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1. Genome-wide association study of circulating interleukin 6 levels identifies novel loci

Author

Martina Müller-Nurasyid, Jerome I. Rotter, David M. Evans, John P. Kemp, Emelia J. Benjamin, Graciela E. Delgado, Vilmundur Gudnason, Ann Hammarstedt, Panos Deloukas, Aroon D. Hingorani, Riccardo E. Marioni, David Stacey, Jenny van Dongen, Eric Boerwinkle, Joachim Heinrich, Yongmei Liu, S. Goya Wannamethee, Delilah Zabaneh, Braxton D. Mitchell, Marie Standl, Jackie F. Price, Maria G. Stathopoulou, Yoav Ben-Shlomo, Joris Deelen, Eero Kajantie, Mohammadreza Abdollahi, Christie M. Ballantyne, Johan G. Eriksson, Ilkka Seppälä, Elnaz Naderi, Barbara J. Jefferis, Richard W Morris, Nicholas J. Timpson, George Dedoussis, Sirpa Jalkanen, Mika Kivimäki, Perminder S. Sachdev, Diana van Heemst, Melanie Waldenberger, Gaurav Singhal, Elisabeth Thiering, Olli T. Raitakari, Anders Hamsten, Zoltán Kutalik, L. Bain, Eco J. C. de Geus, Tarunveer S. Ahluwalia, Yuri Milaneschi, Hubert Scharnagl, Juan P. Casas, Georg Homuth, Claes Ohlsson, Abbas Dehghan, Nicola J. Armstrong, Behrooz Z. Alizadeh, Terho Lehtimäki, Steve E. Humphries, Naveed Sattar, Bram P. Prins, Peter Rossing, Sophie Visvikis-Siest, Joana A. Revez, Ilja M. Nolte, Stella Trompet, Harold Snieder, Marian Beekman, Diana Marek, Beate St Pourcain, Thorkild I. A. Sørensen, Silvia Naitza, Karen A. Mather, Uwe Völker, Eline Slagboom, Tina Shah, Magdalene C. Jawahar, Jens Baumert, Alexander Teumer, Dorret I. Boomsma, Marcus E. Kleber, Peter Vollenweider, Wolfgang Koenig, Brenda W.J.H. Penninx, Kenneth Rice, Ian J. Deary, Pedro Marques-Vidal, Donna K. Arnett, Eleonora Porcu, Jouke-Jan Hottenga, Maria Sabater-Lleal, Bruce M. Psaty, Matthias Nauck, Dan Mellström, Joel Eriksson, Bernhard T. Baune, Debbie A Lawlor, Catherine Toben, Peter H. Whincup, Toshiko Tanaka, Stavroula Kanoni, Katri Räikkönen, Gonneke Willemsen, Bengt Sennblad, Julian N. Trollor, Yalda Jamshidi, Sarah E. Harris, Jari Lahti, Joshua C. Bis, Peter Durda, Yen Pei C. Chang, Jorgen Engmann, Tom R. Gaunt, Stella Aslibekyan, Anbupalam Thalamuthu, Mary F. Feitosa, Angela Silveira, Tine Jess, Stela McLachlan, J. Wouter Jukema, Chen Lu, Simon P. Mooijaart, Tim D. Spector, Harald Grallert, Winfried März, Alexandros M. Petrelis, Manuel A. R. Ferreira, Meena Kumari, Stochastics, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Methodology, CHARGE Inflammation Working Group, Epidemiology, Tampere University, Department of Clinical Chemistry, Clinical Medicine, Steno Diabetes Center, University of Copenhagen = Københavns Universitet (KU), University of Groningen [Groningen], Murdoch University, University of Alabama at Birmingham [ Birmingham] (UAB), QIMR Berghofer Medical Research Institute, University College of London [London] (UCL), Helmholtz-Zentrum München (HZM), Leiden University Medical Center (LUMC), University of Bristol [Bristol], University of Washington [Seattle], University of Maryland School of Medicine, University of Maryland System, Vrije Universiteit Amsterdam [Amsterdam] (VU), VU University Medical Center [Amsterdam], University of Heidelberg, Medical Faculty, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL), Sahlgrenska Academy at University of Gothenburg [Göteborg], National Institute for Health and Welfare [Helsinki], University of Helsinki, William Harvey Research Institute, Barts and the London Medical School, University of Queensland [Brisbane], School of Public Health [Boston], Boston University [Boston] (BU), MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, University of Edinburgh, Amsterdam UMC, Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche [Roma] (CNR), Karolinska Institutet [Stockholm], University of Tampere [Finland], Adelaide Medical School [Australia], University of Adelaide, Universität Greifswald - University of Greifswald, University of New South Wales [Sydney] (UNSW), Prince of Wales Hospital, Ludwig-Maximilians-Universität München (LMU), Baylor College of Medicine (BCM), Baylor University, Boston University School of Medicine (BUSM), VA Boston Healthcare System, Harokopio University of Athens, Max planck Institute for Biology of Ageing [Cologne], Larner College of Medicine [University of Vermont, Burlington], University of Vermont [Burlington], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-Universität Greifswald, University of Turku, St George's, University of London, Statens Serum Institut [Copenhagen], Medical Faculty [Mannheim], Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Johannes Gutenberg - Universität Mainz (JGU), Vrije Universiteit Medical Centre (VUMC), British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, Medical University Graz, Uppsala Universitet [Uppsala], Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft, Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], University of Kentucky, Melbourne Medical School [Melbourne], Faculty of Medicine, Dentistry and Health Sciences [Melbourne], University of Melbourne-University of Melbourne, University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), University of Maryland [Baltimore], Queen Mary University of London (QMUL), University of Iceland [Reykjavik], Ludwig Maximilian University [Munich] (LMU), Melbourne School of Population and Global Health [Melbourne], University of Melbourne, Deutsches Herzzentrum München (DHM), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University of Ulm (UUlm), University of Essex, Greifswald University Hospital, Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), King‘s College London, University of Cambridge [UK] (CAM), Harbor UCLA Medical Center [Torrance, Ca.], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), Human Genome Sequencing Center [Houston] (HGSC), Baylor University-Baylor University, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, HUS Children and Adolescents, Lastentautien yksikkö, Children's Hospital, Clinicum, Department of Bacteriology and Immunology, Department of Public Health, Department of Psychology and Logopedics, Research Programs Unit, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Doctoral Programme in Human Behaviour, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
AcademicSubjects/SCI01140, [SDV]Life Sciences [q-bio], Genome-wide association study, 030204 cardiovascular system & hematology, DISEASE, Pathogenesis, Cohort Studies, 0302 clinical medicine, cytokine, SYSTEMIC-LUPUS-ERYTHEMATOSUS, Association Studies Article, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Genetics, 0303 health sciences, ARCHITECTURE, CHRONIC INFLAMMATION, 1184 Genetics, developmental biology, physiology, General Medicine, RECEPTOR IL-6R GENE, C-REACTIVE PROTEIN, hla-drb1 gene, 3. Good health, Medical genetics, Medical Genetics, chromosomes, medicine.medical_specialty, SUSCEPTIBILITY LOCI, European Continental Ancestry Group, Locus (genetics), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, anti-inflammatory agents, White People, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, Interleukin 6, Molecular Biology, Medicinsk genetik, 030304 developmental biology, PRODUCE IL-6, Interleukin-6, Chromosome, Receptors, Interleukin-6, RHEUMATOID-ARTHRITIS, Interleukin 1 Receptor Antagonist Protein, Gene Expression Regulation, Genetic Loci, CELLS, biology.protein, 1182 Biochemistry, cell and molecular biology, Human genome, 3111 Biomedicine, Genome-Wide Association Study, HLA-DRB1 Chains, Interleukin-1
Abstract

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10−11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10−10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10−122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

Published
2021
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2. Considering adaptive genetic variation in climate change vulnerability assessment reduces species range loss projections

Author

John B. Taggart, Orly Razgour, Sébastien J. Puechmaille, Michaël Bekaert, Javier Juste, Brenna R. Forester, Antton Alberdi, Stéphanie Manel, Roberto Novella-Fernandez, Carlos F. Ibáñez, University of Bristol [Bristol], University of Southampton, Colorado State University [Fort Collins] (CSU), University of Stirling, Estación Biológica de Doñana (EBD), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Ernst-Moritz-Arndt-Universität Greifswald, Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), University of Copenhagen = Københavns Universitet (UCPH), Centre d’Ecologie Fonctionnelle et Evolutive (CEFE), Université Paul-Valéry - Montpellier 3 (UPVM)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE), University of Copenhagen = Københavns Universitet (KU), Université Paul-Valéry - Montpellier 3 (UPVM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-École pratique des hautes études (EPHE), and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
0106 biological sciences, Genetic adaptations, Evolution, Range (biology), Climate Change, ecological niche models, Population, Vulnerability, Biology, Models, Biological, 010603 evolutionary biology, 01 natural sciences, Intraspecific competition, 03 medical and health sciences, Ecosystem model, Chiroptera, [SDV.BA.ZV]Life Sciences [q-bio]/Animal biology/Vertebrate Zoology, Animals, education, Ecosystem, 030304 developmental biology, 0303 health sciences, Adaptive capacity, education.field_of_study, Multidisciplinary, Ecology, Global climate change, Evolutionary rescue, Global warming, global climate change, Genetic Variation, Ecological niche models, Biological Sciences, 15. Life on land, Adaptation, Physiological, genetic adaptations, conservation genomics, 13. Climate action, evolutionary rescue, Conservation genomics, [SDV.EE.BIO]Life Sciences [q-bio]/Ecology, environment/Bioclimatology, Forecasting, Landscape connectivity
Abstract

Significance Forecasts of species vulnerability and extinction risk under future climate change commonly ignore local adaptations despite their importance for determining the potential of populations to respond to future changes. We present an approach to assess the impacts of global climate change on biodiversity that takes into account adaptive genetic variation and evolutionary potential. We show that considering local climatic adaptations reduces range loss projections but increases the potential for competition between species. Our findings suggest that failure to account for within-species variability can result in overestimation of future biodiversity losses. Therefore, it is important to identify the climate-adaptive potential of populations and to increase landscape connectivity between populations to enable the spread of adaptive genetic variation., Local adaptations can determine the potential of populations to respond to environmental changes, yet adaptive genetic variation is commonly ignored in models forecasting species vulnerability and biogeographical shifts under future climate change. Here we integrate genomic and ecological modeling approaches to identify genetic adaptations associated with climate in two cryptic forest bats. We then incorporate this information directly into forecasts of range changes under future climate change and assessment of population persistence through the spread of climate-adaptive genetic variation (evolutionary rescue potential). Considering climate-adaptive potential reduced range loss projections, suggesting that failure to account for intraspecific variability can result in overestimation of future losses. On the other hand, range overlap between species was projected to increase, indicating that interspecific competition is likely to play an important role in limiting species’ future ranges. We show that although evolutionary rescue is possible, it depends on a population’s adaptive capacity and connectivity. Hence, we stress the importance of incorporating genomic data and landscape connectivity in climate change vulnerability assessments and conservation management.

