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2. Preclinical evaluation of the preservation of red blood cell concentrates by hypoxic storage technology for transfusion in sickle cell disease

Author

Laura Bencheikh, Kim-Anh Nguyen, Philippe Chadebech, Laurent Kiger, Gwellaouen Bodivit, Alicia Jouard, Sadaf Pakdaman, Sandia Adypagavane, Etienne Audureau, Khouloud Tebbakha, Thibaut Bocquet, Blandine Mignen, Nicolas Hebert, Marion Seguin, France Pirenne, Samuel Sowemimo-Coker, Andrew Dunham, and Pablo Bartolucci

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2022
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3. Oxygen in Red Blood Cell Concentrates: Influence of Donors’ Characteristics and Blood Processing

Author

Manon Bardyn, Agathe Martin, Nora Dögnitz, Mélanie Abonnenc, Andrew Dunham, Tatsuro Yoshida, and Michel Prudent

Subjects
oxygen saturation (sO2), resonance Raman (RR) spectroscopy, red blood cell, red blood cell concentrate, donor variation, donors’ characteristics, Physiology, QP1-981
Abstract

Objective: Unexpectedly wide distribution (90%) of hemoglobin oxygen saturation (sO2) within red cell concentrates (RCCs) has recently been observed. Causes of such variability are not yet completely explained whereas the roles of oxygen and oxidative lesions during the storage of RCCs are known. The objectives of the present study are to characterize sO2 distribution in RCCs produced in a Swiss blood center and to investigate the influence of processing and donors’ characteristics.Methods: The level of sO2 was measured in 1701 leukocyte-depleted RCCs derived from whole blood donations in both top–bottom (TB; component filtered, SAGM) and top–top (TT; whole blood filtration, PAGGSM) RCCs. The sO2 value was measured non-invasively through the PVC bag prior to storage by resonance Raman spectroscopy. Gender, age, blood type, hemoglobin level, and living altitude of donors, as well as process method and time-to-process were recorded.Results: Overall, the sO2 exhibited a wide non-Gaussian distribution with a mean of 51.2 ± 18.5%. Use of top-top kits resulted in a 16% higher sO2 (P < 0.0001) than with top-bottom ones. Waiting time before processing only had a modest impact, but the blood processing itself reduced the sO2 by almost 12% (P < 0.0001). sO2 was also significantly affected by some donors’ characteristics. RCCs from men exhibited 25% higher sO2 (P < 0.0001) than those donated by women. Multivariate analysis revealed that the apparent correlation observed with hemoglobin level and age was actually due to multicollinearity with the sex variable. Finally, we noticed no significant differences across blood type but found that altitude of residence was associated with the sO2 (i.e., higher in higher living place).Conclusion: These data confirm wide sO2 distribution in RCCs reported recently. The sO2 was impacted by the processing and also by donors’ characteristics such as the gender and the living altitude, but not by the hemoglobin level, blood group and donor age. This study provides new hints on the factors influencing red blood cells storage lesions, since they are known to be related to O2 content within the bags, giving clues to better process and to better store RCCs and therefore potentially improve the efficacy of transfusion.

Published
2020
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4. Hypoxia modulates the purine salvage pathway and decreases red blood cell and supernatant levels of hypoxanthine during refrigerated storage

Author

Travis Nemkov, Kaiqi Sun, Julie A. Reisz, Anren Song, Tatsuro Yoshida, Andrew Dunham, Matthew J. Wither, Richard O. Francis, Robert C. Roach, Monika Dzieciatkowska, Stephen C. Rogers, Allan Doctor, Anastasios Kriebardis, Marianna Antonelou, Issidora Papassideri, Carolyn T. Young, Tiffany A. Thomas, Kirk C. Hansen, Steven L. Spitalnik, Yang Xia, James C. Zimring, Eldad A. Hod, and Angelo D’Alessandro

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Hypoxanthine catabolism in vivo is potentially dangerous as it fuels production of urate and, most importantly, hydrogen peroxide. However, it is unclear whether accumulation of intracellular and supernatant hypoxanthine in stored red blood cell units is clinically relevant for transfused recipients. Leukoreduced red blood cells from glucose-6-phosphate dehydrogenase-normal or -deficient human volunteers were stored in AS-3 under normoxic, hyperoxic, or hypoxic conditions (with oxygen saturation ranging from 95%). Red blood cells from healthy human volunteers were also collected at sea level or after 1–7 days at high altitude (>5000 m). Finally, C57BL/6J mouse red blood cells were incubated in vitro with 13C1-aspartate or 13C5-adenosine under normoxic or hypoxic conditions, with or without deoxycoformycin, a purine deaminase inhibitor. Metabolomics analyses were performed on human and mouse red blood cells stored for up to 42 or 14 days, respectively, and correlated with 24 h post-transfusion red blood cell recovery. Hypoxanthine increased in stored red blood cell units as a function of oxygen levels. Stored red blood cells from human glucose-6-phosphate dehydrogenase-deficient donors had higher levels of deaminated purines. Hypoxia in vitro and in vivo decreased purine oxidation and enhanced purine salvage reactions in human and mouse red blood cells, which was partly explained by decreased adenosine monophosphate deaminase activity. In addition, hypoxanthine levels negatively correlated with post-transfusion red blood cell recovery in mice and – preliminarily albeit significantly - in humans. In conclusion, hypoxanthine is an in vitro metabolic marker of the red blood cell storage lesion that negatively correlates with post-transfusion recovery in vivo. Storage-dependent hypoxanthine accumulation is ameliorated by hypoxia-induced decreases in purine deamination reaction rates.

Published
2018
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5. Metabolism of Citrate and Other Carboxylic Acids in Erythrocytes As a Function of Oxygen Saturation and Refrigerated Storage

Author

Travis Nemkov, Kaiqi Sun, Julie A. Reisz, Tatsuro Yoshida, Andrew Dunham, Edward Y. Wen, Alexander Q. Wen, Rob C. Roach, Kirk C. Hansen, Yang Xia, and Angelo D’Alessandro

Subjects
hypoxia, metabolomics, mass spectrometry, tracing experiments, flux analysis, Medicine (General), R5-920
Abstract

State-of-the-art proteomics technologies have recently helped to elucidate the unanticipated complexity of red blood cell metabolism. One recent example is citrate metabolism, which is catalyzed by cytosolic isoforms of Krebs cycle enzymes that are present and active in mature erythrocytes and was determined using quantitative metabolic flux analysis. In previous studies, we reported significant increases in glycolytic fluxes in red blood cells exposed to hypoxia in vitro or in vivo, an observation relevant to transfusion medicine owing to the potential benefits associated with hypoxic storage of packed red blood cells. Here, using a combination of steady state and quantitative tracing metabolomics experiments with 13C1,2,3-glucose, 13C6-citrate, 13C515N2-glutamine, and 13C1-aspartate via ultra-high performance liquid chromatography coupled on line with mass spectrometry, we observed that hypoxia in vivo and in vitro promotes consumption of citrate and other carboxylates. These metabolic reactions are theoretically explained by the activity of cytosolic malate dehydrogenase 1 and isocitrate dehydrogenase 1 (abundantly represented in the red blood cell proteome), though moonlighting functions of additional enzymes cannot be ruled out. These observations enhance understanding of red blood cell metabolic responses to hypoxia, which could be relevant to understand systemic physiological and pathological responses to high altitude, ischemia, hemorrhage, sepsis, pulmonary hypertension, or hemoglobinopathies. Results from this study will also inform the design and testing of novel additive solutions that optimize red blood cell storage under oxygen-controlled conditions.

Published
2017
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6. Hypoxia and hypocapnia storage of γ-irradiated red cell concentrates

Author

Manon, Bardyn, David, Crettaz, Marie, Borlet, Emmanuel, Längst, Agathe, Martin, Mélanie, Abonnenc, Jean-Daniel, Tissot, Andrew, Dunham, Tatsuro, Yoshida, and Michel, Prudent

Subjects
Blood Components And Regenerative Medicine, Erythrocytes, Hypocapnia, Blood Preservation, Humans, Hypoxia, Hemolysis
Abstract

BACKGROUND: γ-irradiation is used to treat red blood cell (RBC) concentrates (RCCs) transfused to immunosuppressed patients. This treatment damages RBCs and increases storage lesions. Several studies have shown the beneficial effect of reducing O(2) content during RBC storage. The present research work investigated the effect of γ-irradiation on RCCs stored under normal and hypoxia/hypocapnia conditions. MATERIALS AND METHODS: O(2) concentration (measured as oxyhaemoglobin fraction, sO(2)) and ABO-matched RCCs from whole blood donations, leukoreduced and prepared in phosphate, adenine, glucose, guanosine, saline and mannitol (PAGGSM) were pooled and split in two identical RCCs within 24 h post donation. One bag (Hx) was submitted to O(2) and CO(2) adsorption for 3 h on an orbital shaker at 22±2 °C and then transferred to a storage bag impermeable to gas. The other bag (Ctrl) was left as it was. The two bags were then stored at 4 °C. γ-irradiation (25 Gy) was applied at day 2 or 14, and the RCCs were stored until day 43. Different parameters (metabolites, haemolysis, morphology) were measured. RESULTS: Starting sO(2) values were 63.7±18.4% (n=12) in Ctrl and 20.8±9.8% (n=12) in Hx bags, and reached 90.8±9.1% and 6.6±5.9% at day 43, respectively. As expected, an increase in glycolysis rate was observed after deoxygenation. Extracellular potassium concentrations were identical and reached around 70 mM at expiry with an irradiation-dependent kinetic release. No difference in haemolysis was observed after irradiation on day 2 in either group (0.9999). When irradiated at day 14, haemolysis was lower (p=0.033) in RCCs under hypoxia at the end of storage (day 28, 0.67±0.16%) compared to control (1.06±0.33%). Percentages of spherocytes were lower under hypoxia. DISCUSSION: The storage under hypoxia provided equivalent storage when RCCs were irradiated at day 2 and was advantageous when irradiated at day 14. In summary, O(2)-depletion of RCCs enable a better storage of RBCs, particularly when late irradiation is applied.

