Chapter 5 Genetic Models
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Whole-Genome Microarray Detects Deletions and Loss of Heterozygosity of Chromosome 3 Occurring Exclusively in Metastasizing Uveal Melanoma
Anatomy and Pathology Whole-Genome Microarray Detects Deletions and Loss of Heterozygosity of Chromosome 3 Occurring Exclusively in Metastasizing Uveal Melanoma Sarah L. Lake,1 Sarah E. Coupland,1 Azzam F. G. Taktak,2 and Bertil E. Damato3 PURPOSE. To detect deletions and loss of heterozygosity of disease is fatal in 92% of patients within 2 years of diagnosis. chromosome 3 in a rare subset of fatal, disomy 3 uveal mela- Clinical and histopathologic risk factors for UM metastasis noma (UM), undetectable by fluorescence in situ hybridization include large basal tumor diameter (LBD), ciliary body involve- (FISH). ment, epithelioid cytomorphology, extracellular matrix peri- ϩ ETHODS odic acid-Schiff-positive (PAS ) loops, and high mitotic M . Multiplex ligation-dependent probe amplification 3,4 5 (MLPA) with the P027 UM assay was performed on formalin- count. Prescher et al. showed that a nonrandom genetic fixed, paraffin-embedded (FFPE) whole tumor sections from 19 change, monosomy 3, correlates strongly with metastatic death, and the correlation has since been confirmed by several disomy 3 metastasizing UMs. Whole-genome microarray analy- 3,6–10 ses using a single-nucleotide polymorphism microarray (aSNP) groups. Consequently, fluorescence in situ hybridization were performed on frozen tissue samples from four fatal dis- (FISH) detection of chromosome 3 using a centromeric probe omy 3 metastasizing UMs and three disomy 3 tumors with Ͼ5 became routine practice for UM prognostication; however, 5% years’ metastasis-free survival. to 20% of disomy 3 UM patients unexpectedly develop metas- tases.11 Attempts have therefore been made to identify the RESULTS. Two metastasizing UMs that had been classified as minimal region(s) of deletion on chromosome 3.12–15 Despite disomy 3 by FISH analysis of a small tumor sample were found these studies, little progress has been made in defining the key on MLPA analysis to show monosomy 3. -
Dynamics of Individual T Cell Repertoires: from Cord Blood to Centenarians Olga V
Dynamics of Individual T Cell Repertoires: From Cord Blood to Centenarians Olga V. Britanova, Mikhail Shugay, Ekaterina M. Merzlyak, Dmitriy B. Staroverov, Ekaterina V. Putintseva, Maria A. This information is current as Turchaninova, Ilgar Z. Mamedov, Mikhail V. Pogorelyy, of September 27, 2021. Dmitriy A. Bolotin, Mark Izraelson, Alexey N. Davydov, Evgeny S. Egorov, Sofya A. Kasatskaya, Denis V. Rebrikov, Sergey Lukyanov and Dmitriy M. Chudakov J Immunol published online 13 May 2016 Downloaded from http://www.jimmunol.org/content/early/2016/05/12/jimmun ol.1600005 Supplementary http://www.jimmunol.org/content/suppl/2016/05/12/jimmunol.160000 http://www.jimmunol.org/ Material 5.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 27, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published May 13, 2016, doi:10.4049/jimmunol.1600005 The Journal of Immunology Dynamics of Individual T Cell Repertoires: From Cord Blood to Centenarians Olga V. -
In Silico Analysis of Single Nucleotide Polymorphism (Snps) in Human RAG1 and RAG2 Genes of Severe Combined Immunodeficiency
Central JSM Bioinformatics, Genomics and Proteomics Bringing Excellence in Open Access Research Article *Corresponding author Mona Shams Aldeen S. Ali, Department of Applied Bioinformatics, Africa City of Technology, Khartoum, In silico Analysis of Single Sudan, Tel: 249121784688; Email: Submitted: 26 May 2016 Nucleotide Polymorphism Accepted: 17 June 2016 Published: 27 June 2016 (SNPs) in Human RAG1 and Copyright © 2016 Ali et al. RAG2 Genes of Severe OPEN ACCESS Keywords Combined Immunodeficiency • Severe combined immunodeficiency • Primary immunodeficiency Mona Shams Aldeen S. Ali1,2*, Tomador Siddig