Published
2019
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3. Deciphering myeloid-derived suppressor cells: isolation and markers in humans, mice and non-human primates

Author

Marco A. Cassatella, Anna Bujko, Espen S. Baekkevold, Sven Brandau, Ang Lin, Gosse J. Adema, Patrizia Scapini, Carsten Krieg, Karin Loré, Olivia Marini, Mikael Roussel, Anca Dorhoi, Viktor Umansky, Jeffrey W. Pollard, Luca Cassetta, University of Edinburgh, University of Oslo (UiO), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Università degli studi di Verona = University of Verona (UNIVR), Max Planck Institute for Infection Biology (MPIIB), Max-Planck-Gesellschaft, Ernst-Moritz-Arndt-Universität Greifswald, Medical University of South Carolina [Charleston] (MUSC), Karolinska Institutet [Stockholm], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Medizinische Fakultät Mannheim, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Radboud University Medical Center [Nijmegen], Wellcome Trust [101067/Z/13/Z], Medical Research Council [MR/N022556/1], Dutch cancer Society [KUN2013-6111, 11266], COST (European Cooperation in Science and Technology), COST Action [BM1404], Villa Joep, de STOPHT stichting, China Scholarship Council, Karolinska Institutet, Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG20339], Ministero dell'Istruzione, dell'Universita e della Ricerca [PRIN 2015YYKPNN], Jonchère, Laurent, University of Verona (UNIVR), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Cancer Research, Myeloid, Mouse, Neutrophils, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Human, Mye-EUNITER, Myeloid-derived suppressor cells, Non-human primates, Medizin, DONORS, Cell Separation, Disease, Symposium-in-Writing Paper, ARGINASE, Mice, 0302 clinical medicine, Medicine and Health Sciences, Immunology and Allergy, biology, HUMAN NEUTROPHILS, EXPANSION, CANCER, 3. Good health, medicine.anatomical_structure, Oncology, Antibody, medicine.symptom, EXPRESSION, Primates, BONE-MARROW, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Inflammation, Context (language use), Immunophenotyping, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Animals, Humans, Mass cytometry, ACCUMULATION, Myeloid-Derived Suppressor Cells, IMMUNOSUPPRESSIVE ACTIVITY, Biology and Life Sciences, T-CELLS, biology.protein, Myeloid-derived Suppressor Cell, Biomarkers, 030215 immunology
Abstract

International audience; In cancer, infection and inflammation, the immune system's function can be dysregulated. Instead of fighting disease, immune cells may increase pathology and suppress host-protective immune responses. Myeloid cells show high plasticity and adapt to changing conditions and pathological challenges. Despite their relevance in disease pathophysiology, the identity, heterogeneity and biology of myeloid cells is still poorly understood. We will focus on phenotypical and functional markers of one of the key myeloid regulatory subtypes, the myeloid derived suppressor cells (MDSC), in humans, mice and non-human primates. Technical issues regarding the isolation of the cells from tissues and blood, timing and sample handling of MDSC will be detailed. Localization of MDSC in a tissue context is of crucial importance and immunohistochemistry approaches for this purpose are discussed. A minimal antibody panel for MDSC research is provided as part of the Mye-EUNITER COST action. Strategies for the identification of additional markers applying state of the art technologies such as mass cytometry will be highlighted. Such marker sets can be used to study MDSC phenotypes across tissues, diseases as well as species and will be crucial to accelerate MDSC research in health and disease.

Published
2019
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4. Genoscapist: online exploration of quantitative profiles along genomes via interactively customized graphical representations

Author

Cyprien Guérin, Ulrike Mäder, Pierre Nicolas, Sandra Derozier, Université Paris-Saclay, INRAE, BioinfOmics, MIGALE bioinformatics facility (MIGALE), Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Paris-Saclay, Interfaculty Institute for Genetics and Functional Genomics, and Ernst-Moritz-Arndt-Universität Greifswald

Subjects
Statistics and Probability, 0303 health sciences, Computer science, 030302 biochemistry & molecular biology, [INFO.INFO-WB]Computer Science [cs]/Web, Computational biology, Biochemistry, Genome, Computer Science Applications, Transcriptome, 03 medical and health sciences, Computational Mathematics, Computational Theory and Mathematics, Relevance (information retrieval), [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Molecular Biology, 030304 developmental biology, Reference genome
Abstract

Summary Genoscapist is a tool to design web interfaces generating high-quality images for interactive visualization of hundreds of quantitative profiles along a reference genome together with various annotations. Relevance is demonstrated by deployment of two websites dedicated to large condition-dependent transcriptome datasets available for Bacillus subtilis and Staphylococcus aureus. Availability and implementation Websites and source code freely accessible at https://genoscapist.migale.inrae.fr

Published
2021
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5. Drivers of longitudinal telomere dynamics in a long‐lived bat species, Myotis myotis

Author

Nicole M. Foley, Eric J. Petit, Thomas Brazier, Sébastien J. Puechmaille, Graham M. Hughes, John A. Finarelli, Emma C. Teeling, Frédéric Touzalin, University College Dublin [Dublin] (UCD), Écologie et santé des écosystèmes (ESE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Ernst-Moritz-Arndt-Universität Greifswald, Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UR226, AGROCAMPUS OUEST, and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
0106 biological sciences, 0301 basic medicine, longitudinal data, Range (biology), Population, bats, Myotis myotis, Biology, Genus Myotis, heritability, 010603 evolutionary biology, 01 natural sciences, 03 medical and health sciences, Chiroptera, Genotype, Genetics, telomere length, Animals, Humans, education, Child, Ecology, Evolution, Behavior and Systematics, Telomere Shortening, education.field_of_study, Infant, Newborn, conservation, Infant, Bayes Theorem, Heritability, Telomere, biology.organism_classification, 030104 developmental biology, Cross-Sectional Studies, climate change, Ageing, Evolutionary biology, Child, Preschool, [SDE]Environmental Sciences, France, [SDE.BE]Environmental Sciences/Biodiversity and Ecology
Abstract

International audience; ge-related telomere shortening is considered a hallmark of the ageing process. However, a recent cross-sectional ageing study of relative telomere length (rTL) in bats failed to detect a relationship between rTL and age in the long-lived genus Myotis (M. myotis and M. bechsteinii), suggesting some other factors are responsible for driving telomere dynamics in these species. Here, we test if longitudinal rTL data show signatures of age-associated telomere attrition in M. myotis and differentiate which intrinsic or extrinsic factors are likely to drive telomere length dynamics. Using quantitative polymerase chain reaction, rTL was measured in 504 samples from a marked population, from Brittany, France, captured between 2013 and 2016. These represent 174 individuals with an age range of 0 to 7+ years. We find no significant relationship between rTL and age (p = .762), but demonstrate that within-individual rTL is highly variable from year to year. To investigate the heritability of rTL, a population pedigree (n = 1744) was constructed from genotype data generated from a 16-microsatellite multiplex, designed from an initial, low-coverage, Illumina genome for M. myotis. Heritability was estimated in a Bayesian, mixed model framework, and showed that little of the observed variance in rTL is heritable (h(2) = 0.01-0.06). Rather, correlations of first differences, correlating yearly changes in telomere length and weather variables, demonstrate that, during the spring transition, average temperature, minimum temperature, rainfall and windspeed correlate with changes in longitudinal telomere dynamics. As such, rTL may represent a useful biomarker to quantify the physiological impact of various environmental stressors in bats.

