DOCSLIB.ORG

Alfresco—A Workbench for Comparative Genomic Sequence Analysis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Alfresco—A Workbench for Comparative Genomic Sequence Analysis Downloaded from genome.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Letter Alfresco—A Workbench for Comparative Genomic Sequence Analysis Niclas Jareborg1,2,3 and Richard Durbin1 1The Sanger Centre, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom; 2Center for Genomics Research, Karolinska Institutet, S-171 77 Stockholm, Sweden Comparative analysis of genomic sequences provides a powerful tool for identifying regions of potential biologic function; by comparing corresponding regions of genomes from suitable species, protein coding or regulatory regions can be identified by their homology. This requires the use of several specific types of computational analysis tools. Many programs exist for these types of analysis; not many exist for overall view/control of the results, which is necessary for large-scale genomic sequence analysis. Using Java, we have developed a new visualization tool that allows effective comparative genome sequence analysis. The program handles a pair of sequences from putatively homologous regions in different species. Results from various different existing external analysis programs, such as database searching, gene prediction, repeat masking, and alignment programs, are visualized and used to find corresponding functional sequence domains in the two sequences. The user interacts with the program through a graphic display of the genome regions, in which an independently scrollable and zoomable symbolic representation of the sequences is shown. As an example, the analysis of two unannotated orthologous genomic sequences from human and mouse containing parts of the UTY locus is presented. The genome sequencing projects are producing DNA expression levels will be absent from the EST collec- sequence data at an exponentially growing rate. Pres- tions, and ESTs do not tell us about regulatory se- ently there are about 20 microbal genomes completely quences. We will then have to rely on other methods sequenced (Institute for Genomic Research 2000). Of to provide us with this information. For this, there are the eukaryotic genomes, Saccharomyces cerevisiae (Gof- basically two computational options, that is, ab initio feau et al. 1997), Caenorhabditis elegans (C. elegans Se- prediction and finding similarity to other sequences. quencing Consortium 1998), and Drosophila melano- The accuracy of ab initio prediction methods has im- gaster (Adams et al. 2000) are completed. Several other proved in recent years, but these methods are still not projects are well under way, for example, Arabidopsis very accurate (Burge and Karlin 1998). The alternative thaliana and Schizosaccharomyces pombe. Most impor- relies on the availability of homologous sequences, ei- tant, the human genome will be available in rough- ther DNA or protein. A particularly attractive method draft form in 2000, with completion by 2003 (Marshall is to do comparative sequence analysis of correspond- 1999). Following the human rough draft, we can ex- ing chromosomal regions from different species. Com- pect other large genomes to be sequenced in the next paring genomic sequences from species with evolu- few years, including those of other vertebrates such as tionary distance of 50–100 million years, such as hu- mouse (Collins et al. 1998; Pennisi 1999). man–mouse (80 million years, according to Li and Once a genome sequence is available, a primary Graur 1991), will not only reveal protein coding re- goal is to identify functional regions in the sequences, gions but also sequence elements that are important including genes and regulatory sequences. Much of for regulation of gene expression, maintaining the this identification will require new experimental work, structural organization of the genome, and so forth. but some information can be obtained purely compu- Comparative sequence analysis is becoming in- tationally, and since this is fast and cheap, we should creasingly popular, and in recent years, a number of seek to maximize it. For prokaryotic genomes, and for comparative studies of large genomic regions have lower eukaryotic genomes, this has been relatively been done, mainly between human and mouse (re- straightforward, as the gene structures are relatively viewed by Hardison et al. 1997). What is evident from simple with few, if any, introns. In higher eukaryotes, these studies is that gene structures are generally very this task is much more complicated. The EST sequenc- well preserved, even going as far back as the split be- ing projects will most certainly provide us with the tween fish and higher eukaryotes (450 million years, majority of genes but not necessarily with the com- according to Elgar 1996). Noncoding regions, however, plete gene structures. However, some genes with low show a varying degree of conservation. Conservation of noncoding regions at these evolutionary distances is 3Corresponding author. generally believed to imply a functional role. In a re- E-MAIL [email protected]; FAX 46 8 337983. cent study, we estimated that 20% of the length of 1148 Genome Research 10:1148–1157 ©2000 by Cold Spring Harbor Laboratory Press ISSN 1088-9051/00 $5.00; www.genome.org www.genome.org Downloaded from genome.