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Biochemical and Cellular Studies of Vertebrate Globins
Biochemical and Cellular Studies of Vertebrate Globins By Shun Wilford Tse Thesis submitted for the degree of Doctor of Philosophy School of Biological Sciences University of East Anglia September 2015 © This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with the author and that no quotations from the thesis, nor any information derived there-from may be published without the author's prior, written consent. Abstract Human cytoglobin is a small heme-containing protein in the globin superfamily with a wide range of tissue and organ distribution. Although several cellular functions have been proposed for cytoglobin, the exact physiological function is still not fully defined. Recently, cytoglobin has been implicated to have a regulatory role in cancer cells to control cell proliferation and migration depending on cellular oxygen level. In order to gain a better understanding of a structure-to-function relationship of cytoglobin as a heme-protein and to evaluate its possible physiological function(s) in cancer cells, a combination of techniques, including protein engineering and advanced spectroscopies, was deployed. In this study, recombinant human cytoglobin purified from E.coli was purified as a monomeric protein, but displayed a dimeric property in solution. An intra-molecular disulphide bond is formed within the protein which has a redox potential at ca -280 mV. Advanced spectroscopic studies confirmed a low-spin bis-histidyl heme in cytoglobin in both ferric and ferrous state regardless of the state of the disulphide bond. Furthermore, nitrite reductase activitiy in globins was investigated in detail using myoglobin as a model to explore the biochemical basis of the distal histidine residue in determining activity. -
Adult, Embryonic and Fetal Hemoglobin Are Expressed in Human Glioblastoma Cells
514 INTERNATIONAL JOURNAL OF ONCOLOGY 44: 514-520, 2014 Adult, embryonic and fetal hemoglobin are expressed in human glioblastoma cells MARWAN EMARA1,2, A. ROBERT TURNER1 and JOAN ALLALUNIS-TURNER1 1Department of Oncology, University of Alberta and Alberta Health Services, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada; 2Center for Aging and Associated Diseases, Zewail City of Science and Technology, Cairo, Egypt Received September 7, 2013; Accepted October 7, 2013 DOI: 10.3892/ijo.2013.2186 Abstract. Hemoglobin is a hemoprotein, produced mainly in Introduction erythrocytes circulating in the blood. However, non-erythroid hemoglobins have been previously reported in other cell Globins are hemo-containing proteins, have the ability to types including human and rodent neurons of embryonic bind gaseous ligands [oxygen (O2), nitric oxide (NO) and and adult brain, but not astrocytes and oligodendrocytes. carbon monoxide (CO)] reversibly. They have been described Human glioblastoma multiforme (GBM) is the most aggres- in prokaryotes, fungi, plants and animals with an enormous sive tumor among gliomas. However, despite extensive basic diversity of structure and function (1). To date, hemoglobin, and clinical research studies on GBM cells, little is known myoglobin, neuroglobin (Ngb) and cytoglobin (Cygb) repre- about glial defence mechanisms that allow these cells to sent the vertebrate globin family with distinct function and survive and resist various types of treatment. We have tissue distributions (2). During ontogeny, developing erythro- shown previously that the newest members of vertebrate blasts sequentially express embryonic {[Gower 1 (ζ2ε2), globin family, neuroglobin (Ngb) and cytoglobin (Cygb), are Gower 2 (α2ε2), and Portland 1 (ζ2γ2)] to fetal [Hb F(α2γ2)] expressed in human GBM cells. -