Published
2020
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6. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjornsson, Gardar, Fatemifar, Ghazaleh, Hedman, Asa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Arnlov, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Doerr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engstrom, Gunnar, Esko, Tonu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Gudbjartsson, Daniel F, Gutmann, Rebecca, Haggerty, Christopher M, van der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Kober, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, Maerz, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, Stott, David J, Svensson, Per, Tammesoo, Mari-Liis, Taylor, Kent D, Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Gudmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tyl, Benoit, Uitterlinden, Andre G, Veluchamy, Abirami, Voelker, Uwe, Voors, Adriaan A, Wang, Xiaosong, Wareham, Nicholas J, Waterworth, Dawn, Weeke, Peter E, Weiss, Raul, Wiggins, Kerri L, Xing, Heming, Yerges-Armstrong, Laura M, Yu, Bing, Zannad, Faiez, Zhao, Jing Hua, Hemingway, Harry, Samani, Nilesh J, McMurray, John JV, Yang, Jian, Visscher, Peter M, Newton-Cheh, Christopher, Malarstig, Anders, Holm, Hilma, Lubitz, Steven A, Sattar, Naveed, Holmes, Michael V, Cappola, Thomas P, Asselbergs, Folkert W, Hingorani, Aroon D, Kuchenbaecker, Karoline, Ellinor, Patrick T, Lang, Chim C, Stefansson, Kari, Smith, J Gustav, Vasan, Ramachandran S, Swerdlow, Daniel I, Lumbers, R Thomas, Abecasis, Goncalo, Backman, Joshua, Bai, Xiaodong, Balasubramanian, Suganthi, Banerjee, Nilanjana, Baras, Aris, Barnard, Leland, Beechert, Christina, Blumenfeld, Andrew, Cantor, Michael, Chai, Yating, Coppola, Giovanni, Damask, Amy, Dewey, Frederick, Economides, Aris, Eom, Gisu, Forsythe, Caitlin, Fuller, Erin D, Gu, Zhenhua, Gurski, Lauren, Guzzardo, Paloma M, Habegger, Lukas, Hahn, Young, Hawes, Alicia, van Hout, Cristopher, Jones, Marcus B, Khalid, Shareef, Lattari, Michael, Li, Alexander, Lin, Nan, Liu, Daren, Lopez, Alexander, Manoochehri, Kia, Marchini, Jonathan, Marcketta, Anthony, Maxwell, Evan K, McCarthy, Shane, Mitnaul, Lyndon J, O'Dushlaine, Colm, Overton, John D, Padilla, Maria Sotiropoulos, Paulding, Charles, Penn, John, Pradhan, Manasi, Reid, Jeffrey G, Schleicher, Thomas D, Schurmann, Claudia, Shuldiner, Alan, Staples, Jeffrey C, Sun, Dylan, Toledo, Karina, Ulloa, Ricardo H, Widom, Louis, Wolf, Sarah E, Yadav, Ashish, Ye, Bin, Ctr, Regeneron Genetics, Shah, Sonia [0000-0001-5860-4526], Henry, Albert [0000-0001-7422-2288], Roselli, Carolina [0000-0001-5267-6756], Lin, Honghuang [0000-0003-3043-3942], Chaffin, Mark D. [0000-0002-1234-5562], Helgadottir, Anna [0000-0002-1806-2467], Verweij, Niek [0000-0002-4303-7685], Almgren, Peter [0000-0002-0473-0241], Chen, Xu [0000-0002-7299-3238], Ghanbari, Mohsen [0000-0002-9476-7143], Giedraitis, Vilmantas [0000-0003-3423-2021], Gross, Stefan [0000-0003-4121-7161], Guðbjartsson, Daníel F. [0000-0002-5222-9857], Hyde, Craig L. [0000-0002-6939-287X], Ingelsson, Erik [0000-0003-2256-6972], Jukema, J. Wouter [0000-0002-3246-8359], Kleber, Marcus E. [0000-0003-0663-7275], Koekemoer, Andrea [0000-0001-8222-3547], Langenberg, Claudia [0000-0002-5017-7344], Lindgren, Cecilia M. [0000-0002-4903-9374], Lovering, Ruth C. [0000-0002-9791-0064], Luan, Jian’an [0000-0003-3137-6337], Magnusson, Patrik [0000-0002-7315-7899], Mahajan, Anubha [0000-0001-5585-3420], Mordi, Ify R. [0000-0002-2686-729X], Morris, Andrew D. [0000-0002-1766-0473], Nagle, Michael W. [0000-0002-4677-7582], Nelson, Christopher P. [0000-0001-8025-2897], Palmer, Colin N. A. [0000-0002-6415-6560], Rice, Kenneth M. [0000-0002-3071-7278], Rotter, Jerome I. [0000-0001-7191-1723], Salomaa, Veikko [0000-0001-7563-5324], van Setten, Jessica [0000-0002-4934-7510], Svensson, Per [0000-0003-0372-6272], Taylor, Kent D. [0000-0002-2756-4370], Teder-Laving, Maris [0000-0002-5872-1850], Teumer, Alexander [0000-0002-8309-094X], Tyl, Benoit [0000-0001-5297-8412], Uitterlinden, Andre G. [0000-0002-7276-3387], Völker, Uwe [0000-0002-5689-3448], Wiggins, Kerri L. [0000-0003-2749-1279], Hemingway, Harry [0000-0003-2279-0624], Yang, Jian [0000-0003-2001-2474], Visscher, Peter M. [0000-0002-2143-8760], Lubitz, Steven A. [0000-0002-9599-4866], Sattar, Naveed [0000-0002-1604-2593], Cappola, Thomas P. [0000-0002-9630-7204], Asselbergs, Folkert W. [0000-0002-1692-8669], Kuchenbaecker, Karoline [0000-0001-9726-603X], Ellinor, Patrick T. [0000-0002-2067-0533], Vasan, Ramachandran S. [0000-0001-7357-5970], Lumbers, R. Thomas [0000-0002-9077-4741], Apollo - University of Cambridge Repository, Chaffin, Mark D [0000-0002-1234-5562], Guðbjartsson, Daníel F [0000-0002-5222-9857], Hyde, Craig L [0000-0002-6939-287X], Jukema, J Wouter [0000-0002-3246-8359], Kleber, Marcus E [0000-0003-0663-7275], Lindgren, Cecilia M [0000-0002-4903-9374], Lovering, Ruth C [0000-0002-9791-0064], Luan, Jian'an [0000-0003-3137-6337], Mordi, Ify R [0000-0002-2686-729X], Morris, Andrew D [0000-0002-1766-0473], Nagle, Michael W [0000-0002-4677-7582], Nelson, Christopher P [0000-0001-8025-2897], Palmer, Colin NA [0000-0002-6415-6560], Rice, Kenneth M [0000-0002-3071-7278], Rotter, Jerome I [0000-0001-7191-1723], Taylor, Kent D [0000-0002-2756-4370], Uitterlinden, Andre G [0000-0002-7276-3387], Wiggins, Kerri L [0000-0003-2749-1279], Visscher, Peter M [0000-0002-2143-8760], Lubitz, Steven A [0000-0002-9599-4866], Cappola, Thomas P [0000-0002-9630-7204], Asselbergs, Folkert W [0000-0002-1692-8669], Ellinor, Patrick T [0000-0002-2067-0533], Vasan, Ramachandran S [0000-0001-7357-5970], Lumbers, R Thomas [0000-0002-9077-4741], Palmer, Colin N A [0000-0002-6415-6560], Cardiovascular Centre (CVC), University of Queensland [Brisbane], University College of London [London] (UCL), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University Medical Center Groningen [Groningen] (UMCG), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Framingham Heart Study, National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), deCODE genetics [Reykjavik], Karolinska Institutet [Stockholm], Pfizer, University of Pennsylvania [Philadelphia], University of Groningen [Groningen], Imperial College London, Lund University [Lund], Herlev and Gentofte Hospital, Massachusetts General Hospital [Boston], Department of Neurobiology, Care Sciences and Society [Stockholm, Sweden] (Division of Family Medicine), Dalarna University, Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, Department of Biostatistics, University of Washington [Seattle], Emory University School of Medicine, Emory University [Atlanta, GA], The University of Texas Medical School at Houston, Department of Molecular and Functional Genomics, Geisinger, Danville, PA, Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY, Novartis Institutes for BioMedical Research (NIBR), University of Liverpool, Universität Heidelberg [Heidelberg], Medizinische Fakultät Mannheim, The Alan Turing Institute, Ninewells Hospital and Medical School [Dundee], Universität Greifswald - University of Greifswald, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University of Minnesota System, Regeneron Pharmaceuticals [Tarrytown], Department of Clinical Sciences, Cardiovascular Epidemiology, Skane University Hospital [Lund], Institute of Genomics [Tartu, Estonia], University of Tartu, Robertson Centre for Biostatistics, University of Glasgow, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Uppsala University, Brigham & Women’s Hospital [Boston] (BWH), University of Maryland School of Medicine, University of Maryland System, School of Science and Engineering (Reykjavik University), Carver College of Medicine, University of Iowa, Geisinger Health System [Danville, PA, USA], Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford Cardiovascular Institute, Uppsala Universitet [Uppsala], Leiden University Medical Center (LUMC), Einthoven Laboratory for Experimental Vascular Medicine (ELEVM - LEIDEN), Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Glenfield Hospital, University Hospitals Leicester, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Big Data Institute, University of Oxford [Oxford], University of Iowa [Iowa City], The Wellcome Trust Centre for Human Genetics [Oxford], Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Medical University Graz, Skane University Hospital [Malmo], Vanderbilt University School of Medicine [Nashville], University of Edinburgh, Université médicale de Vienne, Autriche, National Institute for Health and Welfare [Helsinki], University of Turku, Birmingham Women's and Children's NHS Foundation Trust, Kaiser Permanente, Harbor UCLA Medical Center [Torrance, Ca.], Los Angeles Biomedical Research Institute (LA BioMed), University Medical Center [Utrecht], University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Seattle Epidemiologic Research and Information Center [Seattle], Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Department of Cardiology, Södersjukhuset, Stockholm, Estonian Genome and Medicine, Landspitali National University Hospital of Iceland, University of Iceland [Reykjavik], Aalborg University [Denmark] (AAU), Institut de Recherches SERVIER (IRS), Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-Universität Greifswald, GlaxoSmithKline, Glaxo Smith Kline, Northeastern Ohio Medical University (NEOMED), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, Department of Cardiovascular Sciences [Leicester], University of Leicester, Queensland Brain Institute, Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, University of Dundee, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Atherosclerosis Risk in Communities Study (ARIC)The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC- 55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694 and RC2 HL102419, National Human Genome Research Institute contract U01HG004402, and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT- CHF)This project was funded by a grant from the European Commission (FP7‐242209‐ BIOSTAT‐CHF, EudraCT 2010–020808–29). Cardiovascular Health Study (CHS) This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, HHSN268200960009C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. deCODE Heart Failure Study (deCODE) We at deCODE thank the women and men of Iceland that have participated in our studies and our colleagues that contributed to data collection and processing. DiscovEHR We acknowledge and thank all participants in Geisinger’s MyCode Community Health Initiative for their support and permission to use their health and genomic information in the DiscovEHR collaboration. This work was supported by the Regeneron Genetics Center and Geisinger. Estonian Genome Center at the University of Tartu (EGCUT) This study was supported by Estonian Research Council Grant IUT20-60, EU, H2020 grant 692145, European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012) GENTRANSMED. Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) The EPHESUS was supported by Pfizer, Inc. The European Prospective Investigation of Cancer, Norfolk study (EPIC-Norfolk) The EPIC-Norfolk Study is supported by programme grants from the Medical Research Council UK (G1000143) and Cancer Research UK (C864/A14136) and with additional support from the European Union, Stroke Association, British Heart Foundation, Research into Ageing, Department of Health, The Wellcome Trust and the Food Standards Agency. NJW and CL also acknowledge support from the Medical Research Council, UK (MC_UU_12015/1, MC_PC_13048). We thank all EPIC participants and staff for their contribution to the study, and thank staff from the Technical, Field Epidemiology and Data Functional Group Teams of the Medical Research Council Epidemiology Unit in Cambridge, UK, for carrying out sample preparation, DNA provision and quality control, genotyping and data handling work. Framingham Heart Study (FHS) This work was conducted using data and resources from the Framingham Heart Study (FHS) of the National Heart Lung and Blood Institute and Boston University School of Medicine. The study was supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (Contract No. N01-HC-25195 and HHSN268201500001I) and its contract with Affymetrix, Inc for genotyping services (Contract No.N02-HL-6-4278). The work was also supported by R01 HL093328, R01 HL105993, and R01 HL71039 (PI: Ramachandran). FINRISK V.S. has been supported by the Finnish Foundation for Cardiovascular Research. Genetics of Diabetes Audit and Research Tayside Scotland GoDARTS) The Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection (supporting GoDARTS) was funded by the Wellcome Trust (072960/Z/03/Z, 084726/Z/08/Z, 084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z) and as part of the EU IMI-SUMMIT programme. We acknowledge the support of the Health Informatics Centre, University of Dundee, for managing and supplying the anonymized data and NHS Tayside, the original data owner. The Genetic Risk Assessment of Defibrillator Events (GRADE) NIH-NHLBI R01 HL77398 (Genetic Modulators of Sudden Death). S.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. The LUdwigshafen RIsk and Cardiovascular Health (LURIC) study We extend our appreciation to the participants of the LURIC study, without their collaboration, this article would not have been written. We thank the LURIC study team who were either temporarily or permanently involved in patient recruitment as well as sample and data handling, in addition to the laboratory staff at the Ludwigshafen General Hospital and the Universities of Freiburg and Ulm, Germany. LURIC has received funding from the 7th Framework Program (RiskyCAD, grant agreement number 305739 and Atheroremo, grant agreement number 201668) of the European Union. Malmö Diet and Cancer Study (MDCS) J. Gustav Smith was supported by grants from the Swedish Heart-Lung Foundation (2016- 0134 and 2016-0315), the Swedish Research Council (2017-02554), the European Research Council (ERC-STG-2015-679242), the Crafoord Foundation, Skåne University Hospital, the Scania county, governmental funding of clinical research within the Swedish National Health Service, a generous donation from the Knut and Alice Wallenberg foundation to the Wallenberg Center for Molecular Medicine in Lund, and funding from the Swedish Research Council (Linnaeus grant Dnr 349-2006-237, Strategic Research Area Exodiab Dnr 2009-1039) and Swedish Foundation for Strategic Research (Dnr IRC15- 0067) to the Lund University Diabetes Center. The Malmo Diet and Cancer Study was made possible by grants from the Swedish Cancer Society, the Swedish Medical Research Council, the Swedish Dairy Association, and the Malmo city council. Penn Heart Failure Study (PHFS) The study was supported by NIH grants (NIH R01L088577 and NIH R01H105993). Prevention of REnal and Vascular ENd-stage Disease (PREVEND) The Prevention of Renal and Vascular Endstage Disease Study (PREVEND) genetics is supported by the Dutch Kidney Foundation (Grant E033), the EU project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (grant LM010098), the Netherlands organisation for health research and development (NWO VENI grant 916.761.70), and the Dutch Inter University Cardiology Institute Netherlands (ICIN). Niek Verweij was supported by NWO VENI grant 016.186.125. PROspective Study of Pravastatin in the Elderly at Risk for vascular disease (PROSPER)The PROSPER study was supported by an investigator-initiated grant obtained from Bristol- Myers Squibb. Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). J.W.J. is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Study of Health in Pomerania (SHIP) SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg- West Pomerania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. Stabilization of Plaque using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID)SOLID-TIMI 52 was funded by GlaxoSmithKline. TwinGene (TwinGene) TwinGene received funding from the Swedish Research Council (M-2005-1112), GenomEUtwin (EU/QLRT-2001-01254, QLG2-CT-2002-01254), NIH DK U01-066134, The Swedish Foundation for Strategic Research (SSF) and the Heart and Lung foundation no. 20070481. TwinGene is part of the Swedish Twin Registry which is managed by Karolinska Institutet and receives funding through the Swedish Research Council (2017–00641). UK Biobank (UKBiobank) This research has been conducted using the UK Biobank Resource under Application Number 15422. This work was supported in part by grants to R.T.L. from the EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking BigData@Heart grant no. 116074, MRC Proximity to Discovery Award Scheme, the American Heart Association Institute for Precision Mecidine, Pfizer Ltd, the University College London British Heart Foundation Research Accelerator (AA/18/6/34223), and was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. A. H. is supported by the British Heart Foundation Cardiovascular Biomedicine PhD studentship. R.T.L is supported by a UK Research and Innovation Rutherford Fellowship and was previously supported by a National Institutes of Health Research Clinical Lectureship. Uppsala Longitudinal Study of Adult Men (ULSAM) J.Ä. is supported by the Swedish Research Council and the Swedish Heart Lung foundation. C.M.L is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds and by the NIHR Biomedical Research Centre, Oxford, by Widenlife and NIH (5P50HD028138- 27). Women’s Genome Health Study (WGHS) The WGHS is supported by the National Heart, Lung, and Blood Institute (HL043851 and HL080467, HL099355) and the National Cancer Institute (CA047988 and UM1CA182913), with collaborative scientific support and funding for genotyping provided by Amgen., Epidemiology, Internal Medicine, Læknadeild (HÍ), Faculty of Medicine (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, and University of Iceland

