DOCSLIB.ORG

A Novel Approach of Homozygous Haplotype Sharing Identifies

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Novel Approach of Homozygous Haplotype Sharing Identifies Hum Genet DOI 10.1007/s00439-011-1094-6 ORIGINAL INVESTIGATION A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder Jillian P. Casey • Tiago Magalhaes • Judith M. Conroy • Regina Regan • Naisha Shah • Richard Anney • Denis C. Shields • Brett S. Abrahams • Joana Almeida • Elena Bacchelli • Anthony J. Bailey • Gillian Baird • Agatino Battaglia • Tom Berney • Nadia Bolshakova • Patrick F. Bolton • Thomas Bourgeron • Sean Brennan • Phil Cali • Catarina Correia • Christina Corsello • Marc Coutanche • Geraldine Dawson • Maretha de Jonge • Richard Delorme • Eftichia Duketis • Frederico Duque • Annette Estes • Penny Farrar • Bridget A. Fernandez • Susan E. Folstein • Suzanne Foley • Eric Fombonne • Christine M. Freitag • John Gilbert • Christopher Gillberg • Joseph T. Glessner • Jonathan Green • Stephen J. Guter • Hakon Hakonarson • Richard Holt • Gillian Hughes • Vanessa Hus • Roberta Igliozzi • Cecilia Kim • Sabine M. Klauck • Alexander Kolevzon • Janine A. Lamb • Marion Leboyer • Ann Le Couteur • Bennett L. Leventhal • Catherine Lord • Sabata C. Lund • Elena Maestrini • Carine Mantoulan • Christian R. Marshall • Helen McConachie • Christopher J. McDougle • Jane McGrath • William M. McMahon • Alison Merikangas • Judith Miller • Fiorella Minopoli • Ghazala K. Mirza • Jeff Munson • Stanley F. Nelson • Gudrun Nygren • Guiomar Oliveira • Alistair T. Pagnamenta • Katerina Papanikolaou • Jeremy R. Parr • Barbara Parrini • Andrew Pickles • Dalila Pinto • Joseph Piven • David J. Posey • Annemarie Poustka • Fritz Poustka • Jiannis Ragoussis • Bernadette Roge • Michael L. Rutter • Ana F. Sequeira • Latha Soorya • Ineˆs Sousa • Nuala Sykes • Vera Stoppioni • Raffaella Tancredi • Maı¨te´ Tauber • Ann P. Thompson • Susanne Thomson • John Tsiantis • Herman Van Engeland • John B. Vincent • Fred Volkmar • Jacob A. S. Vorstman • Simon Wallace • Kai Wang • Thomas H. Wassink • Kathy White • Kirsty Wing • Kerstin Wittemeyer • Brian L. Yaspan • Lonnie Zwaigenbaum • Catalina Betancur • Joseph D. Buxbaum • Rita M. Cantor • Edwin H. Cook • Hilary Coon • Michael L. Cuccaro • Daniel H. Geschwind • Jonathan L. Haines • Joachim Hallmayer • Anthony P. Monaco • John I. Nurnberger Jr. • Margaret A. Pericak-Vance • Gerard D. Schellenberg • Stephen W. Scherer • James S. Sutcliffe • Peter Szatmari • Veronica J. Vieland • Ellen M. Wijsman • Andrew Green • Michael Gill • Louise Gallagher • Astrid Vicente • Sean Ennis Received: 12 May 2011 / Accepted: 15 September 2011 Ó The Author(s) 2011. This article is published with open access at Springerlink.com Annemarie Poustka: deceased. Electronic supplementary material The online version of this article (doi:10.1007/s00439-011-1094-6) contains supplementary material, which is available to authorized users. J. P. Casey Á J. M. Conroy Á R. Regan Á N. Shah Á T. Magalhaes Á C. Correia Á A. F. Sequeira Á A. Vicente D. C. Shields Á A. Green Á S. Ennis Instituto Gulbenkian de Cıˆencia, Rua Quinta Grande, School of Medicine and Medical Science University College, 2780-156 Oeiras, Portugal Dublin 4, Ireland R. Anney Á N. Bolshakova Á S. Brennan Á G. Hughes Á T. Magalhaes Á C. Correia Á A. F. Sequeira Á A. Vicente J. McGrath Á A. Merikangas Á M. Gill Á L. Gallagher Instituto Nacional de Saude Dr Ricardo Jorge, Av Padre Cruz Autism Genetics Group, Department of Psychiatry, 1649-016, Lisbon, Portugal School of Medicine, Trinity College, Dublin 8, Ireland T. Magalhaes Á C. Correia Á A. F. Sequeira Á A. Vicente B. S. Abrahams Á D. H. Geschwind BioFIG, Center for Biodiversity, Functional and Integrative Department of Neurology, Center for Autism Research and Genomics, Campus da FCUL, C2.2.12, Campo Grande, Treatment, Program