Technical Note, Appendix: an Analysis of Blood Processing Methods to Prepare Samples for Genechip® Expression Profiling (Pdf, 1
Appendix 1: Signature genes for different blood cell types. Blood Cell Type Source Probe Set Description Symbol Blood Cell Type Source Probe Set Description Symbol Fraction ID Fraction ID Mono- Lympho- GSK 203547_at CD4 antigen (p55) CD4 Whitney et al. 209813_x_at T cell receptor TRG nuclear cytes gamma locus cells Whitney et al. 209995_s_at T-cell leukemia/ TCL1A Whitney et al. 203104_at colony stimulating CSF1R lymphoma 1A factor 1 receptor, Whitney et al. 210164_at granzyme B GZMB formerly McDonough (granzyme 2, feline sarcoma viral cytotoxic T-lymphocyte- (v-fms) oncogene associated serine homolog esterase 1) Whitney et al. 203290_at major histocompatibility HLA-DQA1 Whitney et al. 210321_at similar to granzyme B CTLA1 complex, class II, (granzyme 2, cytotoxic DQ alpha 1 T-lymphocyte-associated Whitney et al. 203413_at NEL-like 2 (chicken) NELL2 serine esterase 1) Whitney et al. 203828_s_at natural killer cell NK4 (H. sapiens) transcript 4 Whitney et al. 212827_at immunoglobulin heavy IGHM Whitney et al. 203932_at major histocompatibility HLA-DMB constant mu complex, class II, Whitney et al. 212998_x_at major histocompatibility HLA-DQB1 DM beta complex, class II, Whitney et al. 204655_at chemokine (C-C motif) CCL5 DQ beta 1 ligand 5 Whitney et al. 212999_x_at major histocompatibility HLA-DQB Whitney et al. 204661_at CDW52 antigen CDW52 complex, class II, (CAMPATH-1 antigen) DQ beta 1 Whitney et al. 205049_s_at CD79A antigen CD79A Whitney et al. 213193_x_at T cell receptor beta locus TRB (immunoglobulin- Whitney et al. 213425_at Homo sapiens cDNA associated alpha) FLJ11441 fis, clone Whitney et al. 205291_at interleukin 2 receptor, IL2RB HEMBA1001323, beta mRNA sequence Whitney et al. -
Recombinant Human Hemoglobin Subunit Theta-1/HBQ1 (N-6His)
9853 Pacific Heights Blvd. Suite D. San Diego, CA 92121, USA Tel: 858-263-4982 Email: [email protected] 32-8592: Recombinant Human Hemoglobin Subunit theta-1/HBQ1 (N-6His) Gene : HBQ1 Gene ID : 3049 Uniprot ID : P09105 Description Source: E.coli. MW :17.7kD. Recombinant Human Hemoglobin subunit theta-1 is produced by our E.coli expression system and the target gene encoding Met1-Arg142 is expressed with a 6His tag at the N-terminus. Hemoglobin subunit theta-1 is a protein that in humans is encoded by the HBQ1 gene. Theta-globin mRNA is originally found in human fetal erythroid tissue but not in adult erythroid or other nonerythroid tissue. Theta-1 is a member of the human alpha-globin gene cluster that includes five functional genes and two pseudogenes. Research supports a transcriptionally active role for the gene and a functional role for the peptide in specific cells, possibly those of early erythroid tissue. Hemoglobin has a quaternary structure characteristically composed of many multi- subunit globular proteins. Most of the amino acids in hemoglobin form alpha helices, connected by short non-helical segments. Hydrogen bonds stabilize the helical sections inside this protein, causing attractions within the molecule, folding each polypeptide chain into a specific shape. Hemoglobin's quaternary structure comes from its four subunits in roughly a tetrahedral arrangement. Product Info Amount : 10 µg / 50 µg Content : Lyophilized from a 0.2 µm filtered solution of 20mM PB, 150mM NaCl, pH 7.0. Lyophilized protein should be stored at -20°C, though stable at room temperature for 3 weeks. -