Subjects
0301 basic medicine, Dánartíðni, Epidemiology, LOCI, 45/43, General Physics and Astronomy, Muscle Proteins, Genome-wide association study, Disease, Coronary Artery Disease, 030204 cardiovascular system & hematology, Bioinformatics, Genome-wide association studies, DISEASE, Ventricular Function, Left, Coronary artery disease, 0302 clinical medicine, Risk Factors, Atrial Fibrillation, IMPUTATION, Medicine, Blóðrásarsjúkdómar, 692/308/174, lcsh:Science, 2. Zero hunger, RISK, Multidisciplinary, Microfilament Proteins, article, Atrial fibrillation, Mendelian Randomization Analysis, CATALOG, 3. Good health, OBESITY, Erfðarannsóknir, Cardiomyopathies, Medical Genetics, Cyclin-Dependent Kinase Inhibitor p21, Science, 631/208/205/2138, Heart failure, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 631/443/592/2727, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, RESOURCE, Humans, Mortality, METAANALYSIS, Genetic association, Medicinsk genetik, Adaptor Proteins, Signal Transducing, Heart Failure, HYPERTENSION, business.industry, Case-control study, Klinisk medicin, 692/699/75/230, General Chemistry, Cardiovascular genetics, medicine.disease, R1, 030104 developmental biology, Case-Control Studies, lcsh:Q, Morbidity, Clinical Medicine, business, Apoptosis Regulatory Proteins, Carrier Proteins, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein), Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies., We acknowledge the contribution from the EchoGen Consortium.

Published
2020
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7. Mating type determination within a microsatellite multiplex for the fungal pathogen Pseudogymnoascus destructans, the causative agent of white-nose disease in bats

Author

Nicola M. Fischer, Marcus Fritze, Jeffrey T. Foster, Sébastien J. Puechmaille, Andrea Altewischer, Kevin P. Drees, Serena E. Dool, Ernst-Moritz-Arndt-Universität Greifswald, Northern Arizona University [Flagstaff], Universität Greifswald - University of Greifswald, Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UR226

Subjects
0106 biological sciences, 0301 basic medicine, Mating type, Pseudogymnoascus, food.ingredient, Population, [SDV.BDLR.RA]Life Sciences [q-bio]/Reproductive Biology/Asexual reproduction, Asexual reproduction, Biology, 010603 evolutionary biology, 01 natural sciences, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, 03 medical and health sciences, Geomyces, food, Pseudogymnoascus destructans, Genetics, Mating, education, ComputingMilieux_MISCELLANEOUS, Ecology, Evolution, Behavior and Systematics, Mating type determination, education.field_of_study, biology.organism_classification, 3. Good health, 030104 developmental biology, [SDV.EE.IEO]Life Sciences [q-bio]/Ecology, environment/Symbiosis
Abstract

Emerging infectious diseases are a severe conservation threat for a variety of plants and animals. In North America, several bat species are threatened by white-nose disease, which has caused an unprecedented mass mortality of > 6 million bats since 2006. The fungus Pseudogymnoascus (Geomyces) destructans is the causative agent of the disease. Though asexual reproduction is the norm, sexual reproduction is possible as two mating types exist. Sexual reproduction has been implicated in the emergence of virulent strains of fungi but to date no rapid means of mating type characterisation was available for P. destructans. In this study, three mating type-specific primer sets were designed and tested on 80 isolates. The primers were multiplexed with microsatellite loci allowing for rapid and concurrent genotyping and mating type assignment. These markers will have great utility in better understanding and predicting the population dynamics and evolutionary potential of this fungus, including the emergence of virulent strains.

Published
2018
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8. Population level mitogenomics of long-lived bats reveals dynamic heteroplasmy and challenges the Free Radical Theory of Ageing

Author

Nicole M. Foley, Emma C. Teeling, Sébastien J. Puechmaille, David Jebb, Conor V. Whelan, Frédéric Touzalin, University College Dublin [Dublin] (UCD), Evolution et Diversité Biologique (EDB), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Ernst-Moritz-Arndt-Universität Greifswald, Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
0301 basic medicine, Aging, Population level, Free Radicals, Longitudinal data, lcsh:Medicine, Myotis myotis, Biology, DNA, Mitochondrial, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Chiroptera, [SDV.BA.ZV]Life Sciences [q-bio]/Animal biology/Vertebrate Zoology, Animals, lcsh:Science, Free-radical theory of aging, Multidisciplinary, lcsh:R, High-Throughput Nucleotide Sequencing, biology.organism_classification, Heteroplasmy, 030104 developmental biology, Ageing, Evolutionary biology, Mutation, Metabolic rate, lcsh:Q, 030217 neurology & neurosurgery
Abstract

Bats are the only mammals capable of true, powered flight, which drives an extremely high metabolic rate. The “Free Radical Theory of Ageing” (FTRA) posits that a high metabolic rate causes mitochondrial heteroplasmy and the progressive ageing phenotype. Contrary to this, bats are the longest-lived order of mammals given their small size and high metabolic rate. To investigate if bats exhibit increased mitochondrial heteroplasmy with age, we performed targeted, deep sequencing of mitogenomes and measured point heteroplasmy in wild, long lived Myotis myotis. Blood was sampled from 195 individuals, aged between

Published
2018
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9. Male-biased dispersal and the potential impact of human-induced habitat modifications on the Neotropical batTrachops cirrhosus

Author

Sébastien J. Puechmaille, Tanja K. Halczok, Stefan Dominik Brändel, Rachel A. Page, Gerald Kerth, Victoria Flores, Marco Tschapka, Smithsonian Tropical Research Institute, Ernst-Moritz-Arndt-Universität Greifswald, Universität Ulm - Ulm University [Ulm, Allemagne], and University of Chicago

Subjects
0106 biological sciences, 0301 basic medicine, Neotropics, Mitochondrial DNA, Population genetics, 010603 evolutionary biology, 01 natural sciences, Trachops cirrhosus, Gene flow, 03 medical and health sciences, [SDV.BA.ZV]Life Sciences [q-bio]/Animal biology/Vertebrate Zoology, 14. Life underwater, Mating, Ecology, Evolution, Behavior and Systematics, Nature and Landscape Conservation, Panama, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Ecology, biology, population genetics, 15. Life on land, biology.organism_classification, 030104 developmental biology, Habitat, Evolutionary biology, sex-biased dispersal, Biological dispersal, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, gene flow
Abstract

International audience; Gene flow, maintained through natal dispersal and subsequent mating events, is one of the most important processes in both ecology and population genetics. Among mammalian populations, gene flow is strongly affected by a variety of factors, including the species’ ability to disperse, and the composition of the environment which can limit dispersal. Information on dispersal patterns is thus crucial both for conservation management and for understanding the social system of a species. We used 16 polymorphic nuclear microsatellite loci in addition to mitochondrial DNA sequences (1.61 kbp) to analyse the population structure and the sex‐specific pattern of natal dispersal in the frog‐eating fringe‐lipped bat, Trachops cirrhosus, in Central Panama. Our study revealed that—unlike most of the few other investigated Neotropical bats—gene flow in this species is mostly male‐mediated. Nevertheless, distinct genetic clusters occur in both sexes. In particular, the presence of genetic differentiation in the dataset only consisting of the dispersing sex (males) indicates that gene flow is impeded within our study area. Our data are in line with the Panama Canal in connection with the widening of the Río Chagres during the canal construction acting as a recent barrier to gene flow. The sensitivity of T. cirrhosus to human‐induced habitat modifications is further indicated by an extremely low capture success in highly fragmented areas. Taken together, our genetic and capture data provide evidence for this species to be classified as less mobile and thus vulnerable to habitat change, information that is important for conservation management.

