blood and endothelium is differentially regulated by modular assembly of the Ets/Gata hemangioblast code

Author

Josette Renée Landry, Jonathan Frampton, Berthold Göttgens, Kathy Knezevic, Aileen M. Smith, Anja Kolb-Kokocinski, Georges Lacaud, George A. Follows, Mary E. Janes, David Tannahill, John E. Pimanda, Katrin Ottersbach, Wan Y I Chan, Sarah Kinston, Nicola K. Wilson, and Valerie Kouskoff

Subjects
Hemangioblasts, Hematopoietic System, Immunology, Embryonic Development, Mice, Transgenic, Receptors, Cell Surface, Biology, Biochemistry, GATA Transcription Factors, Article, Proto-Oncogene Protein c-ets-1, Mice, Antigens, CD, Animals, Humans, Endothelium, Enhancer, Transcription factor, Cells, Cultured, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, GATA2, Endoglin, Gene Expression Regulation, Developmental, Cell Differentiation, Cell Biology, Hematology, Embryo, Mammalian, Molecular biology, Upstream Enhancer, Chromatin, Blood, Hemangioblast, GATA transcription factor, Chromatin immunoprecipitation
Abstract

Endoglin is an accessory receptor for TGF-β signaling and is required for normal hemangioblast, early hematopoietic, and vascular development. We have previously shown that an upstream enhancer, Eng −8, together with the promoter region, mediates robust endothelial expression yet is inactive in blood. To identify hematopoietic regulatory elements, we used array-based methods to determine chromatin accessibility across the entire locus. Subsequent transgenic analysis of candidate elements showed that an endothelial enhancer at Eng +9 when combined with an element at Eng +7 functions as a strong hemato-endothelial enhancer. Chromatin immunoprecipitation (ChIP)–chip analysis demonstrated specific binding of Ets factors to the promoter as well as to the −8, +7+9 enhancers in both blood and endothelial cells. By contrast Pu.1, an Ets factor specific to the blood lineage, and Gata2 binding was only detected in blood. Gata2 was bound only at +7 and GATA motifs were required for hematopoietic activity. This modular assembly of regulators gives blood and endothelial cells the regulatory freedom to independently fine-tune gene expression and emphasizes the role of regulatory divergence in driving functional divergence.

Published
2008

26. Gata2, Fli1, and Scl form a recursively wired gene-regulatory circuit during early hematopoietic development

Author

Anja Kolb-Kokocinski, Georges Lacaud, Kathy Knezevic, Sarah Kinston, John E. Pimanda, Anthony R. Green, Andrew D. Wood, Wan Y I Chan, Josette Renée Landry, Berthold Göttgens, Katrin Ottersbach, David Tannahill, Nicola K. Wilson, and Valerie Kouskoff

Subjects
Proto-Oncogene Protein c-fli-1, Biology, Mice, Proto-Oncogene Proteins, medicine, Basic Helix-Loop-Helix Transcription Factors, Animals, Enhancer, T-Cell Acute Lymphocytic Leukemia Protein 1, Genetics, Regulation of gene expression, Multidisciplinary, Binding Sites, GATA2, fungi, Hematopoietic stem cell, Biological Sciences, Embryo, Mammalian, Hematopoietic Stem Cells, Embryonic stem cell, Cell biology, Hematopoiesis, GATA2 Transcription Factor, medicine.anatomical_structure, Enhancer Elements, Genetic, Gene Expression Regulation, Hemangioblast, Blood Vessels, Stem cell
Abstract