Published
2020

7. A Method to Exploit the Structure of Genetic Ancestry Space to Enhance Case-Control Studies

Author

Corneliu A. Bodea, Benjamin M. Neale, Stephan Ripke, Mark J. Daly, Bernie Devlin, Kathryn Roeder, Murray Barclay, Laurent Peyrin-Biroulet, Mathias Chamaillard, Jean-Frederick Colombel, Mario Cottone, Anthony Croft, Renata D’Incà, Jonas Halfvarson, Katherine Hanigan, Paul Henderson, Jean-Pierre Hugot, Amir Karban, Nicholas A. Kennedy, Mohammed Azam Khan, Marc Lémann, Arie Levine, Dunecan Massey, Monica Milla, Grant W. Montgomery, Sok Meng Evelyn Ng, Ioannis Oikonomou, Harald Peeters, Deborah D. Proctor, Jean-Francois Rahier, Rebecca Roberts, Paul Rutgeerts, Frank Seibold, Laura Stronati, Kirstin M. Taylor, Leif Törkvist, Kullak Ublick, Johan Van Limbergen, Andre Van Gossum, Morten H. Vatn, Hu Zhang, Wei Zhang, Jane M. Andrews, Peter A. Bampton, Timothy H. Florin, Richard Gearry, Krupa Krishnaprasad, Ian C. Lawrance, Gillian Mahy, Graham Radford-Smith, Rebecca L. Roberts, Lisa A. Simms, Leila Amininijad, Isabelle Cleynen, Olivier Dewit, Denis Franchimont, Michel Georges, Debby Laukens, Emilie Theatre, André Van Gossum, Severine Vermeire, Guy Aumais, Leonard Baidoo, Arthur M. Barrie, Karen Beck, Edmond-Jean Bernard, David G. Binion, Alain Bitton, Steve R. Brant, Judy H. Cho, Albert Cohen, Kenneth Croitoru, Lisa W. Datta, Colette Deslandres, Richard H. Duerr, Debra Dutridge, John Ferguson, Joann Fultz, Philippe Goyette, Gordon R. Greenberg, Talin Haritunians, Gilles Jobin, Seymour Katz, Raymond G. Lahaie, Dermot P. McGovern, Linda Nelson, Sok Meng Ng, Kaida Ning, Pierre Paré, Miguel D. Regueiro, John D. Rioux, Elizabeth Ruggiero, L. Philip Schumm, Marc Schwartz, Regan Scott, Yashoda Sharma, Mark S. Silverberg, Denise Spears, A. Hillary Steinhart, Joanne M. Stempak, Jason M. Swoger, Constantina Tsagarelis, Clarence Zhang, Hongyu Zhao, Jan Aerts, Tariq Ahmad, Hazel Arbury, Anthony Attwood, Adam Auton, Stephen G. Ball, Anthony J. Balmforth, Chris Barnes, Jeffrey C. Barrett, Inês Barroso, Anne Barton, Amanda J. Bennett, Sanjeev Bhaskar, Katarzyna Blaszczyk, John Bowes, Oliver J. Brand, Peter S. Braund, Francesca Bredin, Gerome Breen, Morris J. Brown, Ian N. Bruce, Jaswinder Bull, Oliver S. Burren, John Burton, Jake Byrnes, Sian Caesar, Niall Cardin, Chris M. Clee, Alison J. Coffey, John M.C. Connell, Donald F. Conrad, Jason D. Cooper, Anna F. Dominiczak, Kate Downes, Hazel E. Drummond, Darshna Dudakia, Andrew Dunham, Bernadette Ebbs, Diana Eccles, Sarah Edkins, Cathryn Edwards, Anna Elliot, Paul Emery, David M. Evans, Gareth Evans, Steve Eyre, Anne Farmer, Nicol Ferrier, Edward Flynn, Alistair Forbes, Liz Forty, Jayne A. Franklyn, Timothy M. Frayling, Rachel M. Freathy, Eleni Giannoulatou, Polly Gibbs, Paul Gilbert, Katherine Gordon-Smith, Emma Gray, Elaine Green, Chris J. Groves, Detelina Grozeva, Rhian Gwilliam, Anita Hall, Naomi Hammond, Matt Hardy, Pile Harrison, Neelam Hassanali, Husam Hebaishi, Sarah Hines, Anne Hinks, Graham A. Hitman, Lynne Hocking, Chris Holmes, Eleanor Howard, Philip Howard, Joanna M.M. Howson, Debbie Hughes, Sarah Hunt, John D. Isaacs, Mahim Jain, Derek P. Jewell, Toby Johnson, Jennifer D. Jolley, Ian R. Jones, Lisa A. Jones, George Kirov, Cordelia F. Langford, Hana Lango-Allen, G. Mark Lathrop, James Lee, Kate L. Lee, Charlie Lees, Kevin Lewis, Cecilia M. Lindgren, Meeta Maisuria-Armer, Julian Maller, John Mansfield, Jonathan L. Marchini, Paul Martin, Dunecan C.O. Massey, Wendy L. McArdle, Peter McGuffin, Kirsten E. McLay, Gil McVean, Alex Mentzer, Michael L. Mimmack, Ann E. Morgan, Andrew P. Morris, Craig Mowat, Patricia B. Munroe, Simon Myers, William Newman, Elaine R. Nimmo, Michael C. O’Donovan, Abiodun Onipinla, Nigel R. Ovington, Michael J. Owen, Kimmo Palin, Aarno Palotie, Kirstie Parnell, Richard Pearson, David Pernet, John R.B. Perry, Anne Phillips, Vincent Plagnol, Natalie J. Prescott, Inga Prokopenko, Michael A. Quail, Suzanne Rafelt, Nigel W. Rayner, David M. Reid, Anthony Renwick, Susan M. Ring, Neil Robertson, Samuel Robson, Ellie Russell, David St Clair, Jennifer G. Sambrook, Jeremy D. Sanderson, Stephen J. Sawcer, Helen Schuilenburg, Carol E. Scott, Richard Scott, Sheila Seal, Sue Shaw-Hawkins, Beverley M. Shields, Matthew J. Simmonds, Debbie J. Smyth, Elilan Somaskantharajah, Katarina Spanova, Sophia Steer, Jonathan Stephens, Helen E. Stevens, Kathy Stirrups, Millicent A. Stone, David P. Strachan, Zhan Su, Deborah P.M. Symmons, John R. Thompson, Wendy Thomson, Martin D. Tobin, Mary E. Travers, Clare Turnbull, Damjan Vukcevic, Louise V. Wain, Mark Walker, Neil M. Walker, Chris Wallace, Margaret Warren-Perry, Nicholas A. Watkins, John Webster, Michael N. Weedon, Anthony G. Wilson, Matthew Woodburn, B. Paul Wordsworth, Chris Yau, Allan H. Young, Eleftheria Zeggini, Matthew A. Brown, Paul R. Burton, Mark J. Caulfield, Alastair Compston, Martin Farrall, Stephen C.L. Gough, Alistair S. Hall, Andrew T. Hattersley, Adrian V.S. Hill, Christopher G. Mathew, Marcus Pembrey, Jack Satsangi, Michael R. Stratton, Jane Worthington, Matthew E. Hurles, Audrey Duncanson, Willem H. Ouwehand, Miles Parkes, Nazneen Rahman, John A. Todd, Nilesh J. Samani, Dominic P. Kwiatkowski, Mark I. McCarthy, Nick Craddock, Panos Deloukas, Peter Donnelly, Jenefer M. Blackwell, Elvira Bramon, Juan P. Casas, Aiden Corvin, Janusz Jankowski, Hugh S. Markus, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Chris C.A. Spencer, Gavin Band, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Matti Pirinen, Amy Strange, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Matthew Gillman, Alagurevathi Jayakumar, Owen T. McCann, Jennifer Liddle, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa, Pamela Whittaker, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (MGD) Service de gastro-entérologie, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, and Genomics of Neurological and Neuropsychiatric Disorders