Published
2018
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10. Range expansion is associated with increased survival and fecundity in a long-lived bat species

Author

Anne-Laure Besnard, Wigbert Schorcht, Eric J. Petit, Gerald Kerth, Pierre-Loup Jan, Martin Biedermann, Lisa Lehnen, Sébastien J. Puechmaille, P. Le Gouar, Écologie et santé des écosystèmes (ESE), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Ernst-Moritz-Arndt-Universität Greifswald, Ecosystèmes, biodiversité, évolution [Rennes] (ECOBIO), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Observatoire des Sciences de l'Univers de Rennes (OSUR)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), Office National des Forets (ONF), PROCOPE/DAAD programme [57211773], PROCOPE/PHC programme [35454SB], DFG (RESPONSE exchange grant), Deutsche Forschungsgemeinschaft, German Science Foundation DFG, Interessengemeinschaft Fledermausschutz & Forsch, Bad Liebenstein, Nachtaktiv Biologists Bat Res GbR, Erfurt, Université de Rennes (UR)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Observatoire des Sciences de l'Univers de Rennes (OSUR), Université de Rennes (UR)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Centre National de la Recherche Scientifique (CNRS), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre National de la Recherche Scientifique (CNRS)-Observatoire des Sciences de l'Univers de Rennes (OSUR)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
0106 biological sciences, life history, capture-mark-recapture, Range (biology), media_common.quotation_subject, Rhinolophus hipposideros, Population, Longevity, Population Dynamics, Zoology, Trade-off, 010603 evolutionary biology, 01 natural sciences, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Feces, Chiroptera, Germany, Population growth, Animals, education, Population Growth, range expansion, 030304 developmental biology, General Environmental Science, media_common, trade-off, 0303 health sciences, education.field_of_study, General Immunology and Microbiology, biology, Ecology, Reproduction, General Medicine, DNA, 15. Life on land, Fecundity, biology.organism_classification, Fertility, Habitat, Female, France, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, General Agricultural and Biological Sciences, Animal Distribution
Abstract

The speed and dynamics of range expansions shape species distributions and community composition. Despite the critical impact of population growth rates for range expansion, they are neglected in existing empirical studies, which focus on the investigation of selected life-history traits. Here, we present an approach based on non-invasive genetic capture–mark–recapture data for the estimation of adult survival, fecundity and juvenile survival, which determine population growth. We demonstrate the reliability of our method with simulated data, and use it to investigate life-history changes associated with range expansion in 35 colonies of the bat species Rhinolophus hipposideros . Comparing the demographic parameters inferred for 19 of those colonies which belong to an expanding population with those inferred for the remaining 16 colonies from a non-expanding population reveals that range expansion is associated with higher net reproduction. Juvenile survival was the main driver of the observed reproduction increase in this long-lived bat species with low per capita annual reproductive output. The higher average growth rate in the expanding population was not associated with a trade-off between increased reproduction and survival, suggesting that the observed increase in reproduction stems from a higher resource acquisition in the expanding population. Environmental conditions in the novel habitat hence seem to have an important influence on range expansion dynamics, and warrant further investigation for the management of range expansion in both native and invasive species.

Published
2019
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11. Inhibition of Rho Activity Increases Expression of SaeRS-Dependent Virulence Factor Genes in Staphylococcus aureus, Showing a Link between Transcription Termination, Antibiotic Action, and Virulence

Author

Tarek Msadek, Anna Nagel, Hermann Rath, Michel Débarbouillé, Manuela Gesell Salazar, Stephan Michalik, Jan Maarten van Dijl, Tobias Hertlein, Uwe Völker, Ulrike Mäder, Knut Ohlsen, Universität Greifswald - University of Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-Universität Greifswald, Biologie des Bactéries pathogènes à Gram-positif, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Würzburg, University of Groningen [Groningen], This work was supported by grants from the Deutsche Forschungsgemeinschaft within the framework of the Research Training Group 1870 'Bacterial respiratory infections—Common and specific mechanisms of pathogen adaptation and immune defence' and the SFB TRR34 as well as CEU project LSHG-CT-2006-037469 (BaSysBio)., European Project: 38901,BASYSBIO, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University of Groningen, Microbes in Health and Disease (MHD), and Translational Immunology Groningen (TRIGR)

Subjects
0301 basic medicine, antisense transcription, IMMUNE EVASION, Bacteremia, Virulence Factors/biosynthesis, MESH: Virulence, Protein Kinases/genetics, medicine.disease_cause, Virulence factor, RNA-POLYMERASE, SUBINHIBITORY CONCENTRATIONS, Transcription (biology), MESH: Rho Factor, Gene expression, MESH: Staphylococcus aureus, MESH: Animals, MESH: Bacteremia, MESH: Bacterial Proteins, IN-VIVO, MESH: Gene Expression Regulation, Bacterial, MESH: Genetic Complementation Test, Virulence, Anti-Bacterial Agents/metabolism, Bacterial, PANTON-VALENTINE LEUKOCIDIN, SaeRS TCS, MESH: Transcription Factors, Staphylococcal Infections, QR1-502, Anti-Bacterial Agents, Bacteremia/microbiology, MESH: Proteome, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, 2-COMPONENT SYSTEM SAERS, ESCHERICHIA-COLI, Staphylococcus aureus, MESH: Regulon, MYCOBACTERIUM-TUBERCULOSIS, Transcription Termination, Virulence Factors, bicyclomycin, proteome, REGULATORY SYSTEM, 030106 microbiology, MESH: Staphylococcal Infections, Staphylococcus aureus/drug effects, Transcription Factors/genetics, Biology, Microbiology, Regulon, Rho Factor/genetics, BACILLUS-SUBTILIS, Bicyclomycin, 03 medical and health sciences, MESH: Gene Expression Profiling, Bacterial Proteins, Genetic, MESH: Transcription Termination, Genetic, Virology, MESH: Anti-Bacterial Agents, medicine, Proteome/analysis, Animals, MESH: Protein Kinases, MESH: Virulence Factors, Bacterial Proteins/genetics, Animal, Gene Expression Profiling, Genetic Complementation Test, Gene Expression Regulation, Bacterial, Rho Factor, Bacterial adhesin, Staphylococcal Infections/microbiology, Disease Models, Animal, Gene Expression Regulation, MESH: Gene Deletion, Transcription Termination, Genetic, Disease Models, MESH: Disease Models, Animal, Protein Kinases, Gene Deletion, Transcription Factors
Abstract

International audience; Staphylococcus aureus causes various diseases ranging from skin and soft tissue infections to life-threatening infections. Adaptation to the different host niches is controlled by a complex network of transcriptional regulators. Global profiling of condition-dependent transcription revealed adaptation of S. aureus HG001 at the levels of transcription initiation and termination. In particular, deletion of the gene encoding the Rho transcription termination factor triggered a remarkable overall increase in antisense transcription and gene expression changes attributable to indirect regulatory effects. The goal of the present study was a detailed comparative analysis of S. aureus HG001 and its isogenic rho deletion mutant. Proteome analysis revealed significant differences in cellular and extracellular protein profiles, most notably increased amounts of the proteins belonging to the SaeR regulon in the Rho-deficient strain. The SaeRS two-component system acts as a major regulator of virulence gene expression in staphylococci. Higher levels of SaeRS-dependent virulence factors such as adhesins, toxins, and immune evasion proteins in the rho mutant resulted in higher virulence in a murine bacteremia model, which was alleviated in a rho complemented strain. Inhibition of Rho activity by bicyclomycin, a specific inhibitor of Rho activity, also induced the expression of SaeRS-dependent genes, at both the mRNA and protein levels, to the same extent as observed in the rho mutant. Taken together, these findings indicate that activation of the Sae system in the absence of Rho is directly linked to Rho's transcription termination activity and establish a new link between antibiotic action and virulence gene expression in S. aureusIMPORTANCE The major human pathogen Staphylococcus aureus is a widespread commensal bacterium but also the most common cause of nosocomial infections. It adapts to the different host niches through a complex gene regulatory network. We show here that the Rho transcription termination factor, which represses pervasive antisense transcription in various bacteria, including S. aureus, plays a role in controlling SaeRS-dependent virulence gene expression. A Rho-deficient strain produces larger amounts of secreted virulence factors in vitro and shows increased virulence in mice. We also show that treatment of S. aureus with the antibiotic bicyclomycin, which inhibits Rho activity and is effective against Gram-negative bacteria, induces the same changes in the proteome as observed in the Rho-deficient strain. Our results reveal for the first time a link between transcription termination and virulence regulation in S. aureus, which implies a novel mechanism by which an antibiotic can modulate the expression of virulence factors.

Published
2018
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12. Growing old, yet staying young:The role of telomeres in bats' exceptional longevity

Author

Olivier Farcy, Emma C. Teeling, Mike Clarke, Nicole M. Foley, Roger D. Ransome, Gareth Jones, Hugo Rebelo, David Jebb, Joanna Kacprzyk, Conor V. Whelan, Luísa Rodrigues, Sébastien J. Puechmaille, Mary J. O'Connell, Graham M. Hughes, Zixia Huang, Gerald Kerth, Eric J. Petit, Frédéric Touzalin, University College Dublin [Dublin] (UCD), Écologie et santé des écosystèmes (ESE), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Evolution et Diversité Biologique (EDB), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Bretagne Vivante, School of Biological Sciences [Bristol], University of Bristol [Bristol], University of Leeds, Ernst-Moritz-Arndt-Universität Greifswald, Universidade do Porto [Porto], Universidade de Lisboa (ULISBOA), Instituto de Conservaçao da natureza e das Florestas, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Universidade do Porto = University of Porto, Universidade de Lisboa = University of Lisbon (ULISBOA), ERC-2012-StG311000, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Universidade do Porto

Subjects
0301 basic medicine, Telomerase, animal structures, DNA repair, DNA damage, media_common.quotation_subject, Longevity, Myotis myotis, 03 medical and health sciences, 0302 clinical medicine, Species Specificity, Chiroptera, [SDV.BA.ZV]Life Sciences [q-bio]/Animal biology/Vertebrate Zoology, Genetics, Animals, Selection, Genetic, Gene, Research Articles, media_common, Multidisciplinary, biology, Body Weight, Rhinolophus ferrumequinum, SciAdv r-articles, Telomere, biology.organism_classification, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, 030104 developmental biology, Evolutionary biology, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, 030217 neurology & neurosurgery, Research Article
Abstract

Telomeres do not shorten with age in longest-lived bats., Understanding aging is a grand challenge in biology. Exceptionally long-lived animals have mechanisms that underpin extreme longevity. Telomeres are protective nucleotide repeats on chromosome tips that shorten with cell division, potentially limiting life span. Bats are the longest-lived mammals for their size, but it is unknown whether their telomeres shorten. Using >60 years of cumulative mark-recapture field data, we show that telomeres shorten with age in Rhinolophus ferrumequinum and Miniopterus schreibersii, but not in the bat genus with greatest longevity, Myotis. As in humans, telomerase is not expressed in Myotis myotis blood or fibroblasts. Selection tests on telomere maintenance genes show that ATM and SETX, which repair and prevent DNA damage, potentially mediate telomere dynamics in Myotis bats. Twenty-one telomere maintenance genes are differentially expressed in Myotis, of which 14 are enriched for DNA repair, and 5 for alternative telomere-lengthening mechanisms. We demonstrate how telomeres, telomerase, and DNA repair genes have contributed to the evolution of exceptional longevity in Myotis bats, advancing our understanding of healthy aging.