Conservation of the vertebrate body plan has been attributed to the evolutionary stability of gene-regulatory networks (GRNs). We describe a regulatory circuit made up of Gata2, Fli1, and Scl/Tal1 and their enhancers, Gata2-3 , Fli1 +12, and Scl +19, that operates during specification of hematopoiesis in the mouse embryo. We show that the Fli1 +12 enhancer, like the Gata2-3 and Scl +19 enhancers, targets hematopoietic stem cells (HSCs) and relies on a combination of Ets, Gata, and E-Box motifs. We show that the Gata2-3 enhancer also uses a similar cluster of motifs and that Gata2, Fli1, and Scl are expressed in embryonic day-11.5 dorsal aorta where HSCs originate and in fetal liver where they multiply. The three HSC enhancers in these tissues and in ES cell-derived hemangioblast equivalents are bound by each of these transcription factors (TFs) and form a fully connected triad that constitutes a previously undescribed example of both this network motif in mammalian development and a GRN kernel operating during the specification of a mammalian stem cell.

Published
2007

27. Application of phage display to high throughput antibody generation and characterization

Author

Veronica Clementel, Gillian Flack, Wendy E. Wilson, S. Paul Shadbolt, Jenny Buckell, Kay Clarke, Susan D.J. Chapple, Jennie S. Conquer, Darren Schofield, Anthony Warford, Anthony Richard Pope, William J. Howat, Karen Vincent, Cecile D. Martin, Joanne N. Mitchell, Sandra R.E. Crowther, Yvette Hooks, John McCafferty, Gareth J. Griffin, Susan Kunze, Joyce L. Young, Anja Kolb-Kokocinski, Michael R. Dyson, Maureen O'Sullivan, Jane Xie, Gareth Maslen, Wendy Roake, Rajika L. Perera, Anna M. Crofts, and Apollo - University of Cambridge Repository

Subjects
Phage display, Sequence analysis, medicine.drug_class, Method, Enzyme-Linked Immunosorbent Assay, Monoclonal antibody, law.invention, Flow cytometry, 03 medical and health sciences, Mice, 0302 clinical medicine, Antigen, law, Antibody Specificity, medicine, Animals, Humans, Bacteriophages, In Situ Hybridization, 030304 developmental biology, DNA Primers, 0303 health sciences, biology, medicine.diagnostic_test, Base Sequence, Gene Expression Profiling, Flow Cytometry, Molecular biology, Immunohistochemistry, Recombinant Proteins, 3. Good health, 030220 oncology & carcinogenesis, Antibody Formation, biology.protein, Recombinant DNA, Antibody
Abstract

A phage display library has been constructed containing over 1010 human antibodies, allowing the large-scale generation of antibodies. Over 38,000 recombinant antibodies against 292 antigens were selected, screened and sequenced, and 4,400 resultant unique clones characterized further., We have created a high quality phage display library containing over 1010 human antibodies and describe its use in the generation of antibodies on an unprecedented scale. We have selected, screened and sequenced over 38,000 recombinant antibodies to 292 antigens, yielding over 7,200 unique clones. 4,400 antibodies were characterized by specificity testing and detailed sequence analysis and the data/clones are available online. Sensitive detection was demonstrated in a bead based flow cytometry assay. Furthermore, positive staining by immunohistochemistry on tissue microarrays was found for 37% (143/381) of antibodies. Thus, we have demonstrated the potential of and illuminated the issues associated with genome-wide monoclonal antibody generation.

Published
2007

28. The systematic functional characterisation of Xq28 genes prioritises candidate disease genes

Author

Stephanie Bechtel, Annemarie Poustka, Petra Kioschis, Alexander Mehrle, Jeremy C. Simpson, Anja Kolb-Kokocinski, Stefan Wiemann, and Ruth Wellenreuther

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, X Chromosome, lcsh:QH426-470, lcsh:Biotechnology, Gene Expression, Biology, Proteomics, 03 medical and health sciences, Mice, 0302 clinical medicine, Gene density, Intellectual Disability, lcsh:TP248.13-248.65, Gene expression, Databases, Genetic, Genetics, Animals, Humans, Genetic Predisposition to Disease, Gene, In Situ Hybridization, 030304 developmental biology, 0303 health sciences, Chromosomes, Human, X, Internet, Proteins, Disease gene identification, nervous system diseases, lcsh:Genetics, RNA, Human genome, Identification (biology), DNA microarray, 030217 neurology & neurosurgery, Biotechnology, Research Article
Abstract