Neuroglobin and Cytoglobin Fresh Blood for the Vertebrate Globin Family
EMBO reports Neuroglobin and cytoglobin Fresh blood for the vertebrate globin family Alessandra Pesce, Martino Bolognesi+, Alessio Bocedi1, Paolo Ascenzi1, Sylvia Dewilde2, Luc Moens2, Thomas Hankeln3 & Thorsten Burmester4 Department of Physics–INFM and Center for Excellence in Biomedical Research, University of Genova, Via Dodecaneso 33, I-16146 Genova, 1Department of Biology, University ‘Roma Tre’, Viale Guglielmo Marconi 446, I-00146 Roma, Italy, 2Department of Biochemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium, 3Institute of Molecular Genetics, Johannes Gutenberg University of Mainz, Becherweg 32, D-55099 Mainz and 4Institute of Zoology, Johannes Gutenberg University of Mainz, Müllerweg 6, D-55099 Mainz, Germany Received August 7, 2002; revised October 8, 2002; accepted October 18, 2002 Neuroglobin and cytoglobin are two recently discovered (Wittenberg, 1970, 1992; Antonini and Brunori, 1971; Perutz, members of the vertebrate globin family. Both are intracellular 1979, 1990; Dickerson and Geis, 1983; Bunn and Forget, 1986; proteins endowed with hexacoordinated heme-Fe atoms, in Brunori, 1999; Weber and Vinogradov, 2001; Merx et al., 2002), their ferrous and ferric forms, and display O2 affinities comparable although they can also carry out enzymatic functions (Minning with that of myoglobin. Neuroglobin, which is predominantly et al., 1999; Ascenzi et al., 2001). expressed in nerve cells, is thought to protect neurons from Four types of globin, differing in structure, tissue distribution hypoxic–ischemic injury. It is of ancient evolutionary origin, and likely in function, have been discovered in man and other and is homologous to nerve globins of invertebrates. vertebrates: hemoglobin, myoglobin, neuroglobin and cyto- Cytoglobin is expressed in many different tissues, although at globin. -
A Gene-Environment Study of Cytoglobin in the Human and Rat Hippocampus
A Gene-Environment Study of Cytoglobin in the Human and Rat Hippocampus Christian Ansgar Hundahl1,3, Betina Elfving2, Heidi Kaastrup Mu¨ ller2, Anders Hay-Schmidt3, Gregers Wegener2,4* 1 Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia, 2 Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark, 3 Department of Neuroscience and Pharmacology, The Panum Institute, University of Copenhagen, Copenhagen, Denmark, 4 Unit for Drug Research and Development, School of Pharmacy (Pharmacology), North-West University, Potchefstroom, South Africa Abstract Background: Cytoglobin (Cygb) was discovered a decade ago as the fourth vertebrate heme-globin. The function of Cygb is still unknown, but accumulating evidence from in vitro studies point to a putative role in scavenging of reactive oxygen species and nitric oxide metabolism and in vivo studies have shown Cygb to be up regulated by hypoxic stress. This study