Published
2018
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13. Mycobiomes of sympatric Amorphophallus albispathus (Araceae) and Camellia sinensis (Theaceae) – a case study reveals clear tissue preferences and differences in diversity and composition

Author

David G. Würth, Nikki Heherson A. Dagamac, R. Henrik Nilsson, Kevin D. Hyde, Sébastien J. Puechmaille, Mathilde Borg Dahl, Christian Wurzbacher, Serena E. Dool, Michael G. Schöner, Michelle Galla, Abu Bakar Siddique, Kristina Wicke, Martin Unterseher, Caroline R. Schöner, García Roberto Cruz, Annette Teltewskoi, Samantha C. Karunarathna, Lina Herbst, Ernst-Moritz-Arndt-Universität Greifswald, Kunming Institute of Botany [CAS] (KIB), Chinese Academy of Sciences [Beijing] (CAS), University of Gothenburg (GU), and Mae Fah Luang University [Thaïlande] (MFU)

Subjects
0106 biological sciences, 0301 basic medicine, Biogeography, Biodiversity, 01 natural sciences, 03 medical and health sciences, Amorphophallus, Botany, Camellia sinensis, Mycobiome diversity, Internal transcribed spacer, Ecology, Evolution, Behavior and Systematics, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, High-throughput metabarcoding, Abiotic component, biology, Host (biology), fungi, food and beverages, Host specialization, Camellia, 030108 mycology & parasitology, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, biology.organism_classification, Agricultural and Biological Sciences (miscellaneous), Sympatric speciation, Tissue preferences of endophytes, 010606 plant biology & botany, [SDV.EE.IEO]Life Sciences [q-bio]/Ecology, environment/Symbiosis
Abstract

International audience; Multiple biotic and abiotic parameters influence the dynamics of individual fungal species and entire communities. Major drivers for tropical plant endophytes are undoubtedly seasonality, local habitat conditions and biogeography. However, host specialization and tissue preferences also contribute to the structuring of endophytic mycobiomes. To elucidate such specializations and preferences, we sampled two commercially important, unrelated plant species, Amorphophallus albispathus and Camellia sinensis (tea plant) simultaneously at close proximity. The mycobiomes of different tissue types were assessed with high-throughput amplicon sequencing of the internal transcribed spacer DNA region. Both plants hosted different fungal communities and varied in α-and β-diversity, despite their neighboring occurrence. However, the fungal assemblages of Amorphophallus leaflets shared taxa with the mycobiomes of tea leaves, thereby suggesting common driving forces for leaf-inhabiting fungi irrespective of host plant identity. The mycobiome composition and diversity of tea leaves was clearly driven by leaf age. We suggest that the very youngest tea leaves are colonized by stochastic processes, while mycobiomes of old leaves are rather similar as the result of progressive succession. The biodiversity of fungi associated with A. albispathus was characterized by a large number of unclassified OTUs (at genus and species level) and by tissue-specific composition.This study is the first cultivation-independent high-throughput assessment of fungal biodiversity of an Amorphophallus species, and additionally expands the knowledge base on fungi associated with tea plants.

Published
2018
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14. Is there a link between aging and microbiome diversity in exceptional mammalian longevity?

Author

Emma C. Teeling, Graham M. Hughes, Sébastien J. Puechmaille, John Leech, Jose V. Lopez, University College Dublin [Dublin] (UCD), University College Cork (UCC), Ernst-Moritz-Arndt-Universität Greifswald, and Nova Southeastern University (NSU)

Subjects
0106 biological sciences, 0301 basic medicine, Aging, Evolution, media_common.quotation_subject, lcsh:Medicine, Gut microbiota, Conservation, Myotis myotis, Comparative biology, Gut flora, 010603 evolutionary biology, 01 natural sciences, Microbiology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Information, Bats, Proteobacteria, [SDV.BA.ZV]Life Sciences [q-bio]/Animal biology/Vertebrate Zoology, Juvenile, Microbiome, Organism, media_common, Geography, biology, General Neuroscience, Communities, lcsh:R, Longevity, General Medicine, Fuel, biology.organism_classification, Host phylogeny, Phenotype, Evolutionary Studies, 030104 developmental biology, Metabolism, Flight, Evolutionary biology, Comparative Biology, General Agricultural and Biological Sciences, Zoology, [SDV.EE.IEO]Life Sciences [q-bio]/Ecology, environment/Symbiosis
Abstract

A changing microbiome has been linked to biological aging in mice and humans, suggesting a possible role of gut flora in pathogenic aging phenotypes. Many bat species have exceptional longevity given their body size and some can live up to ten times longer than expected with little signs of aging. This study explores the anal microbiome of the exceptionally long-lived Myotis myotis bat, investigating bacterial composition in both adult and juvenile bats to determine if the microbiome changes with age in a wild, long-lived non-model organism, using non-lethal sampling. The anal microbiome was sequenced using metabarcoding in more than 50 individuals, finding no significant difference between the composition of juvenile and adult bats, suggesting that age-related microbial shifts previously observed in other mammals may not be present in Myotis myotis. Functional gene categories, inferred from metabarcoding data, expressed in the M. myotis microbiome were categorized identifying pathways involved in metabolism, DNA repair and oxidative phosphorylation. We highlight an abundance of ‘Proteobacteria’ relative to other mammals, with similar patterns compared to other bat microbiomes. Our results suggest that M. myotis may have a relatively stable, unchanging microbiome playing a role in their extended ‘health spans’ with the advancement of age, and suggest a potential link between microbiome and sustained, powered flight.

Published
2018
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15. On computing the maximum parsimony score of a phylogenetic network

Author

Celine Scornavacca, Mareike Fischer, Steven Kelk, Leo van Iersel, RS: FSE DACS BMI, DKE Scientific staff, Ernst-Moritz-Arndt-Universität Greifswald, Delft University of Technology (TU Delft), Department of data science and Knowledge Engineering [Maastricht], Maastricht University [Maastricht], Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), and Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE)

Subjects
General Mathematics, F.2, 0206 medical engineering, G.2, approximability, Inference, 02 engineering and technology, Network topology, parsimony, Combinatorics, 03 medical and health sciences, phylogenetic networks, FOS: Mathematics, Mathematics - Combinatorics, [INFO]Computer Science [cs], Quantitative Biology - Populations and Evolution, Integer programming, 030304 developmental biology, Mathematics, Discrete mathematics, 0303 health sciences, Phylogenetic tree, AMS subject classifications. 68W25, 05C20, 90C27, 92B10, software, Populations and Evolution (q-bio.PE), Phylogenetic network, Tree (graph theory), Maximum parsimony, phylogenetic trees, Tree rearrangement, FOS: Biological sciences, fixed-parameter tractability, Combinatorics (math.CO), [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], complexity, Algorithm, 020602 bioinformatics
Abstract

International audience; Phylogenetic networks are used to display the relationship among different species whose evolution is not treelike, which is the case, for instance, in the presence of hybridization events or horizontal gene transfers. Tree inference methods such as maximum parsimony need to be modified in order to be applicable to networks. In this paper, we discuss two different definitions of maximum parsimony on networks, “hardwired” and “softwired,” and examine the complexity of computing them given a network topology and a character. By exploiting a link with the problem Multiterminal Cut, we show that computing the hardwired parsimony score for 2-state characters is polynomial-time solvable, while for characters with more states this problem becomes NP-hard but is still approximable and fixed parameter tractable in the parsimony score. On the other hand we show that, for the softwired definition, obtaining even weak approximation guarantees is already difficult for binary characters and restricted network topologies, and fixed-parameter tractable algorithms in the parsimony score are unlikely. On the positive side we show that computing the softwired parsimony score is fixed-parameter tractable in the level of the network, a natural parameter describing how tangled reticulate activity is in the network. Finally, we show that both the hardwired and the softwired parsimony scores can be computed efficiently using integer linear programming. The software has been made freely available.

Published
2015
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16. Genetic engineering of the branched fatty acid metabolic pathway of Bacillus subtilis for the overproduction of surfactin C14 isoform

Author

Sandrine Auger, Philippe Jacques, Debarun Dhali, Michael Lalk, Vladimir Bidnenko, Joana Sousa, Joachim Niehren, Gabrielle Chataigné, Anthony Arguelles Arias, François Coutte, Cristian Versari, Institut Charles Viollette (ICV) - EA 7394 (ICV), Université d'Artois (UA)-Institut National de la Recherche Agronomique (INRA)-Université du Littoral Côte d'Opale (ULCO)-Institut Supérieur d'Agriculture-Université de Lille, Laboratoire de Procédés Biologiques, Génie Enzymatique et Microbien (ProBioGEM), Université de Lille, Sciences et Technologies-École polytechnique universitaire de Lille (Polytech Lille), Unité de recherche TERRA [Gembloux], Gembloux Agro-Bio Tech [Gembloux], Université de Liège-Université de Liège, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Ernst-Moritz-Arndt-Universität Greifswald, BioComputing, Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 (CRIStAL), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Linking Dynamic Data (LINKS), Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 (CRIStAL), European INTERREG V BioProd project, French National Research Agency (ANR) [ANR-11-EQPX-0037], European Project: 317338,EC:FP7:PEOPLE,FP7-PEOPLE-2012-ITN,AMBER(2013), Centre de Recherche en Informatique, Signal et Automatique de Lille (CRIStAL) - UMR 9189 (CRIStAL), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Ecole Centrale de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Ecole Centrale de Lille, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Informatique, Signal et Automatique de Lille (CRIStAL) - UMR 9189 (CRIStAL), Transfrontalière BioEcoAgro - UMR 1158 (BioEcoAgro), Université d'Artois (UA)-Université de Liège-Université de Picardie Jules Verne (UPJV)-Université du Littoral Côte d'Opale (ULCO)-Université de Lille-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-JUNIA (JUNIA), and Université catholique de Lille (UCL)-Université catholique de Lille (UCL)

Subjects
0301 basic medicine, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Operon, [SDV]Life Sciences [q-bio], 030106 microbiology, Branched-chain amino acid, Mutant, Bacillus subtilis, Metabolic networks, Applied Microbiology and Biotechnology, 03 medical and health sciences, chemistry.chemical_compound, chemistry.chemical_classification, biology, Wild type, Fatty acid, General Medicine, biology.organism_classification, Metabolic pathway, chemistry, Biochemistry, Molecular Medicine, lipids (amino acids, peptides, and proteins), Knockout prediction, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Surfactin, Systems biology
Abstract

International audience; Surfactin, a lipopeptide produced by Bacillus subtilis, is one of the most powerful biosurfactants known. This molecule consists of a cyclic heptapeptide linked to a β-hydroxy fatty acid chain. The isomery and the length of the fatty acid (FA) chain are responsible for the surfactin’s activities. In this study, the gene codY, which encode for the global transcriptional regulator and the gene lpdV, located in the bkd operon (lpdV, bkdAA, bkdAB and bkdB genes), which is responsible for the last step of the branched chain amino acid (BCAA) degradation in acyl- CoA were deleted. The influence of these deletions on the quantitative and qualitative surfactin production was analysed. The surfactin production was quantified by RP-HPLC and the surfactin isoforms were characterized using LC-MS-MS and GC-MS analysis. The results obtained in the mutants showed an enhancement of surfactin specific production by a factor of 5.8 for the codY mutant and 1.4 for lpdV mutant. Moreover qualitative analysis of the lpdV mutant reveals that it mainly produced surfactin C14 isoform (2 fold more than the wild type) with linear FA chain. Complete analysis of the extracellular metabolites using 1H quantitative NMR reveals a reduced production of acetoin in this mutant. This work demonstrates for the first time an original approach to overproduce specifically surfactin with C14 FA chain.