Background Well known for its gene density and the large number of mapped diseases, the human sub-chromosomal region Xq28 has long been a focus of genome research. Over 40 of approximately 300 X-linked diseases map to this region, and systematic mapping, transcript identification, and mutation analysis has led to the identification of causative genes for 26 of these diseases, leaving another 17 diseases mapped to Xq28, where the causative gene is still unknown. To expedite disease gene identification, we have initiated the functional characterisation of all known Xq28 genes. Results By using a systematic approach, we describe the Xq28 genes by RNA in situ hybridisation and Northern blotting of the mouse orthologs, as well as subcellular localisation and data mining of the human genes. We have developed a relational web-accessible database with comprehensive query options integrating all experimental data. Using this database, we matched gene expression patterns with affected tissues for 16 of the 17 remaining Xq28 linked diseases, where the causative gene is unknown. Conclusion By using this systematic approach, we have prioritised genes in linkage regions of Xq28-mapped diseases to an amenable number for mutational screens. Our database can be queried by any researcher performing highly specified searches including diseases not listed in OMIM or diseases that might be linked to Xq28 in the future.

Published
2006

29. Alternative pre-mRNA processing regulates cell-type specific expression of the IL4l1 and NUP62 genes

Author

Anja Kolb-Kokocinski, Annemarie Poustka, and Stefan Wiemann

Subjects
Physiology, Plant Science, Biology, L-Amino Acid Oxidase, Genome, General Biochemistry, Genetics and Molecular Biology, Exon, Mice, Structural Biology, RNA Precursors, Animals, Humans, Gene, lcsh:QH301-705.5, Ecology, Evolution, Behavior and Systematics, Comparative genomics, Genetics, Regulation of gene expression, Flavoproteins, Retroposon, Alternative splicing, Cell Biology, Cell biology, Nuclear Pore Complex Proteins, Alternative Splicing, Gene Expression Regulation, lcsh:Biology (General), RNA splicing, General Agricultural and Biological Sciences, Developmental Biology, Biotechnology, Research Article
Abstract

Background Given the complexity of higher organisms, the number of genes encoded by their genomes is surprisingly small. Tissue specific regulation of expression and splicing are major factors enhancing the number of the encoded products. Commonly these mechanisms are intragenic and affect only one gene. Results Here we provide evidence that the IL4I1 gene is specifically transcribed from the apparent promoter of the upstream NUP62 gene, and that the first two exons of NUP62 are also contained in the novel IL4I1_2 variant. While expression of IL4I1 driven from its previously described promoter is found mostly in B cells, the expression driven by the NUP62 promoter is restricted to cells in testis (Sertoli cells) and in the brain (e.g., Purkinje cells). Since NUP62 is itself ubiquitously expressed, the IL4I1_2 variant likely derives from cell type specific alternative pre-mRNA processing. Conclusion Comparative genomics suggest that the promoter upstream of the NUP62 gene originally belonged to the IL4I1 gene and was later acquired by NUP62 via insertion of a retroposon. Since both genes are apparently essential, the promoter had to serve two genes afterwards. Expression of the IL4I1 gene from the "NUP62" promoter and the tissue specific involvement of the pre-mRNA processing machinery to regulate expression of two unrelated proteins indicate a novel mechanism of gene regulation.