Subjects
0301 basic medicine, Heredity, Genetics, Genetics (clinical), Computer science, Genetic Linkage, Genome-wide association study, VARIANTS, 030105 genetics & heredity, computer.software_genre, Bayes' theorem, Gene Frequency, HISTORY, IMPUTATION, False positive paradox, Genetics(clinical), Disease, 0303 health sciences, education.field_of_study, 030305 genetics & heredity, Inheritance (genetic algorithm), Genotype, DATABASE, Genetic genealogy, POWER, Population, Genomics, POPULATION STRATIFICATION, Biology, INHERITANCE, Population stratification, Machine learning, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, Allele frequency, FAMILY-BASED ASSOCIATION, 030304 developmental biology, Genetic association, business.industry, Bayes Theorem, DISEASE ASSOCIATION, Human genetics, Hierarchical clustering, Genetics, Population, 030104 developmental biology, Case-Control Studies, 3111 Biomedicine, Artificial intelligence, business, computer, Software, Imputation (genetics)
Abstract

A. Palotie on työryhmän Int IBD Genetics Consortium jäsen. One goal of human genetics is to understand the genetic basis of disease, a challenge for diseases of complex inheritance because risk alleles are few relative to the vast set of benign variants. Risk variants are often sought by association studies in which allele frequencies in case subjects are contrasted with those from population-based samples used as control subjects. In an ideal world we would know population-level allele frequencies, releasing researchers to focus on case subjects. We argue this ideal is possible, at least theoretically, and we outline a path to achieving it in reality. If such a resource were to exist, it would yield ample savings and would facilitate the effective use of data repositories by removing administrative and technical barriers. We call this concept the Universal Control Repository Network (UNICORN), a means to perform association analyses without necessitating direct access to individual-level control data. Our approach to UNICORN uses existing genetic resources and various statistical tools to analyze these data, including hierarchical clustering with spectral analysis of ancestry; and empirical Bayesian analysis along with Gaussian spatial processes to estimate ancestry-specific allele frequencies. We demonstrate our approach using tens of thousands of control subjects from studies of Crohn disease, showing how it controls false positives, provides power similar to that achieved when all control data are directly accessible, and enhances power when control data are limiting or even imperfectly matched ancestrally. These results highlight how UNICORN can enable reliable, powerful, and convenient genetic association analyses without access to the individual-level data.

Published
2016
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8. Transfusion des patients drépanocytaires: évaluation préclinique de la technologie Hemanext

Author

Laura Bencheikh, Kim-Anh Nguyen, Philippe Chadebech, Laurent Kiger, Gwellaouen Bodivit, Alicia Jouard, Etienne Audureau, Sadaf Pakdaman, Sandia Adypagavane, Khouloud Tebbakha, Nicolas Hebert, France Pirenne, Samuel Sowemimo-Coker, Andrew Dunham, and Pablo Bartolucci

Subjects
Biochemistry (medical), Clinical Biochemistry, Hematology
Abstract

La drepanocytose est une maladie genetique due a une mutation de l’hemoglobine (Hb), entrainant la falciformation des globules rouges (GR), une hemolyse chronique ainsi que des crises vaso-occlusives tres douloureuses. L’echange transfusionnel est une des strategies therapeutiques utilisees pour remplacer les GR malades et diminuer les crises. La qualite des GR transfuses est primordiale, a la fois pour ameliorer le rendement transfusionnel mais aussi pour limiter les interactions pathologiques entre les GR et les cellules endotheliales, endommagees par l’hemolyse. Or, au cours de leur conservation, la qualite des GR diminue, principalement a cause de dommages oxidatifs. La technologie Hemanext permet de conserver les GR en hypoxie, ameliorant la concentration en ATP, 2-3DPG, l’hemolyse et la deformabilite des GR. Notre etude avait pour but de comparer la qualite des GR conserves de facon conventionnelle a ceux conserves avec la technologie Hemanext. Nous avons demontre une non-inferiorite d’Hemanext en termes d’adherence des GR en flux sur des cellules endotheliales. De plus, nous avons mis en evidence une reduction de la concentration en Hb libre (produite par la lyse des GR) dans les poches Hemanext, une baisse de la senescence des GR et de leur adherence sur la thrombospondine, dont la concentration est augmentee pendant la crise drepanocytaire. Ces resultats suggerent que la technologie Hemanext repond aux criteres de securite pour la transfusion des patients drepanocytaires, et pourrait meme leur apporter un benefice clinique.

Published
2019
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9. Clinical and pathological impact ofVHL, PBRM1, BAP1, SETD2, KDM6A, andJARID1cin clear cell renal cell carcinoma

Author

Nitzan Rosenfeld, Andrew Slatter, Conrad Lichtenstein, Beverley Haynes, Andrew Dunham, Andreas Claas, Anne Y. Warren, Susan J. Shanahan, Tim Forshew, Muhammed Murtaza, Andrew May, Tim Eisen, Francesco Marass, Lucy Gossage, and Ian Roberts

Subjects
Cancer Research, BAP1, Mutation, Somatic cell, Melanoma, Biology, medicine.disease, medicine.disease_cause, PBRM1, Clear cell renal cell carcinoma, SETD2, Genetics, Cancer research, medicine, Clinical significance
Abstract

VHL is mutated in the majority of patients with clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent studies have identified recurrent mutations in histone modifying and chromatin remodeling genes, including BAP1, PBRM1, SETD2, KDM6A, and JARID1c. Current evidence suggests that BAP1 mutations are associated with aggressive disease. The clinical significance of the remaining genes is unknown. In this study, targeted sequencing of VHL and JARID1c (entire genes) and coding regions of BAP1, PBRM1, SETD2, and KDM6A was performed on 132 ccRCCs and matched normal tissues. Associations between mutations and clinical and pathological outcomes were interrogated. Inactivation of VHL (coding mutation or promoter methylation) was seen in 75% of ccRCCs. Somatic noncoding VHL alterations were identified in 29% of ccRCCs and may be associated with improved overall survival. BAP1 (11%), PBRM1 (33%), SETD2 (16%), JARID1c (4%), and KDM6A (3%) mutations were identified. BAP1-mutated tumors were associated with metastatic disease at presentation (P = 0.023), advanced clinical stage (P = 0.042) and a trend towards shorter recurrence free survival (P = 0.059) when compared with tumors exclusively mutated for PBRM1. Our results support those of recent publications pointing towards a role for BAP1 and PBRM1 mutations in risk stratifying ccRCCs. Further investigation of noncoding alterations in VHL is warranted. © 2013 Wiley Periodicals, Inc.

Published
2013
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10. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Author