Published
2017
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17. Global Network Reorganization During Dynamic Adaptations of Bacillus subtilis Metabolism

Author

Claus Hultschig, Patrick Veiga, Edda Klipp, Michael Hecker, Annette Hansen, Etienne Dervyn, Elena Bidnenko, Philippe Noirot, Bernd Hessling, Emma L. Denham, Markus Uhr, Susanne Pohl, Ludovic Le Chat, Joerg Martin Buescher, Benno Schwikowski, Hanne Østergaard Jarmer, Jan Muntel, Bernd Rinn, Pierre Nicolas, Jan Maarten van Dijl, Roelco J. Kleijn, Simon Rasmussen, Colin R. Harwood, Samuel Drulhe, Liza Felicori, Jörg Stelling, Sean Walsh, Kevin M. Devine, Frank Rügheimer, Nathalie Pigeonneau, Dörte Becher, Mark J. Fogg, Peter J. Lewis, Eric Botella, Geoff Doherty, Philippe Bessières, Ulrike Mäder, Marc Schaffer, Sjouke Piersma, Stéphane Aymerich, Anthony J. Wilkinson, Anne Goelzer, Julian Schnidder, F. Molina, Wolfram Liebermeister, Uwe Sauer, Sabine Peres, Sebastian Hubner, Matthieu Jules, François Lecointe, Aurélie Leduc, Institute of Molecular Systems Biology [Zurich], Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Theoretical Biophysics [Berlin], Humboldt Universität zu Berlin, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Department of Biosystems Science and Engineering [ETH Zürich] (D-BSSE), Institut für Mikrobiologie - Institute for Microbiology, Universität Greifswald - University of Greifswald, Smurfit Institute of Genetics, Trinity College Dublin, Unité Mathématique, Informatique et Génome (MIG), Institut National de la Recherche Agronomique (INRA), Department of Medical Microbiology, University of Groningen [Groningen], Biologie systémique - Systems Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), School of Environmental and Life Sciences, Newcastle University [Newcastle], Sysdiag CNRS Bio-Rad UMR 3145, Cap Delta/Parc Euromédecine, Centre National de la Recherche Scientifique (CNRS), York Structural Biology Laboratory, Department of Chemistry, University of York [York, UK], Centre for Bacterial Cell Biology, Institute of Cell and Molecular Biosciences, Center for Information Sciences and Databases - Department of Biosystems Science and Engineering, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark [Lyngby] (DTU), Centre for Bacterial Cell Biology, Institute, of Cell and Molecular Biosciences, University of Northumbria at Newcastle [United Kingdom], Institute Molecular Systems Biology, Center for Information Sciences and Databases, Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Humboldt-Universität zu Berlin, Departement Erdwissenschaften [ETH Zürich] (D-ERDW), Humboldt University Of Berlin, Genes and Behavior Department [Göttingen], Max Planck Institute for Biophysical Chemistry (MPI-BPC), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Ernst-Moritz-Arndt-Universität Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Biosynthèse des Signaux Peptidiques [IBPS] (IBPS-BIOSIPE), Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University Medical Center Groningen, Partenaires INRAE, Biologie Systémique, Institut Pasteur [Paris] (IP), Unité Mathématique Informatique et Génome (MIG), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Sysdiag-Modélisation et Ingénierie des Systèmes Complexes Biologiques pour le Diagnostic (SysDiag ), BIO-RAD-Centre National de la Recherche Scientifique (CNRS), This work was funded through the European Commission 7th Framework project BaSys Bio (LSHG-CT-2006-037469), coordinated by P. Noirot, the Department of Education, Science and Training (CG110055),and the National Health and Medical Research Council (455646), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Faculteit Medische Wetenschappen/UMCG, Microbes in Health and Disease (MHD), and Translational Immunology Groningen (TRIGR)

Subjects
carbon metabolism, Transcription, Genetic, Operon, [SDV]Life Sciences [q-bio], Gene regulatory network, Malates, Bacillus subtilis, Transcriptional regulation, Gene Regulatory Networks, bacteria, Promoter Regions, Genetic, bacterie, 0303 health sciences, Multidisciplinary, TRANSCRIPTIONAL REGULATION, regulation, Adaptation, Physiological, Biochemistry, ESCHERICHIA-COLI, Data Interpretation, Statistical, Metabolome, Algorithms, Metabolic Networks and Pathways, Computational biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Models, Biological, 03 medical and health sciences, Metabolomics, Bacterial Proteins, SYSTEMS, metabolisme du carbone, Computer Simulation, YEAST, RECONSTRUCTION, Reorganization, Gene, 030304 developmental biology, COMPLEXITY, 030306 microbiology, BIOLOGIE, Gene Expression Regulation, Bacterial, BIOLOGIE MOLECULAIRE, biology.organism_classification, Glucose, Adaptation, STARVATION, Genome, Bacterial, Transcription Factors
Abstract

Outside In Acquisition and analysis of large data sets promises to move us toward a greater understanding of the mechanisms by which biological systems are dynamically regulated to respond to external cues. Now, two papers explore the responses of a bacterium to changing nutritional conditions (see the Perspective by Chalancon et al. ). Nicolas et al. (p. 1103 ) measured transcriptional regulation for more than 100 different conditions. Greater amounts of antisense RNA were generated than expected and appeared to be produced by alternative RNA polymerase targeting subunits called sigma factors. One transition, from malate to glucose as the primary nutrient, was studied in more detail by Buescher et al. (p. 1099 ) who monitored RNA abundance, promoter activity in live cells, protein abundance, and absolute concentrations of intracellular and extracellular metabolites. In this case, the bacteria responded rapidly and largely without transcriptional changes to life on malate, but only slowly adapted to use glucose, a shift that required changes in nearly half the transcription network. These data offer an initial understanding of why certain regulatory strategies may be favored during evolution of dynamic control systems.

Published
2012
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18. Isolation and characterisation of microsatellite loci for two species of Spinturnicid bat wing mites (Spinturnix myoti and Spinturnix bechsteini)

Author

Nadia Bruyndonckx, Gerald Kerth, Philippe Christe, Jaap van Schaik, Max Planck Institute for Ornithology, Max-Planck-Gesellschaft, Université de Lausanne (UNIL), and Ernst-Moritz-Arndt-Universität Greifswald

Subjects
0106 biological sciences, Spinturnicidae, Linkage disequilibrium, coadaptation, Arthropoda, Zoology, Population genetics, Locus (genetics), bat, Myotis myotis, Spinturnix, Biology, Acariformes, 010603 evolutionary biology, 01 natural sciences, microsatellites, 03 medical and health sciences, Arachnida, Parasite hosting, Animalia, Acari, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, wing mite, 030304 developmental biology, Taxonomy, 0303 health sciences, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Myotis, ectoparasite, population genetics, Biodiversity, biology.organism_classification, Insect Science, Mesostigmata, Microsatellite, [SDV.EE.IEO]Life Sciences [q-bio]/Ecology, environment/Symbiosis
Abstract

International audience; To investigate the potential for host-parasite coadaptation between bats and their wing mites, we developed microsatellite loci for two species of Spinturnix mites. For Spinturnix myoti, parasite of Myotis myotis, we were able to develop nine polymorphic loci and screened them in 100 mites from five bat colonies. For S. bechsteini, parasite of M. bechsteinii, we developed five polymorphic loci, which were also screened in 100 mites from five bat colonies. In both species, all markers were highly polymorphic (22-46 and 6-23 alleles per locus respectively). The majority of markers for both species exhibited departure from Hardy-Weinberg proportions (8 of 9 and 3 of 5, respectively). One marker pair in S. myoti showed evidence for linkage disequilibrium. As the observed departures from Hardy-Weinberg proportions are most likely a consequence of the biology of the mites, the described microsatellite loci should be useful in studying population genetics and host-parasite dynamics of Spinturnix myoti and Spinturnix bechsteini in relation to their bat hosts.

Published
2011
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19. Investigation of the Staphylococcus aureus GraSR regulon reveals novel links to virulence, stress response and cell wall signal transduction pathways

Author

Ulrike Mäder, Aurélia Hiron, Michel Débarbouillé, Tarek Msadek, Mélanie Falord, Biologie des Bactéries Pathogènes à Gram-positif, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-Universität Greifswald, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Tours (UT), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Université de Tours

Subjects
Operon, [SDV]Life Sciences [q-bio], lcsh:Medicine, Gene Expression, Genetic Networks, Pathogenesis, Transcriptomes, Transcriptome, Cell Wall, Transcriptional regulation, Homeostasis, lcsh:Science, Promoter Regions, Genetic, ComputingMilieux_MISCELLANEOUS, Staphylococci, Regulation of gene expression, Genetics, 0303 health sciences, Multidisciplinary, Virulence, Microbiology and Parasitology, Temperature, Genomics, Microbiologie et Parasitologie, Functional Genomics, Bacterial Pathogens, Host-Pathogen Interaction, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Signal transduction, Research Article, Protein Binding, Signal Transduction, Staphylococcus aureus, Molecular Sequence Data, Biology, Microbiology, Regulon, Molecular Genetics, 03 medical and health sciences, Bacterial Proteins, Genome Analysis Tools, Stress, Physiological, Consensus Sequence, Drug Resistance, Bacterial, Humans, Gene Regulation, Gene Networks, Microbial Pathogens, Gene, 030304 developmental biology, Gram Positive, Binding Sites, Base Sequence, Colistin, 030306 microbiology, Gene Expression Profiling, lcsh:R, Gene Expression Regulation, Bacterial, Oxidative Stress, Genes, Bacterial, lcsh:Q, Gene Function, Genome Expression Analysis, Antimicrobial Cationic Peptides
Abstract

International audience; The GraS/GraR two-component system has been shown to control cationic antimicrobial peptide (CAMP) resistance in the major human pathogen Staphylococcus aureus. We demonstrated that graX, also involved in CAMP resistance and cotranscribed with graRS, encodes a regulatory cofactor of the GraSR signaling pathway, effectively constituting a three-component system. We identified a highly conserved ten base pair palindromic sequence (5' ACAAA TTTGT 3') located upstream from GraR-regulated genes (mprF and the dlt and vraFG operons), which we show to be essential for transcriptional regulation by GraR and induction in response to CAMPs, suggesting it is the likely GraR binding site. Genome-based predictions and transcriptome analysis revealed several novel GraR target genes. We also found that the GraSR TCS is required for growth of S. aureus at high temperatures and resistance to oxidative stress. The GraSR system has previously been shown to play a role in S. aureus pathogenesis and we have uncovered previously unsuspected links with the AgrCA peptide quorum-sensing system controlling virulence gene expression. We also show that the GraSR TCS controls stress reponse and cell wall metabolism signal transduction pathways, sharing an extensive overlap with the WalKR regulon. This is the first report showing a role for the GraSR TCS in high temperature and oxidative stress survival and linking this system to stress response, cell wall and pathogenesis control pathways.