in Neurogenetics, Semel Institute, David 1749-016 Lisbon, Portugal Geffen School of Medicine at UCLA, Los Angeles, USA 123 Hum Genet to detect homozygous segments of identical haplotype Abstract Autism spectrum disorder (ASD) is a highly structure that are shared at a higher frequency amongst heritable disorder of complex and heterogeneous aetiology. ASD patients compared to parental controls. The analysis It is primarily characterized by altered cognitive ability was performed on 1,402 Autism Genome Project trios including impaired language and communication skills and genotyped for 1 million single nucleotide polymorphisms fundamental deficits in social reciprocity. Despite some (SNPs). We identified 25 known and 1,218 novel ASD notable successes in neuropsychiatric genetics, overall, the candidate genes in the discovery analysis including high heritability of ASD (*90%) remains poorly explained CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, by common genetic risk variants. However, recent studies EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. suggest that rare genomic variation, in particular copy Furthermore, 10 of the previously reported ASD genes and number variation, may account for a significant proportion 300 of the novel candidates identified in the discovery of the genetic basis of ASD. We present a large scale analysis were replicated in an independent sample of 1,182 analysis to identify candidate genes which may contain trios. Our results demonstrate that regions of HH are sig- low-frequency recessive variation contributing to ASD nificantly enriched for previously reported ASD candidate while taking into account the potential contribution of genes and the observed association is independent of population differences to the genetic heterogeneity of ASD. gene size (odds ratio 2.10). Our findings highlight the Our strategy, homozygous haplotype (HH) mapping, aims J. Almeida Á F. Duque Á G. Oliveira M. Coutanche Á S. Foley Á S. Wallace Á K. White Hospital Pedia´trico de Coimbra, 3000–076 Coimbra, Department of Psychiatry, University of Oxford, Portugal Warneford Hospital, Headington, Oxford OX3 7JX, UK E. Bacchelli Á E. Maestrini Á F. Minopoli G. Dawson Department of Biology, University of Bologna, Autism Speaks, New York 10016, USA 40126 Bologna, Italy G. Dawson A. J. Bailey Department of Psychiatry, University of North Carolina, Department of Psychiatry, University of British Columbia, Chapel Hill, NC 27599-3366, USA Vancouver V6T 2A1, Canada M. de Jonge Á H. Van Engeland Á J. A. S. Vorstman G. Baird Department of Child and Adolescent Psychiatry, Newcomen Centre, Guy’s Hospital, London SE1 9RT, UK University Medical Center, 3508 Utrecht, GA, The Netherlands A. Battaglia Á R. Igliozzi Á B. Parrini Á R. Tancredi Stella Maris Institute for Child and Adolescent Neuropsychiatry, R. Delorme 56128 Calambrone, Pisa, Italy INSERM U 955, Fondation FondaMental, APHP, Hoˆpital Robert Debre´, Child and Adolescent Psychiatry, T. Berney Á A. Le Couteur Á H. McConachie Á J. R. Parr 75019 Paris, France Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne NE1 7RU, UK E. Duketis Á C. M. Freitag Á F. Poustka Department of Child and Adolescent Psychiatry, T. Berney Á A. Le Couteur Á H. McConachie Á J. R. Parr Psychosomatics and Psychotherapy, Institute of Health and Society, Newcastle University, J.W. Goethe University Frankfurt, 60528 Frankfurt, Germany Newcastle Upon Tyne NE1 7RU, UK A. Estes P. F. Bolton Department of Speech and Hearing Sciences, Department of Child and Adolescent Psychiatry, University of Washington, Seattle, WA 98195, USA Institute of Psychiatry, London SE5 8AF, UK P. Farrar Á R. Holt Á G. K. Mirza Á A. T. Pagnamenta Á T. Bourgeron J. Ragoussis Á I. Sousa Á N. Sykes Á K. Wing Á A. P. Monaco Department of Human Genetics and Cognitive Functions, Wellcome Trust