MZ1,2, Rehab A. • T lymphocytes Elhadi1,2, Muhammad Rahama Yousof2, Siddig Eltyeb Yousif • Recombinase activating genes • non synonymous Single Nucleotide Polymorphisms Abdallah1, Maiada Mohamed Yousif Ahmed2, Nosiba Yahia Mohamed Hassen1, Sulum Omer Masoud Mohamed1, Marwa Mohamed Osman2, and Mohamed A. Hassan2 1Department of Rheumatology, Omdurman Teaching Hospital, Sudan 2Department of Applied Bioinformatics, Africa City of Technology, Sudan Abstract Severe combined immunodeficiency is an inherited Primary immunodeficiency PID, which is characterized by the absence or dysfunction of T lymphocytes. Defects in RAG1 and RAG2 are known to cause a T-B-NK+ form of SCID. Recombinase activating genes RAG1 and RAG2 (OMIM 179615,179616 respectively) are expressed exclusively in lymphocytes and mediate the creation of double-strand. DNA breaks at the sites of recombination and in signal sequences during T− and B− cell receptor gene rearrangement. This study was focused on the effect of nonsynonymous single nucleotide polymorphisms in the function and structure of RAG1& RAG2 genes using In silico analysis. Only nsSNPs and 3’UTR SNPs were selected for computational analysis. Predictions of deleterious nsSNPs were performed by bioinformatics software. -
Characterization of the T Cell Receptor Repertoire of Neonatal T Cells by RT-PCR and Single Strand Conformation Polymorphism Analysis
Bone Marrow Transplantation (2000) 26, 83–89 2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Characterization of the T cell receptor repertoire of neonatal T cells by RT-PCR and single strand conformation polymorphism analysis E Alfani1, AR Migliaccio2, M Sanchez1, AM Passarelli3 and G Migliaccio1 1Laboratory of Cell Biology and 2Clinical Biochemistry, Istituto Superiore di Sanita`, Rome; and 3Ospedale Civile Tivoli, Tivoli, Italy Summary: by other molecular mechanisms which include imprecise joining of V(D)J recombination,6 N-region diversification We have analyzed by reverse transcriptase-polymerase (random addition of nucleotides by terminal deoxy-ribonu- chain reaction (RT-PCR) the individual non-germ line cleotidyl transferase)7,8 and insertions of palindromic configurations of the T cell receptor (TCR) V chains nucleotides9 at specific points of the VD, DJ and VJ junc- expressed by T cells from eight individual cord blood tions. As a result of allele exclusion,10 each T cell clone specimens. cDNA from each cord blood was amplified expresses one and only one specifically rearranged TCR using a common primer coupled with a primer specific V chain. Therefore, the number of TCR V chain for each of 22 variable elements of the V chain family rearrangements expressed by a given population correlates and the amplified fragments were separated under high with its T cell clonality. resolution conditions. With cDNA from adult blood (as Cord blood (CB) has been proven to be a good source a control), all of the TCR chains were amplified as a of stem/progenitor cells for related and unrelated trans- smear consistent with the extensive polyclonality of plants.11,12 Successful engraftment with low graft-versus- adult T cells. -
Distorted TCR Repertoires Define Multisystem Inflammatory Syndrome in Children
medRxiv preprint doi: https://doi.org/10.1101/2021.04.12.21255098; this version posted April 15, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Distorted TCR repertoires define multisystem inflammatory syndrome in children Amna Malik* 1, Eszter N. Tóth* 2, Michelle S. Teng 2, Jacob Hurst 2, Eleanor Watt 3, Lauren Wise 4, Natalie Kent 4, Jack Bartram 5, Louis GranDjean 6, Margarita Dominguez-Villar 7, Stuart ADams† 4 anD Nichola Cooper† 1 1 Centre for Haematology, Department of Immunology anD Inflammation, Imperial College LonDon, LonDon, UniteD KingDom 2 Etcembly Ltd, MagDalen Centre, Robert Robinson Way, OxforD, UniteD KingDom 3 Molecular anD Cellular Immunology Department, UCL Great OrmonD Street Institute of ChilD