Published
2011
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20. Impact of glutamine transporters on pneumococcal fitness under infection-related conditions

Author

Matthias Klein, Sven Hammerschmidt, Uwe Koedel, Tobias Härtel, Manfred Rohde, Lothar Petruschka, and Department of Genetics of Microorganisms, Interfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt Universität Greifswald, Friedrich-Ludwig-Jahn-Str. 15a, D-17487 Greifswald, Germany.

Subjects
Phagocytosis, Immunology, Virulence, Biology, medicine.disease_cause, Microbiology, Pneumococcal Infections, Cell Line, Meningitis, Bacterial, Sepsis, 03 medical and health sciences, Mice, Bacterial Proteins, In vivo, Streptococcus pneumoniae, medicine, Animals, 030304 developmental biology, 0303 health sciences, 030306 microbiology, Computational Biology, Gene Expression Regulation, Bacterial, medicine.disease, Molecular Pathogenesis, Glutamine, Pneumococcal infections, Infectious Diseases, Pneumococcal pneumonia, Mutation, Parasitology, Carrier Proteins
Abstract

The genomic analysis of Streptococcus pneumoniae predicted six putative glutamine uptake systems, which are expressed under in vitro conditions, as shown here by reverse transcription-PCR. Four of these operons consist of glnHPQ , while two lack glnH , which encodes a soluble glutamine-binding protein. Here, we studied the impact of two of these glutamine ATP-binding cassette transporters on S . pneumoniae D39 virulence and phagocytosis, which consist of GlnQ and a translationally fused protein of GlnH and GlnP. Mice infected intranasally with D39Δ gln0411 / 0412 showed significantly increased survival times and a significant delay in the development of pneumococcal pneumonia compared to those infected with D39, as observed in real time using bioluminescent pneumococci. In a mouse sepsis model, the mutant D39Δ gln0411 / 0412 showed only moderate but significant attenuation. In contrast, the D39Δ gln1098 / 1099 knockout strain was massively attenuated in the pneumonia and septicemia mouse infection model. To cause pneumonia or sepsis with D39Δ gln1098 / 1099 , infection doses 100- to 10,000-fold higher than those used for wild-type strain D39 were required. In an experimental mouse meningitis model, D39Δ gln1098 / 1099 produced decreased levels of white blood cells in cerebrospinal fluid and showed decreased numbers of bacteria in the bloodstream compared to D39 and D39Δ gln0411 / 0412 . Phagocytosis experiments revealed significantly decreased intracellular survival rates of mutants D39Δ gln1098 / 1099 and D39Δ gln0411 / 0412 compared to wild-type D39, suggesting that the deficiency of Gln uptake systems impairs resistance to oxidative stress. Taken together, our results demonstrate that both glutamine uptake systems are required for full virulence of pneumococci but exhibit different impacts on the pathogenesis of pneumococci under in vivo conditions.

Published
2010

21. Guidelines for the next 10 years of proteomics

Author

Stephen R. Pennington, Ron D. Appel, Marc R. Wilkins, Michael Hecker, Richard J. Simpson, Scott D. Patterson, Maxey C. M. Chung, Walter Weiss, Thierry Rabilloud, Young Ki Paik, Andrew J. Link, Jennifer E. Van Eyk, Lukas A. Huber, Hanno Langen, Angelika Görg, Michael J. Dunn, Department of Biotechnology and Biomolecular Biosciences, University of New South Wales [Sydney] (UNSW), Swiss Institute of Bioinformatics (SIB/ISB), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Departments of Medicine, Biological Chemistry and Biomedical Engineering, Johns Hopkins University (JHU), Department of Biochemistry, National University of Singapore (NUS), Department of Proteomics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Institut fur Mikrobiologie, Ernst-Moritz-Arndt-Universität Greifswald, Biocenter, Div. Cell Biology, Leopold Franzens Universität Innsbruck - University of Innsbruck, Roche Center for Medical Genomics, F. Hoffmann-La Roche [Basel], Department of Microbiology and Immunology, Vanderbilt University [Nashville], Yonsei Proteome Research Center and Department of Biochemistry, Yonsei University, Amgen, Molecular Sciences, Amgen, Proteome Research Centre, UCD Conway Institute for Biomolecular and Biomedical Research, University College Dublin [Dublin] (UCD), Biochimie et biophysique des systèmes intégrés (BBSI), Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Ludwig Institute for Cancer Research, Université de Lausanne (UNIL)-Université de Lausanne (UNIL), UNIV NATIONALE DE SINGAPOUR, University of Innsbruck, Hoffmann-La Roche, and Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)

Subjects
Proteomics, Computer science, Test data generation, media_common.quotation_subject, Guidelines as Topic, 01 natural sciences, Biochemistry, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Quality (business), Quantitative Biology - Genomics, Electrophoresis, Gel, Two-Dimensional, Biomarker discovery, Set (psychology), Molecular Biology, 030304 developmental biology, media_common, Genomics (q-bio.GN), 0303 health sciences, Rapid rate, MESH: Proteomics, 010401 analytical chemistry, MESH: Biological Markers, MESH: Guidelines as Topic, MESH: Electrophoresis, Gel, Two-Dimensional, Data science, 0104 chemical sciences, Variety (cybernetics), FOS: Biological sciences, Protein identification, Biomarkers
Abstract

International audience; In the last ten years, the field of proteomics has expanded at a rapid rate. A range of exciting new technology has been developed and enthusiastically applied to an enormous variety of biological questions. However, the degree of stringency required in proteomic data generation and analysis appears to have been underestimated. As a result, there are likely to be numerous published findings that are of questionable quality, requiring further confirmation and/or validation. This manuscript outlines a number of key issues in proteomic research, including those associated with experimental design, differential display and biomarker discovery, protein identification and analytical incompleteness. In an effort to set a standard that reflects current thinking on the necessary and desirable characteristics of publishable manuscripts in the field, a minimal set of guidelines for proteomics research is then described. These guidelines will serve as a set of criteria which editors of PROTEOMICS will use for assessment of future submissions to the Journal.

Published
2006
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22. The Bacillus subtilis clpC operon encodes DNA repair and competence proteins

Author

Tarek Msadek, Steffen Ohlmeier, EIke Krüger, Michael Hecker, Ernst-Moritz-Arndt-Universität Greifswald, Biochimie Microbienne, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported by grants from the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie to M. H., and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Operon, MESH: Sequence Analysis, DNA, DNA Repair, Operon, DNA repair, MESH: Sequence Homology, Amino Acid, Ultraviolet Rays, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Bacillus subtilis, MESH: Amino Acid Sequence, MESH: Transformation, Genetic, Biology, MESH: Heat-Shock Proteins, MESH: Phenotype, Microbiology, Genetic recombination, Gene product, 03 medical and health sciences, chemistry.chemical_compound, Open Reading Frames, Transformation, Genetic, Bacterial Proteins, Amino Acid Sequence, Gene, MESH: Bacterial Proteins, Heat-Shock Proteins, 030304 developmental biology, Genetics, MESH: DNA Repair, 0303 health sciences, MESH: Molecular Sequence Data, Sequence Homology, Amino Acid, 030306 microbiology, Sequence Analysis, DNA, MESH: Bacillus subtilis, MESH: Open Reading Frames, biology.organism_classification, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Phenotype, chemistry, Excinuclease, MESH: Ultraviolet Rays, DNA
Abstract

ClpC of Bacillus subtilis, controlling competence gene expression and survival under stress conditions, is encoded by the fourth gene of a six-gene operon. The product of orf1 contains a potential helix-turn-helix motif, but shows no significant similarities with known protein sequences. The second and third genes encode proteins with similarities to zinc-finger proteins (orf2) and arginine kinases (orf3), respectively. The product of orf5 contains a zinc-finger motif and an ATP-binding domain, and is highly similar to the product of the Escherichia coli sms gene. A strain bearing a disruption of orf5 showed increased sensitivity to the alkylating agent methyl methanesulfonate. Furthermore, this mutant strain displayed decreased capacity for genetic recombination as measured by transformation experiments. The last open reading frame, orf6, encodes a protein with limited similarity in its C-terminal part to the B. subtilis comEA gene product and to the UvrC DNA repair excinuclease. Inactivation of orf5 resulted in strongly diminished transformation with all types of DNA. Mutations affecting either orf5 or orf6 resulted in strains with decreased resistance to UV-irradiation in the stationary phase, indicating that these proteins play a role in the development of a nonspecific stationary-phase resistance to UV-irradiation. Moreover, these results suggest an involvement of both proteins in transformation and presumably in DNA repair.

Published
1997
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23. Alternate promoters direct stress-induced transcription of the Bacillus subtilis clpC operon

Author

Elke Krüger, Tarek Msadek, Michael Hecker, Ernst-Moritz-Arndt-Universität Greifswald, Biochimie Microbienne, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported by grants to M.H. from the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie., and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Operon, Transcription, Genetic, Operon, MESH: Puromycin, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Bacillus subtilis, Biology, MESH: Base Sequence, Microbiology, Polymerase Chain Reaction, 03 medical and health sciences, chemistry.chemical_compound, MESH: Autoradiography, Transcription (biology), Sigma factor, RNA polymerase, MESH: Promoter Regions, Genetic, Consensus sequence, MESH: Blotting, Northern, RNA, Messenger, Promoter Regions, Genetic, Molecular Biology, 030304 developmental biology, MESH: RNA, Messenger, 0303 health sciences, MESH: Molecular Sequence Data, Base Sequence, 030306 microbiology, MESH: Transcription, Genetic, fungi, Promoter, MESH: Polymerase Chain Reaction, Hydrogen Peroxide, MESH: Bacillus subtilis, biology.organism_classification, Blotting, Northern, Molecular biology, MESH: Mutagenesis, Site-Directed, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, chemistry, Mutagenesis, Site-Directed, Autoradiography, bacteria, MESH: Hydrogen Peroxide, Puromycin, CLPB
Abstract

International audience; clpC of Bacillus subtilis is part of an operon containing six genes. Northern blot analysis suggested that all genes are co-transcribed and encode stress-inducible proteins. Two promoters (PA and PB) were mapped upstream of the first gene. PA resembles promoters recognized by the vegetative RNA polymerase E sigma A. The other promoter (PB) was shown to be dependent on sigma B, the general stress sigma factor in B. subtilis, suggesting that clpC, a potential chaperone, is expressed in a sigma B-dependent manner. This is the first evidence that sigma B in B. subtilis is involved in controlling the expression of a gene whose counterpart, clpB, is subject to regulation by sigma 32 in Escherichia coli, indicating a new function of sigma B-dependent general stress proteins. PB deviated from the consensus sequence of sigma B promoters and was only slightly induced by starvation conditions. Nevertheless, strong induction by heat, ethanol, and salt stress occurred at the sigma B-dependent promoter, whereas the vegetative promoter was only weakly induced under these conditions. However, in a sigB mutant, the sigma A-like promoter became inducible by heat and ethanol stress, completely compensating for sigB deficiency. Only the downstream sigma A-like promoter was induced by certain stress conditions such as hydrogen peroxide or puromycin. These results suggest that novel stress-induction mechanisms are acting at a vegetative promoter. Involvement of additional elements in this mode of induction are discussed.

Published
1996
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