Centre for Human Genetics, Institut Pasteur, University Paris Diderot-Paris 7, University of Oxford, Oxford OX3 7BN, UK CNRS URA 2182, Fondation FondaMental, 75015 Paris, France B. A. Fernandez P. Cali Á S. J. Guter Á E. H. Cook Disciplines of Genetics and Medicine, Memorial University Department of Psychiatry, Institute for Juvenile Research, of Newfoundland, St John’s Newfoundland A1B 3V6, University of Illinois at Chicago, Chicago, IL 60612, USA Canada C. Corsello Á V. Hus Á C. Lord S. E. Folstein Autism and Communicative Disorders Centre, Department of Psychiatry, University of Miami School University of Michigan, Ann Arbor, MI 48109-2054, USA of Medicine, Miami, FL 33136, USA 123 Hum Genet applicability of HH mapping in complex disorders such as mutation (Durand et al. 2007; Lesch et al. 2008; Wong ASD and offer an alternative approach to the analysis of et al. 2002). Therefore, a rare pathogenic variant and sur- genome-wide association data. rounding haplotype is often enriched in frequency in a group of affected individuals compared with the haplotype frequency in a cohort of unaffected controls (The Interna- Introduction tional HapMap Consortium 2003). We propose that homozygous haplotypes (HH) that are shared by multiple Extended runs of homozygosity (ROH) have recently been affected individuals may be important for the discovery of highlighted as a genomic feature that may be useful to map recessive disease genes in complex disorders. We have recessive disease genes in outbred populations (Hilde- extended the traditional homozygosity mapping method by brandt et al. 2009; Lencz et al. 2007; Yang et al. 2010). analysing the haplotype within shared ROH regions to Furthermore, even in complex disorders, we expect to find identify homozygous segments of identical haplotype that an unusually high number of affected individuals to have are present uniquely or at a higher frequency in ASD the same haplotype in the region surrounding a disease probands compared to parental controls (Fig. 1).
Load more

Recommended publications
  • The Title of the Article
    Mechanism-Anchored Profiling Derived from Epigenetic Networks Predicts Outcome in Acute Lymphoblastic Leukemia Xinan Yang, PhD1, Yong Huang, MD1, James L Chen, MD1, Jianming Xie, MSc2, Xiao Sun, PhD2, Yves A Lussier, MD1,3,4§ 1Center for Biomedical Informatics and Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL 60637 USA 2State Key Laboratory of Bioelectronics, Southeast University, 210096 Nanjing, P.R.China 3The University of Chicago Cancer Research Center, and The Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637 USA 4The Institute for Genomics and Systems Biology, and the Computational Institute, The University of Chicago, Chicago, IL 60637 USA §Corresponding author Email addresses: XY: [email protected] YH: [email protected] JC: [email protected] JX: [email protected] XS: [email protected] YL: [email protected] - 1 - Abstract Background Current outcome predictors based on “molecular profiling” rely on gene lists selected without consideration for their molecular mechanisms. This study was designed to demonstrate that we could learn about genes related to a specific mechanism and further use this knowledge to predict outcome in patients – a paradigm shift towards accurate “mechanism-anchored profiling”. We propose a novel algorithm, PGnet, which predicts a tripartite mechanism-anchored network associated to epigenetic regulation consisting of phenotypes, genes and mechanisms. Genes termed as GEMs in this network meet all of the following criteria: (i) they are co-expressed with genes known to be involved in the biological mechanism of interest, (ii) they are also differentially expressed between distinct phenotypes relevant to the study, and (iii) as a biomodule, genes correlate with both the mechanism and the phenotype.