Morris J. Brown, Sanjeev S. Bhaskar, Alison J. Coffey, Suzanne Rafelt, Kirsten McLay, John Bowes, Francesca Bredin, Alastair Compston, John C. Mansfield, Elaine R. Nimmo, Kate Downes, Peter McGuffin, Neil Walker, Anthony J. Balmforth, Philip Howard, Detelina Grozeva, Helen Stevens, Kate L. Lee, Richard D. Pearson, Gerome Breen, T. Daniel Andrews, Sheila Seal, Anna Elliot, Beverley M. Shields, Andrew T. Hattersley, Sarah Edkins, Ann E. Morgan, Gil McVean, Julian Maller, Millicent A. Stone, Adam Auton, Carol Scott, Michael R. Stratton, Matthew Woodburn, John R. B. Perry, Michael Conlon O'Donovan, Nigel P. Carter, Vincent Plagnol, Stephen Sawcer, Sarah Hines, Mahim Jain, Allan H. Young, Steve Eyre, Elilan Somaskantharajah, Alexander J. Mentzer, Niall Cardin, Eleanor Howard, Inês Barroso, Stephen C. L. Gough, Toby Johnson, Deborah P M Symmons, Christopher Holmes, David St Clair, Patricia B. Munroe, Sue Shaw-Hawkins, Emma Gray, Stephen W. Scherer, Tariq Ahmad, Jaswinder Bull, Debbie Hughes, E. Russell, Timothy M. Frayling, Chris Clee, I. Nicol Ferrier, James Lee, Dominic P. Kwiatkowski, Husam Hebaishi, Anne Hinks, Simon Myers, Gareth Evans, Eleftheria Zeggini, Katarina Spanova, Michael L. Mimmack, David M. Reid, Amanda J. Bennett, Richard T. Scott, Armand Valsesia, Derek P. Jewell, Andrew P. Morris, Peter Donnelly, Mark J. Caulfield, Jake K. Byrnes, Lars Feuk, Pile Harrison, Anna F. Dominiczak, Cathryn Edwards, Andrew Dunham, Dalila Pinto, Inga Prokopenko, Ian Jones, Craig Mowat, Nigel R. Ovington, Willem H. Ouwehand, Edward Flynn, Jason D. Cooper, Louise V. Wain, Alistair Forbes, Bernadette Ebbs, Jennifer Jolley, Jonathan Marchini, Peter S. Braund, Ifejinelo Onyiah, Mark Walker, Adrian V. S. Hill, Cordelia Langford, Anne M. Phillips, George Kirov, David P. Strachan, Oliver S. Burren, Martin D. Tobin, Anthony G. Wilson, Ian N. Bruce, Hana Lango-Allen, Alistair S. Hall, Natalie J. Prescott, Charles Lee, Clare Turnbull, Cecilia M. Lindgren, John D. Isaacs, Jack Satsangi, Liz Forty, John M. C. Connell, Neelam Hassanali, Hazel E. Drummond, Matthew A. Brown, John A. Todd, Joanna M. M. Howson, Jennifer G. Sambrook, Graham A. Hitman, Michael N. Weedon, Christopher Yau, Abiodun Onipinla, Kathy Stirrups, Chris Tyler-Smith, Darshna Dudakia, G. Mark Lathrop, Katherine Gordon-Smith, Nazneen Rahman, Christopher J. Groves, William G. Newman, Kirstie Parnell, Stephen G. Ball, Tomas W Fitzgerald, Paul Gilbert, Kevin Lewis, Charlie W. Lees, Polly Gibbs, Rachel M. Freathy, Aarno Palotie, Katarzyna Blaszczyk, Matthew E. Hurles, Jonathan Stephens, Lynne J. Hocking, Nicholas A. Watkins, Christopher G. Mathew, Helen Schuilenburg, David Pernet, Eleni Giannoulatou, Kimmo Palin, Nigel W. Rayner, Donald F. Conrad, Susan M. Ring, John R. Thompson, Debbie J. Smyth, Wendy L. McArdle, B. Paul Wordsworth, David M. Evans, Dunecan Massey, Naomi Hammond, Diana Eccles, Panos Deloukas, Sian Caesar, Chris P. Barnes, Sophia Steer, Anthony Attwood, Chris Wallace, Richard Redon, Paul Burton, Anne Barton, Marcus Pembrey, Michael John Owen, Jane Worthington, Mary E. Travers, Jeremy D. Sanderson, Meeta Maisuria-Armer, Elaine K. Green, Michael A. Quail, Oliver J. Brand, Anne Farmer, Matthew J. Simmonds, Neil Robertson, Nicholas John Craddock, Zhan Su, Jan Aerts, Martin Farrall, Hazel Arbury, Damjan Vukcevic, Paul Emery, Omer Gokumen, A Hall, Wendy Thomson, Jeffrey C. Barrett, Margaret Warren-Perry, Rhian Gwilliam, Sarah E. Hunt, Samuel Robson, Paul Martin, Audrey Duncanson, Anthony Renwick, John Webster, Lisa Jones, Mark I. McCarthy, Nilesh J. Samani, Matthew Hardy, Miles Parkes, John Burton, Jayne A. Franklyn, Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Statistics [Oxford], University of Oxford, The Wellcome Trust Centre for Human Genetics [Oxford], The Wellcome Trust Case Control Consortium, Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Oxford [Oxford], and Medical Research Council (MRC)

Subjects
endocrine system diseases, [SDV]Life Sciences [q-bio], Genome-wide association study, Pilot Projects, CCL3L1, SUSCEPTIBILITY, Arthritis, Rheumatoid, Diabetes mellitus genetics, 0302 clinical medicine, Crohn Disease, Gene Frequency, DUPLICATIONS, SCHIZOPHRENIA, Disease, Copy-number variation, Oligonucleotide Array Sequence Analysis, Genetics, 0303 health sciences, Multidisciplinary, PSORIASIS, HERITABILITY, LARGE-SCALE, Nucleic Acid Hybridization, Science & Technology - Other Topics, Wellcome Trust Case Control Consortium, Quality Control, DNA Copy Number Variations, General Science & Technology, Single-nucleotide polymorphism, COPY-NUMBER VARIATION, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, MD Multidisciplinary, mental disorders, Genetic predisposition, Diabetes Mellitus, SNP, Humans, Genetic Predisposition to Disease, Allele frequency, POLYMORPHISMS, 030304 developmental biology, Genetic association, Science & Technology, MULTIDISCIPLINARY SCIENCES, DELETION, C431 Medical Genetics, Case-Control Studies, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with diseaseIRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetesalthough in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. © 2010 Macmillan Publishers Limited. All rights reserved.

Published
2016
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11. Genome-wide and fine-resolution association analysis of malaria in West Africa

Author

Muminatou, Jallow, Yik Ying Teo, Small, Kerrin S., Rockett, Kirk A., Panos, Deloukas, Clark, Taane G., Katja, Kivinen, Bojang, Kalifa A., Conway, David J., Margaret, Pinder, Giorgio, Sirugo, Fatou Sisay Joof, Stanley, Usen, Sarah, Auburn, Bumpstead, Suzannah J., Susana, Campino, Alison, Coffey, Andrew, Dunham, Fry, Andrew E., Angela, Green, Rhian, Gwilliam, Hunt, Sarah E., Michael, Inouye, Jeffreys, Anna E., Alieu, Mendy, Aarno, Palotie, Simon, Potter, Jiannis, Ragoussis, Jane, Rogers, Kate, Rowlands, Elilan, Somaskantharajah, Pamela, Whittaker, Claire, Widden, Peter, Donnelly, Bryan, Howie, Jonathan, Marchini, Andrew, Morris, Miguel, Sanjoaquin, Eric Akum Achidi, Tsiri, Agbenyega, Angela, Allen, Olukemi, Amodu, Patrick, Corran, Abdoulaye, Djimde, Amagana, Dolo, Doumbo, Ogobara K., Chris, Drakeley, Sarah, Dunstan, Jennifer, Evans, Jeremy, Farrar, Hien Tt, Fernando D., Horstmann, R. D., Ibrahim, M., Karunaweera, N., Kokwaro, G., Koram, K. A., Lemnge, M., Makani, J., Marsh, K., Michon, P., David, Modiano, Molyneux, M. E., Mueller, I., Parker, M., Peshu, N., Plowe, C. V., Puijalon, O., Reeder, J., Reyburn, H., Riley, E. M., Sakuntabhai, A., Singhasivanon, P., Sirima, S., Tall, A., Taylor, T. E., Thera, M., Troye Blomberg, M., Williams, T. N., Wilson, M., Wellcome Trust Case Control Consortium Kwiatkowski, D. P., Epidemiology Network: Achidi, Malaria Genomic E. A., Agbenyega, T., Ahmad, T., Alcock, D., Allen, S., Amenga Etego, L., Amodu, O., Apinjoh, T. O., Attwood, A. P., Auburn, S., Ball, S. G., Balmforth, A. J., Ban, M., Barbour, J., Barnwell, D., Barrett, J. C., Barrett, J. H., Barton, A., Bentley, D., Bishop, D. T., Bojang, K., Boorman, J. P., Bougouma, E., Bradbury, L. A., Braga Marcano, C. A., Braund, P. S., Bredin, F., Breen, G., Brown, M. A., Brown, M. J., Bruce, I. N., Bryan, C., Bull, S., Bumpstead, S. J., Burke, B., Burton, P. R., Caesar, S., Campino, S., Cant, B., Cardin, N. J., Cardon, L. R., Carucci, D., Caulfield, M., Chaney, A., Clark, T., Clayton, D. G., Collier, D. A., Compston, A., Compston, D. A., Connell, J., Conway, D., Cook, K., Corran, P., Craddock, N., Cummings, F. R., Davison, D., Deloukas, P., Devries, J., Dewasurendra, R., Diakite, M., Dixon, R. J., Djimde, A., Dobson, R., Dolo, A., Dominiczak, A., Donnelly, P., Donovan, H., Doumbo, O., Downes, K., Doyle, A., Drakeley, C., Drummond, H., Duffy, P., Duncanson, A., Dunger, D. B., Dunstan, S., Duombo, O., Easton, D., Elkin, A., Elliott, K. S., Elzein, A., Enimil, A., Evans, D., Evans, J., Everson, U., Eyre, S., Farmer, A., Farrall, M., Farrar, C., Farrar, J., Fernando, D., Ferreira, T., Ferrier, I. N., Fisher, S. A., Fitzpatrick, K., Forbes, A., Franklyn, J. A., Fraser, C., Frayling, T. M., Freathy, R. M., Ghansah, A., Ghori, J., Gilbert, P. D., Gordon Smith, K., Goris, A., Gottlieb, M., Gough, S. C., Green, A., Green, E. K., Groves, C. J., Grozeva, D., Gungadoo, J., Gwilliam, R., Hall, A. S., Hallgrimsdóttir, I. B., Hamshere, M. L., Hart, L., Hattersley, A. T., Heward, J. M., Hider, S. L., Tran Tinh Hien, Hill, A. V., Hilton, E., Hinks, A. M., Hitman, G. A., Holmans, P. A., Horstmann, Rolf D., Howie, B. N., Hubbart, C., Hughes, C., Hunt, S. E., Hussein, A., Hussey, J. M., Muntaser, Ibrahim, Iles, M. M., Inouye, M., Ishengoma, D., Jallow, M., Jeffreys, A. E., Jewell, D. P., John, Sl, Jolley, J. D., Jones, I. R., Jones, L., Jones, R. W., Nadira, Karunaweera, Keniry, A., King, E., Kirov, G., Kivinen, K., Knight, A. S., Koch, K., Gilbert, Kokwaro, Koram, Kwadwo A., Lango, H., Lathrop, G. M., Lee, K. L., Lees, C. W., Martha, Lemnge, Leung, H. T., Lewis, C. M., Lin, E., Lindgren, C. M., Ly, A., Macinnis, B., Julie, Makani, Mangano, Valentina, Mangino, M., Manjurano, A., Manning, L., Mansfield, J. C., Manske, M., Maqbool, A., Marchini, J. L., Kevin, Marsh, Maslen, G., Mathew, C. G., Mcardle, W. L., Mccarthy, M. I., Mccreight, M., Mcginnis, R., Mcguffin, P., Meech, E., Mendy, A., Pascal, Michon, Mohiuddin, M. K., Molyneux, Malcolm E., Morris, A. P., Moskvina, V., Moyes, C., Ivo, Mueller, Munroe, P. B., Mutabingwa, T., Ndila, C. M., Newhouse, S. J., Newport, M., Nikolov, I., Nimmo, E. R., Nutland, S., Nyirongo, V., O'Donovan, M. C., Oluoch, T., Onipinla, A., Onnie, C. M., Ouwehand, W. H., Owen, M. J., Michael, Parker, Parkes, M., Pembrey, M., Pereira Gale, J., Perry, J. R., Norbert, Peshu, Plowe, Christopher V., Pointon, J. J., Potter, C., Potter, S., Prescott, N. J., Prowse, C. V., Odile, Puijalon, Quyen, N. T., Ragoussis, J., Rahman, N., Ravindrarajah, R., Rayner, N. W., John, Reeder, Hugh, Reyburn, Riley, Eleanor M., Ring, S. M., Risley, P., Rockett, K. A., Rogers, J., Rowlands, K., Anavaj, Sakuntabhai, Samani, N. J., Sanderson, J., Sanjoaquin, M., Satsangi, J., Sawcer, S. J., Seal, S., Shields, B. M., Silman, A. J., Simmonds, M. J., Pratap, Singhasivanon, Sodiomon, Sirima, Sirugo, G., Small, K. S., Somaskantharajah, E., Spencer, C. C., St Clair, D., Stevens, H. E., Stevens, M., Stevens, S., Strachan, D. P., Stratton, M. R., Su, Z., Suriyaphol, P., Symmons, D. P., Adama, Tall, Taylor, N. C., Taylor, Terrie E., Teo, Y., Teo, Y. Y., Mahamadou, Thera, Thompson, J. R., Thomson, W., Timpson, N. J., Tobin, M. D., Todd, J. A., Todhunter, C. E., Toure, O., Tremelling, M., Marita Troye Blomberg, Vanderwal, A., Vukcevic, D., Walker, M., Walker, N. M., Wallace, C., Walters, G. R., Walton, R., Watkins, N. A., Watson, R., Webster, J., Weedon, M. N., Whittaker, P., Widmer, B., Williams, Thomas N., Williamson, R., Michael, Wilson, Winzer, T., Withers, D., Wordsworth, P., Worthington, J., Wrigley, R., Xue, M., Young, A. H., Yuldasheva, N., and Zeggini, E.