addresses three main questions related to Cygb expression in the hippocampus: 1) Is the rat hippocampus a valid neuroanatomical model for the human hippocampus; 2) What is the degree of co-expression of Cygb and neuronal nitric oxide synthase (nNOS) in the rat hippocampus; 3) The effect of chronic restraint stress (CRS) on Cygb and nNOS expression. Methods: Immunohistochemistry was used to compare Cygb expression in the human and rat hippocampi as well as Cygb and nNOS co-expression in the rat hippocampus. Transcription and translation of Cygb and nNOS were investigated using quantitative real-time polymerase chain reaction (real-time qPCR) and Western blotting on hippocampi from Flinders (FSL/ FRL) rats exposed to CRS. Principal Findings: Cygb expression pattern in the human and rat hippocampus was found to be similar. -
Simultaneous Detection of Target Cnvs and Snvs of Thalassemia by Multiplex PCR and Next‑Generation Sequencing
MOLECULAR MEDICINE REPORTS 19: 2837-2848, 2019 Simultaneous detection of target CNVs and SNVs of thalassemia by multiplex PCR and next‑generation sequencing DONG-MEI FAN1*, XU YANG2*, LI-MIN HUANG1, GUO-JUN OUYANG3, XUE-XI YANG1 and MING LI1 1Institute of Antibody Engineering, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515; 2Clinical Innovation and Research Center, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong 518110; 3Guangzhou Darui Biotechnology Co., Ltd., Guangzhou, Guangdong 510663, P.R. China Received May 16, 2018; Accepted December 3, 2018 DOI: 10.3892/mmr.2019.9896 Abstract. Thalassemia is caused by complex mechanisms, Introduction including copy number variants (CNVs) and single nucleotide variants (SNVs). The CNV types of α-thalassemia are typi- Thalassemia is caused by copy number variants (CNVs) and cally detected by gap-polymerase chain reaction (PCR). The single nucleotide variants (SNVs) in the α-globin (HBA) or SNV types are detected by Sanger sequencing. In the present β-globin (HBB) genes that result in the absence or lack of α- or study, a novel method was developed that simultaneously β-globin chains, and ultimately hemolytic anemia. It is esti- detects CNVs and SNVs by multiplex PCR and next-genera- mated that ~7% of the world population carries the gene for the tion sequencing (NGS). To detect CNVs, 33 normal samples disease (1), and the birth rate of children with hemoglobin (Hb) were used as a cluster of control values to build a baseline, disorders is ≥2.4% per year (2). Thalassemia occurs most in the and the A, B, C, and D ratios were developed to evaluate-SEA, Mediterranean region, East South Asia, and the subcontinents -α4.2, -α3.7, and compound or homozygous CNVs, respectively. -
Normal, C=Critical
Patient Report |FINAL Client: Example Client ABC123 Patient: Patient, Example 123 Test Drive Salt Lake City, UT 84108 DOB 7/22/1970 UNITED STATES Gender: Female Patient Identifiers: 01234567890ABCD, 012345 Physician: Doctor, Example Visit Number (FIN): 01234567890ABCD Collection Date: 00/00/0000 00:00 Hemoglobin Evaluation Reflexive Cascade ARUP test code 2005792 Hemoglobin A 97.1 % (Ref Interval: 95.0-97.9) Hemoglobin A2 2.6 % (Ref Interval: 2.0-3.5) Hemoglobin F 0.3 % (Ref Interval: 0.0-2.1) REFERENCE INTERVAL: Hemoglobin F Access complete set of age- and/or gender-specific reference intervals for this test in the ARUP Laboratory Test Directory (aruplab.com). Hemoglobin