    [Show full text]
  • Regulation and Evolutionary Origins of Repulsive
    REGULATION AND EVOLUTIONARY ORIGINS OF REPULSIVE GUIDANCE MOLECULE C / HEMOJUVELIN EXPRESSION: A MUSCLE-ENRICHED GENE INVOLVED IN IRON METABOLISM by Christopher John Severyn B.A. (University of California, Berkeley) 2002 A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in BIOCHEMISTRY AND MOLECULAR BIOLOGY Presented to the Department of Biochemistry & Molecular Biology OREGON HEALTH & SCIENCE UNIVERSITY School of Medicine July 2010 Department of Biochemistry & Molecular Biology, School of Medicine OREGON HEALTH & SCIENCE UNIVERSITY _________________________________________________ CERTIFICATE OF APPROVAL _________________________________________________ This is to certify that the Ph.D. dissertation of Christopher J. Severyn has been approved by the following: __________________________ Peter Rotwein, M.D., dissertation advisor Professor of Biochemistry and Department Chair __________________________ Maureen Hoatlin, Ph.D., committee chair Associate Professor of Biochemistry __________________________ Matt Thayer, Ph.D., committee member Professor of Biochemistry __________________________ Ujwal Shinde, Ph.D., committee member Professor of Biochemistry __________________________ Jim Lundblad, M.D., Ph.D., committee member Associate Professor of Medicine and Chief of Endocrinology TABLE OF CONTENTS Page List of Tables iii List of Figures iv List of Abbreviations vii Acknowledgements xiv Publications arising from this Dissertation xvi Abstract xvii Key words xix Chapter 1: Introduction 1. 1 General Overview 2 1. 2 Expression and Regulation of RGMc 3 1. 3 Gene Regulation: Transcription from an evolutionary perspective 4 1. 4 Gene Regulation: Translation 6 1. 5 Iron Metabolism in Eukaryotes 6 1. 6 Dissertation Overview 7 Chapter 2: Repulsive Guidance Molecule Family 2. 1 Summary 15 2. 2 Introduction 16 2. 3 RGMa 16 2. 4 RGMb 21 2.
    [Show full text]
  • Cross-Modulatory Actions of Cell Cycle Machinery on Estrogen Receptor-Α Level and Transcriptional Activity in Breast Cancer Cells
    CROSS-MODULATORY ACTIONS OF CELL CYCLE MACHINERY ON ESTROGEN RECEPTOR-α LEVEL AND TRANSCRIPTIONAL ACTIVITY IN BREAST CANCER CELLS BY SHWETA BHATT DISSERTATION Submitted In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Biochemistry in the Graduate College of the University of Illinois at Urbana-Champaign, 2010 Urbana, Illinois Doctoral Committee: Professor Benita S. Katzenellenbogen (Chair) Professor David J. Shapiro Professor Milan K. Bagchi Professor Paul J. Hergenrother THESIS ABSTRACT Breast cancer is one of the most highly diagnosed cancers in women and the second largest cause of death of women in United States. The anti-estrogen tamoxifen which blocks gene expression through estradiol bound ERα, and hence the growth stimulatory effects of estradiol, has been widely used for decades for treating patients with ERα positive or hormone dependent breast cancer. Despite its obvious benefits, in as high as 40% of the patients receiving tamoxifen therapy there is an eventual relapse of the disease largely due to acquired resistance to the drug, underlying mechanism for which is rather poorly understood. Elucidating the molecular basis underlying “acquired tamoxifen resistance” and agonistic effects of tamoxifen on cellular growth was the primary focus of my doctoral research. We addressed this by two approaches, one being studying the molecular mechanism for the regulation of cellular levels of ERα so as to prevent its loss in ERα positive or restore its levels in ERα negative breast cancers and second to investigate the role of tamoxifen in modulating the expression of ERα target genes independent of estradiol as a function of its stimulatory or estrogenic effects on breast cancer cell growth.