Subjects
Linkage disequilibrium, Hemoglobin, Sickle, Population, Genome-wide association study, Locus (genetics), Biology, Population stratification, Polymorphism, Single Nucleotide, Severity of Illness Index, Linkage Disequilibrium, Article, Gene mapping, Reference Values, Ethnicity, Genetics, Humans, education, Genetic association, education.field_of_study, Polymorphism, Genetic, Chromosome Mapping, Genetic Variation, Malaria, Gambia, Imputation (genetics), Genome-Wide Association Study
Abstract

We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10(-7) to P = 4 × 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.

Published
2009
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12. The DNA sequence of the human X chromosome

Author

Gernot Glöckner, Karen Thomas, Christine Lloyd, Huda Y. Zoghbi, Adrienne Hunt, Fiona Francis, Annemarie Poustka, George M. Weinstock, Xuehong Wei, Alan Tracey, Gabriele Nordsiek, Ines Müller, Graham Clarke, Oliver Beasley, John Sulston, Alfred Beck, Christian J. Buhay, Thomas Meitinger, Manjula Maheshwari, Yvonne Ramsey, Kirsten McLay, Shannon Dugan-Rocha, James G. R. Gilbert, Louisa Faulkner, Sidney Morris, Margaret Morgan, Huntington F. Willard, Leni S. Jacob, Hermela Loulseged, K M Porter, T. Daniel Andrews, Cordelia Langford, Paul Wray, Guan Chen, Juliane Ramser, Nigel P. Carter, Georgina Warry, Ruby Banerjee, Graeme Bethel, LaDeana W. Hillier, Anne Hodgson, Stephen M. J. Searle, K F Barlow, David R. Bentley, Paul E. Tabor, Kathryn L. Evans, Russell J. Grocock, Rebecca Woodmansey, Alex V Pearce, Christie Kovar-Smith, Angela Williamson, Dean Chavez, Roy Storey, Kevin L. Howe, Zhijian J. Chen, Lesette Perez, Richard A. Gibbs, Michele D'Urso, Karen N Bates, Jackie Bye, Shirin S. Joseph, Bernd Hinzmann, Paul Heath, Susan H. Kelly, Jennifer Hume, Paula E. Burch, David Buck, Mark T. Ross, David A. Wheeler, Matthew C. Jones, A K Babbage, Erica Sodergren, Sophie Palmer, Jie Ma, Elizabeth C. Sotheran, Margaret A. Leversha, Cerissa Hamilton, Hans Lehrach, Swaroop Aradhya, Michael L. Metzker, S. M. Clegg, Elizabeth J. Huckle, Audrey Fraser, Sarah Bray-Allen, C. D. Skuce, Petra Galgoczy, Richard K. Wilson, Patrick Minx, Richard E Connor, Tamsin Eades, Alfons Meindl, Michelle Smith, John M. Davis, André Rosenthal, Stuart McLaren, Geoffery Okwuonu, M. Vaudin, Laura Carrel, Ryan J. Lozado, Harminder Sehra, Richard Pandian, Sue Y Clark, Anna Kosiura, Wen Liu, Simon G. Gregory, A Tromans, Alexandra Emery-Cohen, Charles Shaw-Smith, Donna Villasana, Joseph Chako, Katja Heitmann, Robert G. David, Jennifer L. Ashurst, Craig Chinault, S Lawlor, Paul Havlak, Jane E. Loveland, Lucy Matthews, Jianling Zhou, S. Whitehead, Paul Hunt, E Sheridan, Richard Reinhardt, Tim Hubbard, Mary G. Schueler, Patrick Meidl, Helen Beasley, David Beare, Donna M. Muzny, Kerry A Ridler, Joanne C Chapman, Jennifer McDowall, Andrew Dunham, Anne Bridgeman, Gabrielle Williams, Amanda McMurray, Stefan Taudien, Matthew E. Hurles, Helen Williamson, Preethi H. Gunaratne, Alfredo Ciccodicola, R Ainscough, Alison J. Coffey, Charlotte G. Cole, Stephan Beck, Frances L Lovell, Alan Coulson, Qiaoyan Wang, Sally Jones, Charles A. Steward, Michael Hoffs, Kim C. Worley, Sarah Pelan, David Bonnin, David Schlessinger, Mathew N Whiteley, Graham Scott, Christopher N O'Dell, Tineace Taylor, Susan Rhodes, Anthony P. West, E. Hart, Ian P. Barrett, Andrea Thorpe, D. Pearson, Huyen Dinh, Susan M. Gribble, Andrew J Knights, Laurens G. Wilming, N Corby, Steven E. Scherer, Pawandeep Dhami, Gerald Nyakatura, J Lovell, M. Ali Ansari-Lari, Kerstin P. Clerc-Blankenburg, David Swarbreck, Sara Zorilla, Yanghong Gu, Karin Blechschmidt, Matthew Dunn, Andrew Brown, Kirsten M. Timms, Darren Grafham, Yan Ding, Elspeth A. Bruford, Leanne Williams, Melanie M. Wall, Hua Shen, Dina Patel, Joanne K Kershaw, Rachel Gill, Yuan Chen, Joy Davies, D C Burford, John Burton, Vicky Cobley, R I S Ashwell, Nicola Brady, Ellson Y. Chen, Ngoc Nguyen, Gaiping Wen, Gavin K. Laird, Julia E. Parrish, Carol Scott, C Griffiths, Ratna Shownkeen, Ralf Sudbrak, Denise R. DeShazo, Shiran Pasternak, Ireena Dutta, Brian Teague, Rachael Lyne, David Parker, Jane Rogers, Steve Dodsworth, Mary J. Brown, Gary E Barker, Steve Trevanion, Joanne Burgess, Jane E. Wilkinson, James T. Warren, Jen S. Conquer, R Mark Swann, Oliver Delgado, Heather R. Draper, Shailesh L Mistry, Chris Clee, Richard Durbin, Karen Clifford, John Frankland, Sarah E. Hunt, David Steffen, Christine Burrows, Daniel Verduzco, C Carder, Robert H. Waterston, Stephen Richards, Andrea Ballabio, Catherine M. Rice, David Willey, Helen Errington, Andrew Cree, K. James Durbin, Lora Lewis, D. M. Lloyd, Helen E. Steingruber, Adam Whittaker, K D Ambrose, Rhian Gwilliam, Adam Frankish, Robert S. Fulton, Judith Hernandez, Claire L Bagguley, Pieter J. de Jong, Jennifer Yen, Matthew Ellwood, Christine P. Bird, Rui Chen, Sarah Milne, Clay Davis, Alicia Hawes, Jing Lu, Sven Klages, David L. Nelson, Wayne Burrill, Jingkun Zhang, Judith Isherwood, Kathrin Reichwald, Lenee Waldron, Rebecca Deadman, Steffen Hennig, Ziad Khan, Sarah Ho, Matthias Platzer, Gareth R. Howell, Stephen Keenan, Petra Kioschis, Phillip J Howden, George Miner, David W. Johnson, and James C. Mullikin