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Comparative Genomic Sequence Analysis Workbench introns is conserved between mouse and human (Jare- and it seemed to us worth developing an application borg et al. 1999). Some parts of these conserved regions that built this in from the start. We also were commit- are involved in regulating splicing of the introns, but ted to using Java and did not have an available public other parts (e.g., the btk gene) are probably involved in domain Java source code to build on when we started regulating gene expression (Oeltjen et al. 1997). the project. There are a number of analysis programs available In it’s first instance, Alfresco was implemented as a that are applicable to comparative sequence analysis, stand-alone program that handled a pair of genomic and genome sequence analysis in general. These in- sequences and could access external programs through clude alignment programs, programs for identifying re- system calls on any computer running the UNIX oper- petitive elements, programs for identifying CpG is- ating system. However, since it might be impractical lands, gene prediction programs, and database- for all users to install analysis programs locally, Al- searching programs. All these different programs use fresco offers the possibility to run the analysis pro- different file formats for input and output, and the grams remotely on a server using the CORBA (Com- results are most often not intuitively interpretable. mon Object Request Broker Architecture) technology Graphic representations of sequences and features as- [Object Management Group 1999, see below]. To- sociated with these are often more attractive for the gether with Java, this provides platform independence average biologist. Our aim was to develop a graphic for the program. Alfresco can thus be used on UNIX, front end that would simplify both the execution of Macintosh, and Windows systems even though the relevant analyses and the interpretation of the results analysis programs used are UNIX based. of these analyses. Although there exist other programs When Alfresco is first started, the user is presented that give this type of functionality, for example, the with the main window (Fig. 1A). In the upper half, ACEDB genome database-management system (Durbin there are two buttons for selecting input sequences. and Thierry Mieg 1991), the Genotator annotation Alfresco reads DNA sequence files in FASTA format. workbench (Harris 1997), or the Java based Bioviews Underneath the file selection buttons are four rows for package (Helt et al. 1998), none existed that was tai- status messages: the general status of the program, cur- lored for comparative genome sequence analysis. Here rent zoom levels of the sequences, and a selected- we present such a program, which we have called Al- feature label. The bottom half contains the sequence fresco, that in its current implementation handles a map canvas. Menus provide different types of func- pair of genomic sequences of several hundred kilobases tionality, such as calling various analysis programs and (kb) and provides functionality for doing comparative opening/saving analyzed sequence pairs. analyses. The sequences and the features determined through different analyses are presented as graphic ob- Sequence Map Canvas jects that the user can examine interactively. The user The central part of the Alfresco main window is the can select and investigate further specific regions that sequence map canvas. It is on this canvas that the appear interesting, construct gene structures, and save graphic representations of the sequences are shown, and retrieve a working set of analysis and results. and it is through this display that the user interacts with the sequences and their associated features. The RESULTS sequence representations can be independently scrolled using the horizontal scrollbars above and be- General Overview low the map canvas. The horizontal scrollbar at the We decided to develop Alfresco using the Java pro- bottom of the window allows the sequences to be syn- gramming language (Gosling and Arnold 1996), as this chronously scrolled. Similarly, the rightmost vertical provided several advantages such as object orientation, scrollbar is used for synchronous zooming
Load more

Recommended publications
  • Human OMG Blocking Peptide (CDBP2120) This Product Is for Research Use Only and Is Not Intended for Diagnostic Use
    Human OMG blocking peptide (CDBP2120) This product is for research use only and is not intended for diagnostic use. PRODUCT INFORMATION Product Overview Blocking/Immunizing peptide for anti-OMG antibody Antigen Description OMG (oligodendrocyte myelin glycoprotein) is a protein-coding gene. Diseases associated with OMG include patulous eustachian tube, and internuclear ophthalmoplegia, and among its related super-pathways are p75NTR regulates axonogenesis and Development MAG-dependent inhibition of neurite outgrowth. GO annotations related to this gene include identical protein binding. Nature Synthetic Expression System N/A Species Human Species Reactivity Human Conjugate Unconjugated Applications Apuri, BL, ELISA Procedure None Format Lyophilized powder Size 100 μg Preservative None Storage Shipped at ambient temperature, store at -20°C. ANTIGEN GENE INFORMATION Gene Name OMG oligodendrocyte myelin glycoprotein [ Homo sapiens ] Official Symbol OMG Synonyms OMG; oligodendrocyte myelin glycoprotein; oligodendrocyte-myelin glycoprotein; OMGP; Entrez Gene ID 4974 mRNA Refseq NM_002544 45-1 Ramsey Road, Shirley, NY 11967, USA Email: [email protected] Tel: 1-631-624-4882 Fax: 1-631-938-8221 1 © Creative Diagnostics All Rights Reserved Protein Refseq NP_002535 UniProt ID P23515 Chromosome Location 17q11-q12 Pathway Axonal growth inhibition (RHOA activation), organism-specific biosystem; Signal Transduction, organism-specific biosystem; Signalling by NGF, organism-specific biosystem; p75 NTR receptor-mediated signalling, organism-specific biosystem; p75(NTR)-mediated signaling, organism-specific biosystem; p75NTR regulates axonogenesis, organism-specific biosystem; Function identical protein binding; 45-1 Ramsey Road, Shirley, NY 11967, USA Email: [email protected] Tel: 1-631-624-4882 Fax: 1-631-938-8221 2 © Creative Diagnostics All Rights Reserved.