    [Show full text]
  • ARTICLE Complex Inheritance Pattern Resembling Autosomal Recessive Inheritance Involving a Microdeletion in Thrombocytopenia– Absent Radius Syndrome
    ARTICLE Complex Inheritance Pattern Resembling Autosomal Recessive Inheritance Involving a Microdeletion in Thrombocytopenia– Absent Radius Syndrome Eva Klopocki,* Harald Schulze,* Gabriele Strauß, Claus-Eric Ott, Judith Hall, Fabienne Trotier, Silke Fleischhauer, Lynn Greenhalgh, Ruth A. Newbury-Ecob, Luitgard M. Neumann, Rolf Habenicht, Rainer Ko¨nig, Eva Seemanova, Andre´ Megarbane, Hans-Hilger Ropers, Reinhard Ullmann, Denise Horn, and Stefan Mundlos Thrombocytopenia–absent radius (TAR) syndrome is characterized by hypomegakaryocytic thrombocytopenia and bi- lateral radial aplasia in the presence of both thumbs. Other frequent associations are congenital heart disease and a high incidence of cow’s milk intolerance. Evidence for autosomal recessive inheritance comes from families with several affected individuals born to unaffected parents, but several other observations argue for a more complex pattern of inheritance. In this study, we describe a common interstitial microdeletion of 200 kb on chromosome 1q21.1 in all 30 investigated patients with TAR syndrome, detected by microarray-based comparative genomic hybridization. Analysis of the parents revealed that this deletion occurred de novo in 25% of affected individuals. Intriguingly, inheritance of the deletion along the maternal line as well as the paternal line was observed. The absence of this deletion in a cohort of control individuals argues for a specific role played by the microdeletion in the pathogenesis of TAR syndrome. We hypothesize that TAR syndrome is associated with a deletion on chromosome 1q21.1 but that the phenotype develops only in the presence of an additional as-yet-unknown modifier (mTAR). Thrombocytopenia–absent radius (TAR) syndrome (MIM Cow’s milk allergy or intolerance appears to be relatively 274000) is a clinically well-characterized malformation common among patients with TAR syndrome and may syndrome.
    [Show full text]
  • Open Data for Differential Network Analysis in Glioma
    International Journal of Molecular Sciences Article Open Data for Differential Network Analysis in Glioma , Claire Jean-Quartier * y , Fleur Jeanquartier y and Andreas Holzinger Holzinger Group HCI-KDD, Institute for Medical Informatics, Statistics and Documentation, Medical University Graz, Auenbruggerplatz 2/V, 8036 Graz, Austria; [email protected] (F.J.); [email protected] (A.H.) * Correspondence: [email protected] These authors contributed equally to this work. y Received: 27 October 2019; Accepted: 3 January 2020; Published: 15 January 2020 Abstract: The complexity of cancer diseases demands bioinformatic techniques and translational research based on big data and personalized medicine. Open data enables researchers to accelerate cancer studies, save resources and foster collaboration. Several tools and programming approaches are available for analyzing data, including annotation, clustering, comparison and extrapolation, merging, enrichment, functional association and statistics. We exploit openly available data via cancer gene expression analysis, we apply refinement as well as enrichment analysis via gene ontology and conclude with graph-based visualization of involved protein interaction networks as a basis for signaling. The different databases allowed for the construction of huge networks or specified ones consisting of high-confidence interactions only. Several genes associated to glioma were isolated via a network analysis from top hub nodes as well as from an outlier analysis. The latter approach highlights a mitogen-activated protein kinase next to a member of histondeacetylases and a protein phosphatase as genes uncommonly associated with glioma. Cluster analysis from top hub nodes lists several identified glioma-associated gene products to function within protein complexes, including epidermal growth factors as well as cell cycle proteins or RAS proto-oncogenes.