Published
2005

30. Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Author

Huang, J, Howie, B, Mccarthy, S, Memari, Y, Walter, K, Min, Jl, Danecek, P, Malerba, Giovanni, Trabetti, Elisabetta, Zheng, Hf, Gambaro, G, Richards, Jb, Durbin, R, Timpson, Nj, Marchini, J, Soranzo, N, Al Turki, S, Amuzu, A, Anderson, Ca, Anney, R, Antony, D, Artigas, Ms, Ayub, M, Bala, S, Barrett, Jc, Barroso, I, Beales, P, Benn, M, Bentham, J, Bhattacharya, S, Birney, E, Blackwood, D, Bobrow, M, Bochukova, E, Bolton, Pf, Bounds, R, Boustred, C, Breen, G, Calissano, M, Carss, K, Casas, Jp, Chambers, Jc, Charlton, R, Chatterjee, K, Chen, L, Ciampi, A, Cirak, S, Clapham, P, Clement, G, Coates, G, Cocca, M, Collier, Da, Cosgrove, C, Cox, T, Craddock, N, Crooks, L, Curran, S, Curtis, D, Daly, A, Day, In, Day Williams, A, Dedoussis, G, Down, T, Du, Y, van Duijn, Cm, Dunham, I, Edkins, S, Ekong, R, Ellis, P, Evans, Dm, Farooqi, Is, Fitzpatrick, Dr, Flicek, P, Floyd, J, Foley, Ar, Franklin, Cs, Futema, M, Gallagher, L, Gasparini, P, Gaunt, Tr, Geihs, M, Geschwind, D, Greenwood, C, Griffin, H, Grozeva, D, Guo, X, Gurling, H, Hart, D, Hendricks, Ae, Holmans, P, Huang, L, Hubbard, T, Humphries, Se, Hurles, Me, Hysi, P, Iotchkova, V, Isaacs, A, Jackson, Dk, Jamshidi, Y, Johnson, J, Joyce, C, Karczewski, Kj, Kaye, J, Keane, T, Kemp, Jp, Kennedy, K, Kent, A, Keogh, J, Khawaja, F, Kleber, Me, van Kogelenberg, M, Kolb Kokocinski, A, Kooner, Js, Lachance, G, Langenberg, C, Langford, C, Lawson, D, Lee, I, van Leeuwen, Em, Lek, M, Li, R, Li, Y, Liang, J, Lin, H, Liu, R, Lönnqvist, J, Lopes, Lr, Lopes, M, Luan, J, Macarthur, Dg, Mangino, M, Marenne, G, März, W, Maslen, J, Matchan, A, Mathieson, I, Mcguffin, P, Mcintosh, Am, Mckechanie, Ag, Mcquillin, A, Metrustry, S, Migone, N, Mitchison, Hm, Moayyeri, A, Morris, J, Morris, R, Muddyman, D, Muntoni, F, Nordestgaard, Bg, Northstone, K, O'Donovan, Mc, O'Rahilly, S, Onoufriadis, A, Oualkacha, K, Owen, Mj, Palotie, A, Panoutsopoulou, K, Parker, V, Parr, Jr, Paternoster, L, Paunio, T, Payne, F, Payne, Sj, Perry, Jr, Pietilainen, O, Plagnol, V, Pollitt, Rc, Povey, S, Quail, Ma, Quaye, L, Raymond, L, Rehnström, K, Ridout, Ck, Ring, S, Ritchie, Gr, Roberts, N, Robinson, Rl, Savage, Db, Scambler, P, Schiffels, S, Schmidts, M, Schoenmakers, N, Scott, Rh, Scott, Ra, Semple, Rk, Serra, E, Sharp, Si, Shaw, A, Shihab, Ha, Shin, Sy, Skuse, D, Small, Ks, Smee, C, Smith, Gd, Southam, L, Spasic Boskovic, O, Spector, Td, St Clair, D, St Pourcain, B, Stalker, J, Stevens, E, Sun, J, Surdulescu, G, Suvisaari, J, Syrris, P, Tachmazidou, I, Taylor, R, Tian, J, Tobin, Md, Toniolo, D, Traglia, M, Tybjaerg Hansen, A, Valdes, Am, Vandersteen, Am, Varbo, A, Vijayarangakannan, P, Visscher, Pm, Wain, Lv, Walters, Jt, Wang, G, Wang, J, Wang, Y, Ward, K, Wheeler, E, Whincup, P, Whyte, T, Williams, Hj, Williamson, Ka, Wilson, C, Wilson, Sg, Wong, K, Xu, C, Yang, J, Zaza, Gianluigi, Zeggini, E, Zhang, F, Zhang, P, Zhang, W., Clinicum, Department of Psychiatry, Jie, Huang, Bryan, Howie, Shane, Mccarthy, Yasin, Memari, Klaudia, Walter, Josine L., Min, Petr, Danecek, Giovanni, Malerba, Elisabetta, Trabetti, Hou Feng, Zheng, Saeed Al, Turki, Antoinette, Amuzu, Carl A., Anderson, Richard, Anney, Dinu, Antony, María Soler, Artiga, Muhammad, Ayub, Senduran, Bala, Jeffrey C., Barrett, Inês, Barroso, Phil, Beale, Marianne, Benn, Jamie, Bentham, Shoumo, Bhattacharya, Ewan, Birney, Douglas, Blackwood, Martin, Bobrow, Elena, Bochukova, Patrick F., Bolton, Rebecca, Bound, Chris, Boustred, Gerome, Breen, Mattia, Calissano, Keren, Car, Juan