Health, LonDon, UniteD KingDom 4 SIHMDS-Haematology, Great OrmonD Street Hospital for ChilDren, LonDon, UniteD Kingdom 5 Department of Haematology, Great OrmonD Street Hospital for ChilDren, LonDon, UniteD Kingdom 6 PaeDiatric Infectious Diseases, Great OrmonD Street Hospital for ChilDren, LonDon, UniteD Kingdom 7 Department of Infectious Diseases, Imperial College LonDon, LonDon, UniteD KingDom *These authors have contributed equally to this work †These authors have jointly supervised CorresponDing author: Nichola Cooper Tel: +44 20 3313 4017 E-mail: [email protected] KeyworDs: Sars-Cov2, coronavirus, COVID-19, multisystem inflammatory synDrome, MIS-C, superantigen, TCR, immune repertoire, sequencing NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. -
Autoaggressive T Cells in the Periphery RAG2
Cutting Edge: CD40-Induced Expression of Recombination Activating Gene (RAG) 1 and RAG2: A Mechanism for the Generation of Autoaggressive T Cells in the Periphery This information is current as of September 25, 2021. Gisela M. Vaitaitis, Michelle Poulin, Richard J. Sanderson, Kathryn Haskins and David H. Wagner, Jr. J Immunol 2003; 170:3455-3459; ; doi: 10.4049/jimmunol.170.7.3455 http://www.jimmunol.org/content/170/7/3455 Downloaded from References This article cites 24 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/170/7/3455.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 25, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE JOURNAL OF IMMUNOLOGY CUTTING EDGE Cutting Edge: CD40-Induced Expression of Recombination Activating Gene (RAG) 1 and RAG2: A Mechanism for the Generation of Autoaggressive T Cells in the Periphery1 Gisela M. -
Defining Natural Antibodies
PERSPECTIVE published: 26 July 2017 doi: 10.3389/fimmu.2017.00872 Defining Natural Antibodies Nichol E. Holodick1*, Nely Rodríguez-Zhurbenko2 and Ana María Hernández2* 1 Department of Biomedical Sciences, Center for Immunobiology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, United States, 2 Natural Antibodies Group, Tumor Immunology Division, Center of Molecular Immunology, Havana, Cuba The traditional definition of natural antibodies (NAbs) states that these antibodies are present prior to the body encountering cognate antigen, providing a first line of defense against infection thereby, allowing time for a specific antibody response to be mounted. The literature has a seemingly common definition of NAbs; however, as our knowledge of antibodies and B cells is refined, re-evaluation of the common definition of NAbs may be required. Defining NAbs becomes important as the function of NAb production is used to define B cell subsets (1) and as these important molecules are shown to play numerous roles in the immune system (Figure 1). Herein, we aim to briefly summarize our current knowledge of NAbs in the context of initiating a discussion within the field of how such an important and multifaceted group of molecules should be defined. Edited by: Keywords: natural antibody, antibodies, natural antibody repertoire, B-1 cells, B cell subsets, B cells Harry W. Schroeder, University of Alabama at Birmingham, United States NATURAL ANTIBODY (NAb) PRODUCING CELLS Reviewed by: Andre M. Vale, Both murine and human NAbs have been discussed in detail since the late 1960s (2, 3); however, Federal University of Rio cells producing NAbs were not identified until 1983 in the murine system (4, 5). -
U Klein Lecture 3