    [Show full text]
  • SZDB: a Database for Schizophrenia Genetic Research
    Schizophrenia Bulletin vol. 43 no. 2 pp. 459–471, 2017 doi:10.1093/schbul/sbw102 Advance Access publication July 22, 2016 SZDB: A Database for Schizophrenia Genetic Research Yong Wu1,2, Yong-Gang Yao1–4, and Xiong-Jian Luo*,1,2,4 1Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, China; 2Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China; 3CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China 4YGY and XJL are co-corresponding authors who jointly directed this work. *To whom correspondence should be addressed; Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China; tel: +86-871-68125413, fax: +86-871-68125413, e-mail: [email protected] Schizophrenia (SZ) is a debilitating brain disorder with a Introduction complex genetic architecture. Genetic studies, especially Schizophrenia (SZ) is a severe mental disorder charac- recent genome-wide association studies (GWAS), have terized by abnormal perceptions, incoherent or illogi- identified multiple variants (loci) conferring risk to SZ. cal thoughts, and disorganized speech and behavior. It However, how to efficiently extract meaningful biological affects approximately 0.5%–1% of the world populations1 information from bulk genetic findings of SZ remains a and is one of the leading causes of disability worldwide.2–4 major challenge. There is a pressing
    [Show full text]
  • BAC Array CGH in Patients with Velocardiofacial Syndrome-Like
    BMC Medical Genetics BioMed Central Research article Open Access BAC array CGH in patients with Velocardiofacial syndrome-like features reveals genomic aberrations on chromosome region 1q21.1 Anna Brunet1,2, Lluís Armengol1, Damià Heine3, Jordi Rosell3, Manel García- Aragonés1, Elisabeth Gabau2, Xavier Estivill*1,4 and Miriam Guitart*2 Address: 1Genes and Disease Program, CIBER en Epidemiología y Salud Pública (CIBERESP), Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain, 2Genetic laboratory UDIAT-Centre Diagnòstic, Fundació Parc Taulí - Institut Universitari UAB, Corporació Sanitària Parc Taulí, Sabadell, Catalonia, Spain, 3Hospital Universitari Son Dureta, Mallorca, Spain and 4Pompeu Fabra University (UPF), Barcelona, Catalonia, Spain Email: Anna Brunet - [email protected]; Lluís Armengol - [email protected]; Damià Heine - [email protected]; Jordi Rosell - [email protected]; Manel García-Aragonés - [email protected]; Elisabeth Gabau - [email protected]; Xavier Estivill* - [email protected]; Miriam Guitart* - [email protected] * Corresponding authors Published: 23 December 2009 Received: 14 January 2009 Accepted: 23 December 2009 BMC Medical Genetics 2009, 10:144 doi:10.1186/1471-2350-10-144 This article is available from: http://www.biomedcentral.com/1471-2350/10/144 © 2009 Brunet et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Microdeletion of the chromosome 22q11.2 region is the most common genetic aberration among patients with velocardiofacial syndrome (VCFS) but a subset of subjects do not show alterations of this chromosome region.
    [Show full text]
  • Supplementary Materials and Tables a and B
    SUPPLEMENTARY MATERIAL 1 Table A. Main characteristics of the subset of 23 AML patients studied by high-density arrays (subset A) WBC BM blasts MYST3- MLL Age/Gender WHO / FAB subtype Karyotype FLT3-ITD NPM status (x109/L) (%) CREBBP status 1 51 / F M4 NA 21 78 + - G A 2 28 / M M4 t(8;16)(p11;p13) 8 92 + - G G 3 53 / F M4 t(8;16)(p11;p13) 27 96 + NA G NA 4 24 / M PML-RARα / M3 t(15;17) 5 90 - - G G 5 52 / M PML-RARα / M3 t(15;17) 1.5 75 - - G G 6 31 / F PML-RARα / M3 t(15;17) 3.2 89 - - G G 7 23 / M RUNX1-RUNX1T1 / M2 t(8;21) 38 34 - + ND G 8 52 / M RUNX1-RUNX1T1 / M2 t(8;21) 8 68 - - ND G 9 40 / M RUNX1-RUNX1T1 / M2 t(8;21) 5.1 54 - - ND G 10 63 / M CBFβ-MYH11 / M4 inv(16) 297 80 - - ND G 11 63 / M CBFβ-MYH11 / M4 inv(16) 7 74 - - ND G 12 59 / M CBFβ-MYH11 / M0 t(16;16) 108 94 - - ND G 13 41 / F MLLT3-MLL / M5 t(9;11) 51 90 - + G R 14 38 / F M5 46, XX 36 79 - + G G 15 76 / M M4 46 XY, der(10) 21 90 - - G NA 16 59 / M M4 NA 29 59 - - M G 17 26 / M M5 46, XY 295 92 - + G G 18 62 / F M5 NA 67 88 - + M A 19 47 / F M5 del(11q23) 17 78 - + M G 20 50 / F M5 46, XX 61 59 - + M G 21 28 / F M5 46, XX 132 90 - + G G 22 30 / F AML-MD / M5 46, XX 6 79 - + M G 23 64 / M AML-MD / M1 46, XY 17 83 - + M G WBC: white blood cell.