S 0.0 % (Ref Interval: 0.0-0.0) Hemoglobin C 0.0 % (Ref Interval: 0.0-0.0) Hemoglobin E 0.0 % (Ref Interval: 0.0-0.0) Hemoglobin - Other 0.0 % (Ref Interval: 0.0-0.0) Sickle Cell Solubility Not Performed Hemoglobin, Capillary Electrophoresis Performed Hemoglobin Evaluation See Note Beta Globin Full Gene Sequencing Not Applicable H=High, L=Low, *=Abnormal, C=Critical Patient: Patient, Example ARUP Accession: 21-048-400496 Patient Identifiers: 01234567890ABCD, 012345 Visit Number (FIN): 01234567890ABCD Page 1 of 4 | Printed: 3/11/2021 11:41:09 AM 4848 Patient Report |FINAL Beta Globin (HBB) Del/Dup Result Not Applicable Alpha Thalassemia HBA1 and HBA2 Seq Not Applicable Gamma Globin (HBG1 and HBG2) Sequencing Not Applicable Hemoglobin Cascade Interpretation See Note H=High, L=Low, *=Abnormal, C=Critical Patient: Patient, Example ARUP Accession: 21-048-400496 Patient Identifiers: 01234567890ABCD, 012345 Visit Number (FIN): 01234567890ABCD Page 2 of 4 | Printed: 3/11/2021 11:41:09 AM 4848 Patient Report |FINAL RESULT Normal hemoglobin evaluation. -
Apoptotic Cells Inflammasome Activity During the Uptake of Macrophage
Downloaded from http://www.jimmunol.org/ by guest on September 29, 2021 is online at: average * The Journal of Immunology , 26 of which you can access for free at: 2012; 188:5682-5693; Prepublished online 20 from submission to initial decision 4 weeks from acceptance to publication April 2012; doi: 10.4049/jimmunol.1103760 http://www.jimmunol.org/content/188/11/5682 Complement Protein C1q Directs Macrophage Polarization and Limits Inflammasome Activity during the Uptake of Apoptotic Cells Marie E. Benoit, Elizabeth V. Clarke, Pedro Morgado, Deborah A. Fraser and Andrea J. Tenner J Immunol cites 56 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription http://www.jimmunol.org/content/suppl/2012/04/20/jimmunol.110376 0.DC1 This article http://www.jimmunol.org/content/188/11/5682.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 29, 2021. The Journal of Immunology Complement Protein C1q Directs Macrophage Polarization and Limits Inflammasome Activity during the Uptake of Apoptotic Cells Marie E. -
The Expression Profile of Cytoglobin in Human
THE EXPRESSION PROFILE OF CYTOGLOBIN IN HUMAN FIBROTIC LUNG, AND THE PROTECTIVE ROLE OF CYTOGLOBIN IN HYPOXIA AND OXIDATIVE STRESS IN VITRO. By MELINDA CARPENTER A thesis submitted to the The University of Birmingham for the degree of DOCTOR OF PHILOSOPHY School of Bioscience University of Birmingham September 2009 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Abstract Cytoglobin (CYGB), a novel member of the globin family, has been shown to be upregulated in response to hypoxia, oxidative stress and fibrogenesis. Presented here is evidence of CYGB expression within cells of fibrotic lesions taken from patients with Idiopathic Pulmonary Fibrosis (IPF) and Chronic Obstructive Pulmonary Disease (COPD). CYGB staining was observed in fibroblasts, endothelial cells, type II pneumocytes, type I pneumocytes, haematopoietic stem cells and inflammatory cells, which were identified using cell specific markers. Cell types which express other members of the globin family, including smooth muscle and red blood cells were negative for CYGB. Fibroblasts were consistently positive for CYGB. CYGB expression was consistently positive within the lesion, and more variable at the edge. This study also provides evidence of an increase in CYGB expression in response to hypoxic and oxidative stress in vitro; however there was no evidence of cytoprotection with over expression of CYGB in response to these insults. -