Introduction to Immunology Antigen Receptors and Generation of Antibody and T-Cell Receptor Diversity Ulf Klein [email protected] Adaptive Immunity The Adaptive or Acquired Immune Respone: • Is the response of antigen-specific lymphocytes to antigen, including the development of immunological memory • Are mediated by the clonal selection of antigen-specific lymphocytes • Immunoglobulins and T-cell receptors are the highly variable recognition molecules of adaptive immunity Effector Molecules of Adaptive Immunity The Antibodies Made Against a Pathogen Are Highly Specific for That Pathogen The Diversity of Antibodies and T-Cell Receptors Is Generated by Gene Rearrangement Through Somatic DNA Recombination Gene Rearrangement Produces a Diversity of Antigen Receptors in Lymphocytes Clonal Selection of B and T Lymphocytes 1. 3. 2. 4. The Immunoglobulin Molecule: • Made up of 2 identical heavy chains and 2 identical light chains • The antibody molecule has 2 functional domains Features of the Immunoglobulin Molecule • The flexible hinge allows it to bind with both arms to antigens on the surfaces of pathogens • The heavy and light chains are made from a series of similar protein domains The Hypervariable Regions of Antibody V Domains Lie in Discrete Loops at One End of the Domain Structure • The hypervariable loops contribute much of the antigen specificity of the antigen-binding site Hypervariable Regions in Heavy and Light-Chains Antigen-Binding Sites Can Have Diverse Structures • Epitopes of antigens can bind to pockets, grooves, extended -
Regulating Antigen-Receptor Gene Assembly
REVIEWS REGULATING ANTIGEN-RECEPTOR GENE ASSEMBLY Mark S. Schlissel The genes encoding antigen receptors are unique because of their high diversity and their assembly in developing lymphocytes from gene segments through a series of site-specific DNA recombination reactions known as V(D)J rearrangement. This review focuses on our understanding of how recombination of immunoglobulin and T-cell receptor gene segments is tightly regulated despite being catalysed by a common lymphoid recombinase, which recognizes a widely distributed conserved recombination signal sequence. Probable mechanisms involve precise expression of the lymphoid-restricted recombination-activating genes RAG1 and RAG2, and developmentally regulated epigenetic alterations in template accessibility, which are targeted by transcriptional regulatory elements and involve chromatin-modifying enzymes. RECOMBINATION SIGNAL It has been nearly 25 years since Tonegawa and col- V(D)J recombination: levels of regulation 1 SEQUENCES leagues shattered one of the basic assumptions of V(D)J recombination has three types of regulation — (RSSs). Short, conserved DNA molecular biology, the inviolate structure of the lineage specificity, order within a lineage and allelic sequences that flank all genome, and in so doing solved a fundamental puzzle exclusion. Transcriptional regulation limits the expres- rearranging gene segments and serve as the recognition elements in immunology — the generation of antigen-receptor sion of RAG proteins to the progenitor stages of B- for the recombinase machinery. -
Allelic Exclusion of the Immunoglobulin Heavy Chain Locus Is Independent of Its Nuclear Localization in Mature B Cells Sjoerd J
Published online 7 June 2013 Nucleic Acids Research, 2013, Vol. 41, No. 14 6905–6916 doi:10.1093/nar/gkt491 Allelic exclusion of the immunoglobulin heavy chain locus is independent of its nuclear localization in mature B cells Sjoerd J. B. Holwerda1, Harmen J. G. van de Werken1, Claudia Ribeiro de Almeida2, Ingrid M. Bergen2, Marjolein J. W. de Bruijn2, Marjon J. A. M. Verstegen1, Marieke Simonis1, Erik Splinter1, Patrick J. Wijchers1, Rudi W. Hendriks2,* and Wouter de Laat1,* 1Hubrecht Institute-KNAW & University Medical Center Utrecht, Utrecht 3584 CT, The Netherlands and 2Department of Pulmonary Medicine, Erasmus MC Rotterdam, Rotterdam, Box 2040, 3000 CA, The Netherlands Received April 7, 2013; Revised May 6, 2013; Accepted May 11, 2013 ABSTRACT INTRODUCTION In developing B cells, the immunoglobulin heavy B and T lymphocytes express a large repertoire of antigen chain (IgH) locus is thought to move from repressive receptors that safeguard the robustness of our adaptive to permissive chromatin compartments to facili- immune response. Lymphocyte development uniquely tate its scheduled rearrangement. In mature B relies on scheduled genomic rearrangement of V (variable), D (diversity) and J (joining) gene segments in cells, maintenance of allelic exclusion has been the antigen receptor loci (1–3). proposed to involve recruitment of the non-product- The murine IgH locus spans nearly 3Mb, with ive IgH allele to pericentromeric heterochromatin. upstream 150 functional VH segments spread over Here, we used an allele-specific chromosome con- 2.4 Mb, followed by DH and JH segments and a 200 kb formation capture combined with sequencing constant (CH) gene region. -