Pablo, Casa, John C., Chamber, Ruth, Charlton, Krishna, Chatterjee, Lu, Chen, Antonio, Ciampi, Sebahattin, Cirak, Peter, Clapham, Gail, Clement, Guy, Coate, Cocca, Massimiliano, David A., Collier, Catherine, Cosgrove, Tony, Cox, Nick, Craddock, Lucy, Crook, Sarah, Curran, David, Curti, Allan, Daly, Ian N. M., Day, Aaron Day, William, George, Dedoussi, Thomas, Down, Yuanping, Du, Cornelia M., van Duijn, Ian, Dunham, Sarah, Edkin, Rosemary, Ekong, Peter, Elli, David M., Evan, I., Sadaf Farooqi, David R., Fitzpatrick, Paul, Flicek, James, Floyd, A., Reghan Foley, Christopher S., Franklin, Marta, Futema, Louise, Gallagher, Gasparini, Paolo, Tom R., Gaunt, Matthias, Geih, Daniel, Geschwind, Celia, Greenwood, Heather, Griffin, Detelina, Grozeva, Xiaosen, Guo, Xueqin, Guo, Hugh, Gurling, Deborah, Hart, Audrey E., Hendrick, Peter, Holman, Liren, Huang, Tim, Hubbard, Steve E., Humphrie, Matthew E., Hurle, Pirro, Hysi, Valentina, Iotchkova, Aaron, Isaac, David K., Jackson, Yalda, Jamshidi, Jon, Johnson, Chris, Joyce, Konrad J., Karczewski, Jane, Kaye, Thomas, Keane, John P., Kemp, Karen, Kennedy, Alastair, Kent, Julia, Keogh, Farrah, Khawaja, Marcus E., Kleber, Margriet van, Kogelenberg, Anja Kolb, Kokocinski, Jaspal S., Kooner, Genevieve, Lachance, Claudia, Langenberg, Cordelia, Langford, Daniel, Lawson, Irene, Lee, Elisabeth M., van Leeuwen, Monkol, Lek, Rui, Li, Yingrui, Li, Jieqin, Liang, Hong, Lin, Ryan, Liu, Jouko, Lönnqvist, Luis R., Lope, Margarida, Lope, Jian'An, Luan, Daniel G., Macarthur, Massimo, Mangino, Gaëlle, Marenne, Winfried, März, John, Maslen, Angela, Matchan, Iain, Mathieson, Peter, Mcguffin, Andrew M., Mcintosh, Andrew G., Mckechanie, Andrew, Mcquillin, Sarah, Metrustry, Nicola, Migone, Hannah M., Mitchison, Alireza, Moayyeri, James, Morri, Richard, Morri, Dawn, Muddyman, Francesco, Muntoni, Børge G., Nordestgaard, Kate, Northstone, Michael C., O'Donovan, Stephen, O'Rahilly, Alexandros, Onoufriadi, Karim, Oualkacha, Michael J., Owen, Aarno, Palotie, Kalliope, Panoutsopoulou, Victoria, Parker, Jeremy R., Parr, Lavinia, Paternoster, Tiina, Paunio, Felicity, Payne, Stewart J., Payne, John R. B., Perry, Olli, Pietilainen, Vincent, Plagnol, Rebecca C., Pollitt, Sue, Povey, Michael A., Quail, Lydia, Quaye, Lucy, Raymond, Karola, Rehnström, Cheryl K., Ridout, Susan, Ring, Graham R. S., Ritchie, Nicola, Robert, Rachel L., Robinson, David B., Savage, Peter, Scambler, Stephan, Schiffel, Miriam, Schmidt, Nadia, Schoenmaker, Richard H., Scott, Robert A., Scott, Robert K., Semple, Eva, Serra, Sally I., Sharp, Adam, Shaw, Hashem A., Shihab, So Youn, Shin, David, Skuse, Kerrin S., Small, Carol, Smee, George Davey, Smith, Lorraine, Southam, Olivera Spasic, Boskovic, Timothy D., Spector, David St, Clair, Beate St, Pourcain, Jim, Stalker, Elizabeth, Steven, Jianping, Sun, Gabriela, Surdulescu, Jaana, Suvisaari, Petros, Syrri, Ioanna, Tachmazidou, Rohan, Taylor, Jing, Tian, Martin D., Tobin, Daniela, Toniolo, Michela, Traglia, Anne Tybjaerg, Hansen, Ana M., Valde, Anthony M., Vandersteen, Anette, Varbo, Parthiban, Vijayarangakannan, Peter M., Visscher, Louise V., Wain, James T. R., Walter, Guangbiao, Wang, Jun, Wang, Yu, Wang, Kirsten, Ward, Eleanor, Wheeler, Peter, Whincup, Tamieka, Whyte, Hywel J., William, Kathleen A., Williamson, Crispian, Wilson, Scott G., Wilson, Kim, Wong, Changjiang, Xu, Jian, Yang, Gianluigi, Zaza, Eleftheria, Zeggini, Feng, Zhang, Pingbo, Zhang, Weihua, Zhang, Giovanni, Gambaro, J., Brent Richard, Richard, Durbin, Nicholas J., Timpson, Jonathan, Marchini, and Nicole, Soranzo