Subjects
Male, Genetic Linkage, Genetics, Medical, Centromere, HUMAN GENOME SEQUENCE, Biology, Y chromosome, Polymorphism, Single Nucleotide, Article, Evolution, Molecular, Contig Mapping, Chromosome 16, Antigens, Neoplasm, Dosage Compensation, Genetic, Sequence Homology, Nucleic Acid, Chromosome 19, Testis, Animals, Humans, Crossing Over, Genetic, X chromosome, Repetitive Sequences, Nucleic Acid, Genetics, Chromosomes, Human, X, Chromosomes, Human, Y, Multidisciplinary, INACTIVATION CENTER, LINKED MENTAL-RETARDATION, Genomics, Sequence Analysis, DNA, REPEAT HYPOTHESIS, MAMMALIAN Y-CHROMOSOME, Chromosome 4, Chromosome 3, RNA, Female, Chromosome 21, Chromosome 22
Abstract

The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.

Published
2005
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13. A physical map of the human genome

Author

Anuradha Madan, S. Naylor, Kami Dixon, Wonhee Jang, John Douglas Mcpherson, Asao Fujiyama, Simon G. Gregory, Jacquelyn R. Idol, Takashi Sasaki, David Haussler, Hong Seok Park, Jun Kudoh, Ai Shintani, Erica Sodergren, Barbara J. Trask, Norma J. Nowak, Gerald Nyakatura, Gregory D. Schuler, Shinsei Minoshima, Raluca Yonescu, J. Harley Gorrell, Roland Heilig, Vivian G. Cheung, Steve Scherer, Kazunori Shibuya, Hsiu Chuan Chen, Olivia Velasquez, Scot Kennedy, Leroy Hood, Richard Reinhardt, Lucía Ramírez, Richard M. Myers, Atsushi Toyoda, Tetsushi Yada, Nobuyoshi Shimizu, Eric D. Green, Dawn Garcia, Owen T. McCann, Kate Montgomery, Asif T. Chinwalla, Elaine R. Mardis, Peter Seranski, Valerie Maduro, W. James Kent, Cynthia Friedman, Kazutoyo Osoegawa, Carol Scott, Juliane Ramser, Marco A. Marra, Caryn Wagner-McPherson, William B. Barbazuk, Thomas Reid, Mandeep Sekhon, Lee Rowen, Nancy E. Stone, Richard A. Gibbs, Lisa French, Trevor Hawkins, J. de Jong, Jin Shang, Tamara A. Kucaba, Robert H. Waterston, Adam Whittaker, Jeremy Schmutz, Richard K. Wilson, Kristine M. Wylie, Masahira Hattori, Atsushi Shimizu, Ilan R. Kirsch, Jean Weissenbach, Céline Hoff, Julie R. Korenberg, Markus Schilhabel, Sanja Rogic, David R. Bentley, Shuichi Asakawa, Paul E. Tabor, Terrence S. Furey, Kerstin P. Clerc-Blankenburg, Raju Kucherlapati, Joseph J. Catanese, Shizhen Qin, Annemarie Poustka, Suzanne Emerling, Reiner Siebert, Brigitte Schlegelberger, Hans Lehrach, Monica Dors, Thomas Brüls, Hillary Massa, R Evans, Steven J.M. Jones, Gernot Gloeckner, Elbert Branscomb, Andrew Dunham, Jane L. Holden, Xiao Ning Chen, Ashley Miller, Jan Fang Cheng, André Rosenthal, John W. Wallis, Eunice Lee, Gaiping Wen, Sean Humphray, Carol Soderlund, Robert S. Fulton, Yoshiyuki Sakaki, David R. Cox, Norman A. Doggett, Kazuhiko Kawasaki, Anne S. Olsen, Graeme Bethel, and LaDeana W. Hillier

Subjects
Genetics, Cancer genome sequencing, Whole genome sequencing, Chromosomes, Artificial, Bacterial, Multidisciplinary, Contig, Genome, Human, Computational biology, Genome project, Biology, ENCODE, DNA Fingerprinting, Genome, Chimpanzee genome project, Contig Mapping, Gene Duplication, Humans, Cloning, Molecular, In Situ Hybridization, Fluorescence, Repetitive Sequences, Nucleic Acid, Reference genome
Abstract

The human genome is by far the largest genome to be sequenced, and its size and complexity present many challenges for sequence assembly. The International Human Genome Sequencing Consortium constructed a map of the whole genome to enable the selection of clones for sequencing and for the accurate assembly of the genome sequence. Here we report the construction of the whole-genome bacterial artificial chromosome (BAC) map and its integration with previous landmark maps and information from mapping efforts focused on specific chromosomal regions. We also describe the integration of sequence data with the map.

Published
2001
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14. Contigs Built with Fingerprints, Markers, and FPC V4.7

Author

Lisa French, Andrew Dunham, Sean Humphray, and Carol Soderlund

Subjects
Genetic Markers, Databases, Factual, DNA Fragmentation, Computational biology, Biology, Contig Mapping, Methods, Genetics, Humans, Computer Simulation, Genetics (clinical), Internet, Models, Statistical, Chromosomes, Human, Pair 13, Contig, Gene map, Chromosomes, Human, Pair 10, Physical Chromosome Mapping, Computational Biology, food and beverages, Numerical Analysis, Computer-Assisted, DNA Fingerprinting, Human sequence, Fingerprint database, DNA profiling, Chromosomes, Human, Pair 9, Software
Abstract

Contigs have been assembled, and over 2800 clones selected for sequencing for human chromosomes 9, 10 and 13. Using the FPC (FingerPrinted Contig) software, the contigs are assembled with markers and complete digest fingerprints, and the contigs are ordered and localised by a global framework. Publicly available resources have been used, such as, the 1998 International Gene Map for the framework and the GSC Human BAC fingerprint database for the majority of the fingerprints. Additional markers and fingerprints are generated in-house to supplement this data. To support the scale up of building maps, FPC V4.7 has been extended to use markers with the fingerprints for assembly of contigs, new clones and markers can be automatically added to existing contigs, and poorly assembled contigs are marked accordingly. To test the automatic assembly, a simulated complete digest of 110 Mb of concatenated human sequence was used to create datasets with varying coverage, length of clones, and types of error. When no error was introduced and a tolerance of 7 was used in assembly, the largest contig with no false positive overlaps has 9534 clones with 37 out-of-order clones, that is, the starting coordinates of adjacent clones are in the wrong order. This paper describes the new features in FPC, the scenario for building the maps of chromosomes 9, 10 and 13, and the results from the simulation.