Additional File 3.Pdf
************ globins ************ >Pdu_Egb_A1a MNGITVFLILAMASASLADDCTQLDMIKVKHQWAEVYGVESNRQEFGLAVFKRFFVIHPD RSLFVNVHGDNVYSPEFQAHVARVLAGVDILISSMDQEAIFKAAQKHYADFHKSKFGEVPLVEFGTAMRDVLP KYVGLRNYDNDSWSRCYAYITSKVE >Pdu_Egb_A1b MKGLLVFLVLASVSASLASECSSLDKIKVKNQWA RIHGSPSNRKAFGTAVFKRFFEDHPDRSLFANVNGNDIYSADFQAHVQRVFGGLDILIVSLDQDDLFTAAKSH YSEFHKKLGDVPFAEFGVAFLDTLSDFLPLRDYNQDPWSRCYNYIIS >Pdu_Egb_A1c MNTVTVVLVLLG CIASAMTGDCNTLQRTKVKYQWSIVYGATDNRQAFGTLVWRDFFGLYPDRSLFSGVRGENIYSPEFRAHVVRV FAGFDILISLLDQEDILNSALAHYAAFHKQFPSIPFKEFGVVLLEALAKTIPEQFDQDAWSQCYAVIVAGVTA >Pdu_Egb_A1d_alpha MYQILSVAVLVLSCLALGTLGEEVCGPLERIKVQHQWVSVYGADHDRLKVSTL VWKDFFEHHPEERARFERVNSDNIFSGDFRAHMVRVFAGFDLLIGVLNEEEIFKSAMIHYTKMHNDLGVTTEI IKEFGKSIARVLPEFMDGKPDITAWRPCFNLIAAGVSE >Pdu_Egb_A1d_beta MYFSYFTAAASYLSVAVLVLSCLVQGILGEEVCGPLEKIKVQHQWASAYRGDHD RLKMSTLVWKDFFAHNPEERARFERVHSDDIYSGDFRAHMVRVFAGFDLLIGALNQEDIFRSAMIHYTKMHKK LGVTYEIGIEFGKSIGRVLPEFIDGKLDITAWRPCYKLIATGVDE >Pdu_Egb_A1d_gamma MYLSVAVLVLSCLALGTQGEEVCGPLEKIKVQHQWASAYRGDHDRLKMSTLVW KDFFAHHPEERARFERVHSDDIYSGDFRAHMVRVFAGFDLLIGVLNQDEIFKSAMIHYTKMHNDLGVKTEIVL EFGKSIARVLPDFIDGKPDITAWRPCFKLIAAGVSE >Pdu_Egb_A2 MNNLVILVGLLCLGLTSATKCGPL QRLKVKQQWAKAYGVGHERLELGIALWKSIFAQDPESRSIFTRVHGDDVRHPAFEAHIARVFNGFDRIISSLT DEDVLQAQLAHLKAQHIKLGISAHHFKLMRTGLSYVLPAQLGRCFDKEAWGSCWDEVIYPGIKSL >Pdu_Egb_B1 MLVLAVFVAALGLAAADQCCSIEDRNEVQALWQSIWSAENTGKRTIIGHQIFEELFDINP GTKDLFKRVNVEDTSSPEFEAHVLRVMNGLDTLIGVLDDPATGYSLITHLAEQHKAREGFKPSYFKDIGVALK RVLPQVASCFNPEAWDHCFNGFVEAITNKMNAL >Pdu_Egb_B2 MLVLVLSLAFLGSALAEDCCSAADRKTVLRDWQSVWSAEFTGRRVAIGTAIFEELFAIDA GAKDVFKNVAVDKPESAEWAAHVIRVINGLDLAINLLEDPRALKEELLHLAKQHRERDGVKAVYFDEIGRALL -
Globin Variants Modify Hematologic and Other Clinical Phenotypes in Sickle Cell Trait and Disease
Common α-globin variants modify hematologic and other clinical phenotypes in sickle cell trait and disease The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Raffield, L. M., J. C. Ulirsch, R. P. Naik, S. Lessard, R. E. Handsaker, D. Jain, H. M. Kang, et al. 2018. “Common α-globin variants modify hematologic and other clinical phenotypes in sickle cell trait and disease.” PLoS Genetics 14 (3): e1007293. doi:10.1371/journal.pgen.1007293. http://dx.doi.org/10.1371/ journal.pgen.1007293. Published Version doi:10.1371/journal.pgen.1007293 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:37068183 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA RESEARCH ARTICLE Common α-globin variants modify hematologic and other clinical phenotypes in sickle cell trait and disease Laura M. Raffield1☯, Jacob C. Ulirsch2,3,4☯, Rakhi P. Naik5☯, Samuel Lessard6,7, Robert E. Handsaker4,8,9, Deepti Jain10, Hyun M. Kang11, Nathan Pankratz12, Paul L. Auer13, Erik L. Bao2,3,4, Joshua D. Smith14, Leslie A. Lange15, Ethan M. Lange15, Yun Li1,16,17, Timothy A. Thornton11, Bessie A. Young18,19, Goncalo R. Abecasis20, Cathy C. Laurie10, Deborah A. Nickerson14, Steven A. McCarroll4,8,9, Adolfo Correa21, James G. Wilson22, NHLBI a1111111111 Trans-Omics for Precision Medicine (TOPMed) Consortium, Hematology & Hemostasis, a1111111111 Diabetes, and Structural Variation TOPMed Working Groups¶, Guillaume Lettre6,7³, Vijay a1111111111 G.