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2003/0194725A1 Greener Et Al
    US 2003O194725A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0194725A1 Greener et al. (43) Pub. Date: Oct. 16, 2003 (54) METHODS FOR IDENTIFYING AND Publication Classification VALIDATING POTENTIAL DRUG TARGETS (51) Int. Cl." ........................... C12O 1/68; G01N 33/53; (76) Inventors: Tsvika Greener, Ness-Ziona (IL); G06F 19/00; G01N 33/48; Avishai Levy, Rishon-Le-Zion (IL); GO1N 33/50 Yuval Reiss, Kiriat-Ono (IL); Danny (52) U.S. Cl. ................... 435/6; 435/7.1; 702/19; 702/20 Ben-Avraham, Tel-Aviv (IL); Iris Alroy, Ness-Ziona (IL) (57) ABSTRACT Correspondence Address: ROPES & GRAY LLP - X ONE INTERNATIONAL PLACE This application provides methods for identifying and Vali BOSTON, MA 02110-2624 (US) dating potential drug targets. In one aspect, the application provides a Systematic method of creating a database of (21) Appl. No.: 10/299,991 related protein or nucleic acid Sequences with annotations of the potential disease associations of the Sequences, and a (22) Filed: Nov. 19, 2002 method for testing the potential disease associations by Related U.S. Application Data means of a biological assay and validating the disease asSociation by either decreasing expression of the Sequence (60) Provisional application No. 60/331,701, filed on Nov. of interest or increasing expression of the Sequence of 19, 2001. interest. (, OO Download sequence data 102 clean sequence 104 data identify E3 proteins from cleaned 106 sequence data associate disease or biological active with E3 proteins 108 based on their characteristic(s) Patent Application Publication Oct. 16, 2003 Sheet 1 of 5 US 2003/0194725 A1 (, OO re Download sequence data 102 clean sequence data 104 identify E3 proteins from cleaned 106 Sequence data associate disease or biological active with E3 proteins 108 based on their characteristic(s) F.G.
    [Show full text]
  • Developpement D'outils Bioinformatiques Et Statistiques Pour L'analyse Du Transcriptome Hepatique Humain Par Puces A
    Developpement d’outils bioinformatiques et statistiques pour l’analyse du transcriptome hepatique humain par puces a ADN : application a la reponse inflammatoire aigue systemique. Gregory Lefebvre To cite this version: Gregory Lefebvre. Developpement d’outils bioinformatiques et statistiques pour l’analyse du transcrip- tome hepatique humain par puces a ADN : application a la reponse inflammatoire aigue systemique.. Sciences du Vivant [q-bio]. Université de Rouen, 2006. Français. tel-00182773 HAL Id: tel-00182773 https://tel.archives-ouvertes.fr/tel-00182773 Submitted on 28 Oct 2007 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. No d’ordre: 00000 THESE` pr´esent´ee devant l’Universit´ede Rouen pour obtenir le grade de : Docteur de l’Universite´ de Rouen Mention Biologie moleculaire´ par Gr´egory LEFEBVRE Equipe´ d’accueil : INSERM - Unit´e519 Ecole´ Doctorale : Chimie-Biologie de Haute-Normandie Titre de la th`ese : D´eveloppement d’outils bioinformatiques et statistiques pour l’analyse du transcriptome h´epatique humain par puces `aADN : application `ala r´eponse inflammatoire aigu¨esyst´emique. soutenue le 17 novembre 2006 devant la commission d’examen compos´ee de : M. le Pr Fran¸cois Tron Pr´esident M.