Subjects
Computer science, General Physics and Astronomy, Genome-wide association study, 0302 clinical medicine, Gene Frequency, Haplotype, Genetics,Biological sciences, Settore MED/14 - NEFROLOGIA, Aged, 80 and over, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, TWINSUK, Middle Aged, single-nucleotide polymorphism, Whole-genome sequencing, WGS imputation panel, single-nucleotide polymorphism, Biological sciences, Italy, MAP, Adult, Adolescent, Genotype, WGS imputation panel, Population, Single-nucleotide polymorphism, FORMAT, Computational biology, GENOTYPE IMPUTATION, Polymorphism, Single Nucleotide, Article, White People, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, Humans, GENOME-WIDE ASSOCIATION, 1000 Genomes Project, education, Allele frequency, Alleles, Aged, 030304 developmental biology, Whole-genome sequencing, Models, Statistical, Models, Genetic, Genome, Human, Genetic Variation, General Chemistry, United Kingdom, Minor allele frequency, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Haplotypes, 3111 Biomedicine, 030217 neurology & neurosurgery, Imputation (genetics)
Abstract

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants., Imputation uses genotype information from SNP arrays to infer the genotypes of missing markers. Here, the authors show that an imputation reference panel derived from whole-genome sequencing of 3,781 samples from the UK10K project improves the imputation accuracy and coverage of low frequency variants compared to existing methods.

Published
2015

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