Antigen-Receptor Genes & B Cell Development Learning
Katherine L. Knight, Ph.D. Host Defense 2011 Antigen-Receptor Genes and B Cell Development ANTIGEN-RECEPTOR GENES & B CELL DEVELOPMENT Date: Friday, March 18, 2011 Monday, March 21, 2011 10:30 AM – 11:30 AM 10:30 AM – 11:30 AM LEARNING GOAL You will be able to diagram and describe the stages of B cell development including somatic DNA rearrangements, and explain how a large antibody repertoire is developed. You will also be able to diagram the structure and rearrangement of T cell receptor (TCR) genes and explain how a large TCR repertoire develops. OBJECTIVES To attain the goal for these lectures you will be able to: • State the approximate size of antibody repertoire needed for immune protection. • Diagram the order of H and L chain gene rearrangements that occur during B cell development. • Describe the mechanism by which individual B cells make only one antibody (allelic exclusion) • Diagram the sequence of events leading from rearrangements of germline Ig genes to production of an Ig molecule. • Describe how antibody diversity is generated through combinatorial joining, junctional diversity, and N segment addition. • Describe how antibody diversity is generated in secondary lymphoid tissues • Describe the maturation of B cells from stem cells, including the pre-B cell receptor. • State the cell origin of CLL, Burkitt’s lymphoma, Hodgkin’s lymphoma, ALL, and multiple myeloma • Draw the structure of αβ and γδ T cell receptors. • Diagram the mechanism by which T cells express a single antigen receptor READING ASSIGNMENT Janeway’s Immunobiology (2008), Chapter 4; Chapter 7, pp 262-272; 308-312 LECTURER Katherine L. -
Collaboration of RAG2 with RAG1-Like Proteins During the Evolution of V(D)J Recombination
Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Collaboration of RAG2 with RAG1-like proteins during the evolution of V(D)J recombination Lina Marcela Carmona,1 Sebastian D. Fugmann,2,3 and David G. Schatz1,4 1Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, 06520, USA; 2Department of Biomedical Sciences, Chang Gung University, Tao-Yuan City 33302, Taiwan; 3Chang Gung Immunology Consortium, Chang Gung Memorial Hospital, Chang Gung University, Tao-Yuan City 33302, Taiwan; 4Howard Hughes Medical Institute, New Haven, Connecticut 06511, USA The recombination-activating gene 1 (RAG1) and RAG2 proteins initiate V(D)J recombination, the process that assembles the B- and T-lymphocyte antigen receptor genes of jawed vertebrates. RAG1 and RAG2 are thought to have arisen from a transposable element, but the origins of this element are not understood. We show that two ancestral RAG1 proteins, Transib transposase and purple sea urchin RAG1-like, have a latent ability to initiate V(D)J recombination when coexpressed with RAG2 and that in vitro transposition by Transib transposase is stimulated by RAG2. Conversely, we report low levels of V(D)J recombination by RAG1 in the absence of RAG2. Recombination by RAG1 alone differs from canonical V(D)J recombination in having lost the requirement for asymmetric DNA substrates, implicating RAG2 in the origins of the “12/23 rule,” a fundamental regulatory feature of the reaction. We propose that evolution of RAG1/RAG2 began with a Transib transposon whose intrinsic recombination activity was enhanced by capture of an ancestral RAG2, allowing for the development of adaptive immunity.