    [Show full text]
  • 1 Novel Expression Signatures Identified by Transcriptional Analysis
    ARD Online First, published on October 7, 2009 as 10.1136/ard.2009.108043 Ann Rheum Dis: first published as 10.1136/ard.2009.108043 on 7 October 2009. Downloaded from Novel expression signatures identified by transcriptional analysis of separated leukocyte subsets in SLE and vasculitis 1Paul A Lyons, 1Eoin F McKinney, 1Tim F Rayner, 1Alexander Hatton, 1Hayley B Woffendin, 1Maria Koukoulaki, 2Thomas C Freeman, 1David RW Jayne, 1Afzal N Chaudhry, and 1Kenneth GC Smith. 1Cambridge Institute for Medical Research and Department of Medicine, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0XY, UK 2Roslin Institute, University of Edinburgh, Roslin, Midlothian, EH25 9PS, UK Correspondence should be addressed to Dr Paul Lyons or Prof Kenneth Smith, Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 0XY, UK. Telephone: +44 1223 762642, Fax: +44 1223 762640, E-mail: [email protected] or [email protected] Key words: Gene expression, autoimmune disease, SLE, vasculitis Word count: 2,906 The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non-exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if accepted) to be published in Annals of the Rheumatic Diseases and any other BMJPGL products to exploit all subsidiary rights, as set out in their licence (http://ard.bmj.com/ifora/licence.pdf). http://ard.bmj.com/ on September 29, 2021 by guest. Protected copyright. 1 Copyright Article author (or their employer) 2009.
    [Show full text]
  • Comparative Analysis of the Ubiquitin-Proteasome System in Homo Sapiens and Saccharomyces Cerevisiae
    Comparative Analysis of the Ubiquitin-proteasome system in Homo sapiens and Saccharomyces cerevisiae Inaugural-Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Universität zu Köln vorgelegt von Hartmut Scheel aus Rheinbach Köln, 2005 Berichterstatter: Prof. Dr. R. Jürgen Dohmen Prof. Dr. Thomas Langer Dr. Kay Hofmann Tag der mündlichen Prüfung: 18.07.2005 Zusammenfassung I Zusammenfassung Das Ubiquitin-Proteasom System (UPS) stellt den wichtigsten Abbauweg für intrazelluläre Proteine in eukaryotischen Zellen dar. Das abzubauende Protein wird zunächst über eine Enzym-Kaskade mit einer kovalent gebundenen Ubiquitinkette markiert. Anschließend wird das konjugierte Substrat vom Proteasom erkannt und proteolytisch gespalten. Ubiquitin besitzt eine Reihe von Homologen, die ebenfalls posttranslational an Proteine gekoppelt werden können, wie z.B. SUMO und NEDD8. Die hierbei verwendeten Aktivierungs- und Konjugations-Kaskaden sind vollständig analog zu der des Ubiquitin- Systems. Es ist charakteristisch für das UPS, daß sich die Vielzahl der daran beteiligten Proteine aus nur wenigen Proteinfamilien rekrutiert, die durch gemeinsame, funktionale Homologiedomänen gekennzeichnet sind. Einige dieser funktionalen Domänen sind auch in den Modifikations-Systemen der Ubiquitin-Homologen zu finden, jedoch verfügen diese Systeme zusätzlich über spezifische Domänentypen. Homologiedomänen lassen sich als mathematische Modelle in Form von Domänen- deskriptoren (Profile) beschreiben. Diese Deskriptoren können wiederum dazu verwendet werden, mit Hilfe geeigneter Verfahren eine gegebene Proteinsequenz auf das Vorliegen von entsprechenden Homologiedomänen zu untersuchen. Da die im UPS involvierten Homologie- domänen fast ausschließlich auf dieses System und seine Analoga beschränkt sind, können domänen-spezifische Profile zur Katalogisierung der UPS-relevanten Proteine einer Spezies verwendet werden. Auf dieser Basis können dann die entsprechenden UPS-Repertoires verschiedener Spezies miteinander verglichen werden.
    [Show full text]