Published
2000
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15. High-Resolution Landmark Framework for the Sequence-Ready Mapping of Xq23–q26.1

Author

Gareth Maslen, Elizabeth C. Sotheran, Rhian Gwilliam, Pawandeep Dhami, Margaret A. Leversha, Carol Scott, S. M. Clegg, Mark T. Ross, Alison J. Coffey, Andrew Dunham, Sarah E. Hunt, David R. Bentley, Gareth R. Howell, Elizabeth J. Huckle, Cari Soderlund, Helen E. Steingruber, and Paul Hunt

Subjects
Genetic Markers, Yeast artificial chromosome, Letter, X Chromosome, Sequence analysis, Computational biology, Biology, Contig Mapping, Genetics, medicine, Humans, Chromosomes, Artificial, Yeast, In Situ Hybridization, Fluorescence, Genetics (clinical), X chromosome, medicine.diagnostic_test, Contig, Chromosome Mapping, Sequence Analysis, DNA, Electrophoresis, Gel, Pulsed-Field, Blotting, Southern, Genetic marker, Female, Human genome, Fluorescence in situ hybridization
Abstract

We have established a landmark framework map over 20–25 Mb of the long arm of the human X chromosome using yeast artificial chromosome (YAC) clones. The map has approximately one landmark per 45 kb of DNA and stretches from DXS7531 in proximal Xq23 to DXS895 in proximal Xq26, connecting to published framework maps on its proximal and distal sides. There are three gaps in the framework map resulting from the failure to obtain clone coverage from the YAC resources available. Estimates of the maximum sizes of these gaps have been obtained. The four YAC contigs have been positioned and oriented using somatic-cell hybrids and fluorescence in situ hybridization, and the largest is estimated to cover ∼15 Mb of DNA. The framework map is being used to assemble a sequence-ready map in large-insert bacterial clones, as part of an international effort to complete the sequence of the X chromosome. PAC and BAC contigs currently cover 18 Mb of the region, and from these, 12 Mb of finished sequence is available.

Published
1999
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16. Clinical and pathological impact of VHL, PBRM1, BAP1, SETD2, KDM6A, and JARID1c in clear cell renal cell carcinoma

Author

Lucy, Gossage, Muhammed, Murtaza, Andrew F, Slatter, Conrad P, Lichtenstein, Anne, Warren, Beverley, Haynes, Francesco, Marass, Ian, Roberts, Susan J, Shanahan, Andreas, Claas, Andrew, Dunham, Andrew P, May, Nitzan, Rosenfeld, Tim, Forshew, and Tim, Eisen

Subjects
Histone Demethylases, Male, Tumor Suppressor Proteins, Nuclear Proteins, Oxidoreductases, N-Demethylating, Histone-Lysine N-Methyltransferase, DNA Methylation, Middle Aged, Chromatin Assembly and Disassembly, Kidney Neoplasms, DNA-Binding Proteins, Cytoskeletal Proteins, Humans, Female, Carrier Proteins, Carcinoma, Renal Cell, Ubiquitin Thiolesterase, Aged, Molecular Chaperones, Retrospective Studies, Transcription Factors
Abstract

VHL is mutated in the majority of patients with clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent studies have identified recurrent mutations in histone modifying and chromatin remodeling genes, including BAP1, PBRM1, SETD2, KDM6A, and JARID1c. Current evidence suggests that BAP1 mutations are associated with aggressive disease. The clinical significance of the remaining genes is unknown. In this study, targeted sequencing of VHL and JARID1c (entire genes) and coding regions of BAP1, PBRM1, SETD2, and KDM6A was performed on 132 ccRCCs and matched normal tissues. Associations between mutations and clinical and pathological outcomes were interrogated. Inactivation of VHL (coding mutation or promoter methylation) was seen in 75% of ccRCCs. Somatic noncoding VHL alterations were identified in 29% of ccRCCs and may be associated with improved overall survival. BAP1 (11%), PBRM1 (33%), SETD2 (16%), JARID1c (4%), and KDM6A (3%) mutations were identified. BAP1-mutated tumors were associated with metastatic disease at presentation (P = 0.023), advanced clinical stage (P = 0.042) and a trend towards shorter recurrence free survival (P = 0.059) when compared with tumors exclusively mutated for PBRM1. Our results support those of recent publications pointing towards a role for BAP1 and PBRM1 mutations in risk stratifying ccRCCs. Further investigation of noncoding alterations in VHL is warranted.

Published
2013

17. Depositional history of the upper Calvert Bluff and lower Carrizo formations, Bastrop, Texas

Author

Kevin Durney, Andrew Dunham, and Thomas E. Yancey

Subjects
Sedimentary depositional environment, Paleontology, Bluff, Outcrop, Group (stratigraphy), Transgressive, Paleosol, Geology, Marine transgression
Abstract

This fi eld trip examines exposures of transgressive and highstand marine deposits of the Sabinetown transgression that forms the upper part of the Calvert Bluff Formation of the Wilcox Group in the outcrop belt. The horizon of maximum fl ood in the Sabinetown transgression at Bastrop contains molluscs and diverse vertebrate fossils characteristic of open marine environments. The highstand deposits coarsen upward and are capped with a well-developed paleosol. These deposits are dated as early Eocene.

Published
2013
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19. The physical maps for sequencing human chromosomes 1, 6, 9, 10, 13, 20 and X

Author

Nigel P. Carter, Ian Dunham, A. L. Atkinson, Jaime Hughes, M. Izmajlowicz, Richard Durbin, Mark T. Ross, Soumi Joseph, Adam Butler, G. L. Harper, Louise McDonald, Rohan Taylor, W. D. Burrill, Graeme Bethel, S. R. Prathalingam, David R. Bentley, Theologia Sarafidou, Vassos Neocleous, John Sulston, F. L. Dearden, C. M. Rice, E. C. Sotheran, Carol A. Edwards, S. M. Clegg, N. Brady, T. E. Wilmer, B. L. Hopkins, G. L. Maslen, Simon G. Gregory, Owen T. McCann, Andrew J. Mungall, M.A. Leversha, Elisabeth Dawson, K. J. Phillips, R Evans, A. A. Thorpe, C M Clee, Cordelia Langford, E. J. Huckle, Helen E. Steingruber, Carol Scott, Y. H. Ramsey, John E. Collins, Gareth R. Howell, Adam Whittaker, M. E. Earthrowl, M. H. Lehvaslaiho, Pamela Whittaker, G. Laird, J. C. Brook, D. J. Scott, K. J. Ashcroft, S. H. Williams, Georgina Warry, Nicholas K. Moschonas, D. M. Pearson, K. S. Halls, C. L. Wright, R. W. Heathcott, C. Carder, Jane L. Holden, D. C. Burford, S. A. Ranby, P. J. Howard, K. Aubin, K. M. Porter, E. Holloway, R. A. Cooper, A. J. Coffey, David Beare, J. J. Catanese, C. A. Jones, J. S. Conquer, J. Ghori, E. J. Tinsley, Lisa French, Charlotte G. Cole, P. D. Dhami, K. M. Culley, Christopher J. Gillson, Sarah E. Hunt, Rhian Gwilliam, Panagiotis Deloukas, V. Cobley, Carol Soderlund, A. Taylor, G. J. Sharp, Luc J. Smink, S. Hammond, Andrew Dunham, L. J. Rogers, D. Mistry, Richard Wooster, P. J. De Jong, Jane Rogers, P. J. Hunt, L D Green, C. J. Shaw-Smith, Jennifer McDowall, C. Burrows, and Sean Humphray

Subjects
Genetics, Multidisciplinary, X Chromosome, Contig, Gene map, Chromosomes, Human, Pair 13, Chromosomes, Human, Pair 10, Genome, Human, Chromosomes, Human, Pair 20, food and beverages, Chromosome, Computational biology, Biology, Genome, Contig Mapping, Gene mapping, Chromosomes, Human, Pair 1, Humans, Chromosomes, Human, Pair 6, X chromosome, Genomic organization
Abstract

We constructed maps for eight chromosomes (1, 6, 9, 10, 13, 20, X and (previously) 22), representing one-third of the genome, by building landmark maps, isolating bacterial clones and assembling contigs. By this approach, we could establish the long-range organization of the maps early in the project, and all contig extension, gap closure and problem-solving was simplified by containment within local regions. The maps currently represent more than 94% of the euchromatic (gene-containing) regions of these chromosomes in 176 contigs, and contain 96% of the chromosome-specific markers in the human gene map. By measuring the remaining gaps, we can assess chromosome length and coverage in sequenced clones.

Published
2001

20. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene

Author

Massimo Zollo, Anthony P. Cahn, Gareth R. Howell, Paul Wray, Alison J. Coffey, Toshitaka Oohashi, Arpad Lanyi, Jack R. Davis, Robert A. Brooksbank, Marco Seri, Margaret A. Leversha, Charles Shaw-Smith, Luo Yin, Ann Harris, Susan Rhodes, Genevieve de St Basile, Mark T. Ross, Alfons Meindl, Reinhard Fässler, Volker Schuster, Janos Sumegi, Alessandra Bolino, Giovanni Romeo, Alison Jones, Jillian Durham, Helene Achatz, Paul Heath, Jan Murken, M. Vaudin, Bakary S. Sylla, Gilbert M. Lenoir, Brunella Franco, David R. Bentley, Jacqueline M. Bye, David Webster, Elizabeth J. Huckle, Giovanni Porta, Andrew Dunham, Bernd H. Behloradsky, Jane Wilkinson, Oliver Brandau, Paola Serafini, Rebecca Pavitt, Coffey, A. J., and Zollo, Massimo

Subjects
Male, Herpesvirus 4, Human, X Chromosome, Genetic Linkage, T-Lymphocytes, Molecular Sequence Data, Immunoglobulins, Receptors, Cell Surface, medicine.disease_cause, Virus, src Homology Domains, Hypogammaglobulinemia, Immune system, Signaling Lymphocytic Activation Molecule Family Member 1, Antigen, Antigens, CD, hemic and lymphatic diseases, Genetics, medicine, Humans, Gammaherpesvirinae, Signaling Lymphocytic Activation Molecule Associated Protein, X-Linked Lymphoproliferative Syndrome, Cloning, Molecular, Glycoproteins, Sequence Deletion, B-Lymphocytes, biology, Intracellular Signaling Peptides and Proteins, X-linked lymphoproliferative disease, Herpesviridae Infections, medicine.disease, biology.organism_classification, Epstein–Barr virus, Virology, Lymphoproliferative Disorders, Pedigree, Mutation, Immunology, Female, Carrier Proteins, Sequence Alignment
Abstract

X-linked lymphoproliferative syndrome (XLP or Duncan disease) is characterized by extreme sensitivity to Epstein-Barr virus (EBV), resulting in a complex phenotype manifested by severe or fatal infectious mononucleosis, acquired hypogammaglobulinemia and malignant lymphoma. We have identified a gene, SH2D1A, that is mutated in XLP patients and encodes a novel protein composed of a single SH2 domain. SH2D1A is expressed in many tissues involved in the immune system. The identification of SH2D1A will allow the determination of its mechanism of action as a possible regulator of the EBV-induced immune response.

Published
1998

21. Correction: Initial sequencing and analysis of the human genome

Author

Paul Predki, John Sulston, William Morris, Sarah Wenning, Jun Gu, Danielle Thierry-Mieg, Roger A. Schultz, Michael J. Morgan, Michael Doyle, Joseph Szustakowki, Lorenzo Cerutti, A. Coulson, Alex Bateman, Patrick Wincker, Michael C. Zody, Mark T. Ross, Paul G. Richardson, Keri Devon, Yasushi Totoki, Karsten Hokamp, George M. Weinstock, John Howland, Arek Kaspryzk, James G. R. Gilbert, Cher Miranda, Aristides Patrinos, William Saurin, A. Pia Abola, Kazuhiko Kawasaki, John Bouck, Marvin Frazier, Wonhee Jang, Jan Fang Cheng, Stephanie L. Chissoe, Matthew C. Jones, Glen A. Evans, Huanming Yang, Daniel G. Brown, Richard Durbin, Jennifer Baldwin, Tracie L. Miner, Asif T. Chinwalla, Arian F.A. Smit, C M Clee, Elaine R. Mardis, Henning Hermjakob, Nicole Stange-Thomann, Maynard V. Olson, Jian Wang, Cyrus L. Harmon, Shiaw Pyng Yang, André Rosenthal, Catherine Robert, Masahira Hattori, Jane Peterson, Ratna Shownkeen, Maria Athanasiou, Christopher B. Burge, Erica Sodergren, Carrie Sougnez, Lynn Doucette-Stamm, Hidemi Watanabe, Ronald W. Davis, Tarjei S. Mikkelsen, Mark Rosetti, Christopher J. Elkin, Todd M. Lowe, LaDeana W. Hillier, Jane Grimwood, Kazutoyo Osoegawa, Richard R. Copley, Simon Kasif, Joseph J. Catanese, Keith Weinstock, Lee Rowen, Roel Funke, Paul Kitts, Lukas Wagner, Guy Slater, Anne S. Olsen, Edward Uberbacher, Lucinda Fulton, Andrew Dunham, Andrew Heaford, David Kulp, Elbert Branscomb, William Fitzhugh, Eugene V. Koonin, Leroy Hood, Anup Madan, Jean Thierry-Mieg, Richard Reinhardt, Kim C. Worley, Richard M. Myers, Dudley Wyman, Jean Weissenbach, David R. Bentley, Panos Deloukas, Philippe Brottier, H. Blöcker, Stephan Beck, Marc Rubenfield, Terrence S. Furey, Ken Dewar, Michael L. Metzker, Rajinder Kaul, Guyang Huang, Hsiu Chuan Chen, Ewan Birney, Warren Gish, John Douglas Mcpherson, Asao Fujiyama, Aoife McLysaght, Shinsei Minoshima, Sandra W. Clifton, Lisa Kann, R Ainscough, K. Hornischer, Simon G. Gregory, Lauren Linton, Kim D. Delehaunty, James C. Mullikin, Neilay Dedhia, Matthias Platzer, Gerald Nyakatura, John V. Moran, Andrew J. Mungall, Chiharu Kawagoe, François Artiguenave, Deanna M. Church, Elia Stupka, Jun Yu, Peer Bork, Evan E. Eichler, L. Aravind, James H. Gorrell, Bruce A. Roe, Raymond Wheeler, Norman A. Doggett, Douglas R. Smith, Yu Juin Chen, David Haussler, Todd D. Taylor, Stefan Taudien, Susan Lucas, Rebecca Deadman, Hans Lehrach, Hiroaki Shizuya, Doron Lancet, Greg Schuler, Nigel P. Carter, John Burton, Huaqin Pan, Eric S. Lander, Andreas Rump, Nikola Stojanovic, Victor J. Pollara, Alan Williams, Melissa De La Bastide, W. James Kent, Mark S. Guyer, Nicola Mulder, Sarah Milne, Bruce W. Birren, John W. Wallis, Joann Dubois, Tom Slezak, Lisa Cook, Raju Kucherlapati, Andrew Delehaunty, Lucy Matthews, Ian Dunham, L. Steven Johnson, Robert H. Waterston, Andrew Sheridan, Jörg Schultz, Nancy A. Federspiel, Jason B. Kramer, Tim Hubbard, Ru Fang Yeh, Steven E. Scherer, Francis S. Collins, David L. Nelson, Sean Humphray, Tobias Doerks, Chad Nusbaum, Darren Grafham, Mei Lee Hong, Michael Proctor, Christopher K. Raymond, Diane Gage, Kris A. Wetterstrand, Feng Chen, Simon Mercer, Thomas A. Jones, Trevor Hawkins, Aravind Subramanian, Jeffrey A. Bailey, Amanda McMurray, Serafim Batzoglou, Jeremy Schmutz, Jill P. Mesirov, Shizen Qin, Rosie Levine, Adam Felsenfeld, Thomas Brüls, Kevin McKernan, Michele E. Clamp, Christine Lloyd, Susan L. Naylor, Gabriele Nordsiek, Jessica A. Lehoczky, Adrienne Hunt, Marco A. Marra, David R. Cox, Mark Dickson, Michael C. Wendl, Yuri I. Wolf, Jane Rogers, Ian F Korf, Eric Pelletier, Takehiko Itoh, Juliane Ramser, Robert S. Fulton, Sarah Sims, Richard A. Gibbs, Lisa French, Katrina Harris, Richa Agarwala, Christina Raymond, James Meldrim, Sangdun Choi, Richard K. Wilson, Patrick Minx, Douglas L. Johnson, Yoshiyuki Sakaki, Scot Kennedy, Pieter J. de Jong, Yoshihide Hayashizaki, W. Richard McCombie, Sean R. Eddy, Donna M. Muzny, Jerome Naylor, Paul A. McEwan, Atsushi Toyoda, Tetsushi Yada, Nobuyoshi Shimizu, Robert W. Plumb, Catherine M. Rives, Chris P. Ponting, Ralph Santos, Kenneth H. Wolfe, Kymberlie H. Pepin, Roland Heilig, and James E. Galagan

Subjects
Multidisciplinary, Correction, Human genome, Computational biology, Biology
Published
2001
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22. Effect of Practice Procedure on Skill Acquisition

Author

Trey Dunham, Timothy Andrew Dunham, and Paul Dunham

Subjects
Basketball, MEDLINE, Experimental and Cognitive Psychology, Sensory Systems, Dreyfus model of skill acquisition, Motor Skills, Practice, Psychological, Schema (psychology), Humans, Child, Psychology, Motor skill, Sports, Cognitive psychology
Abstract

49 children in Grade 1 in an isolated community were assessed on their form and skill in making a basket for a one-step basketball lay-up following practice using a pseudoshaping, specific, or schema procedure. Analysis gave a significant form effect but no difference in success of making baskets.

Published
1988
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