    [Show full text]
  • CALIFORNIA STATE UNIVERSITY, NORTHRIDGE Bioinformatic
    CALIFORNIA STATE UNIVERSITY, NORTHRIDGE Bioinformatic Comparison of the EVI2A Promoter and Coding Regions A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science in Biology By Max Weinstein May 2020 The thesis of Max Weinstein is approved: Professor Rheem D. Medh Date Professor Virginia Oberholzer Vandergon Date Professor Cindy Malone, Chair Date California State University Northridge ii Table of Contents Signature Page ii List of Figures v Abstract vi Introduction 1 Ecotropic Viral Integration Site 2A, a Gene within a Gene 7 Materials and Methods 11 PCR and Cloning of Recombinant Plasmid 11 Transformation and Cell Culture 13 Generation of Deletion Constructs 15 Transfection and Luciferase Assay 16 Identification of Transcription Factor Binding Sites 17 Determination of Region for Analysis 17 Multiple Sequence Alignment (MSA) 17 Model Testing 18 Tree Construction 18 Promoter and CDS Conserved Motif Search 19 Results and Discussion 20 Choice of Species for Analysis 20 Mapping of Potential Transcription Factor Binding Sites 20 Confirmation of Plasmid Generation through Gel Electrophoresis 21 Analysis of Deletion Constructs by Transient Transfection 22 EVI2A Coding DNA Sequence Phylogenetics 23 EVI2A Promoter Phylogenetics 23 EVI2A Conserved Leucine Zipper 25 iii EVI2A Conserved Casein kinase II phosphorylation site 26 EVI2A Conserved Sox-5 Binding Site 26 EVI2A Conserved HLF Binding Site 27 EVI2A Conserved cREL Binding Site 28 EVI2A Conserved CREB Binding Site 28 Summary 29 Appendix: Figures 30 Literature Cited 44 iv List of Figures Figure 1. EVI2A is nested within the gene NF1 30 Figure 2 Putative Transcriptions Start Site 31 Figure 3. Gel Electrophoresis of pGC Blue cloned, Restriction Digested Plasmid 32 Figure 4.
    [Show full text]
  • Discoveryspace: an Interactive Data Analysis Application
    Open Access Software2007RobertsonetVolume al. 8, Issue 1, Article R6 DiscoverySpace: an interactive data analysis application comment Neil Robertson, Mehrdad Oveisi-Fordorei, Scott D Zuyderduyn, Richard J Varhol, Christopher Fjell, Marco Marra, Steven Jones and Asim Siddiqui Address: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Research Centre (BCCRC), British Columbia Cancer Agency (BCCA), Vancouver, BC, Canada. reviews Correspondence: Neil Robertson. Email: [email protected]. Mehrdad Oveisi-Fordorei. Email: [email protected]. Asim Siddiqui. Email: [email protected] Published: 08 January 2007 Received: 24 March 2006 Revised: 4 July 2006 Genome Biology 2007, 8:R6 (doi:10.1186/gb-2007-8-1-r6) Accepted: 8 January 2007 The electronic version of this article is the complete one and can be found online at http://genomebiology.com/2007/8/1/R6 reports © 2007 Robertson 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. Interactive<p>DiscoverySpace, data analysis a graphical application for bioinformatics data analysis, in particular analysis of SAGE data, is described</p> deposited research Abstract DiscoverySpace is a graphical application for bioinformatics data analysis. Users can seamlessly traverse references between biological databases and draw together annotations in an intuitive tabular interface. Datasets can be compared using a suite of novel tools to aid in the identification of significant patterns. DiscoverySpace is of broad utility and its particular strength is in the analysis of serial analysis of gene expression (SAGE) data.
    [Show full text]
  • In This Table Protein Name, Uniprot Code, Gene Name P-Value
    Supplementary Table S1: In this table protein name, uniprot code, gene name p-value and Fold change (FC) for each comparison are shown, for 299 of the 301 significantly regulated proteins found in both comparisons (p-value<0.01, fold change (FC) >+/-0.37) ALS versus control and FTLD-U versus control. Two uncharacterized proteins have been excluded from this list Protein name Uniprot Gene name p value FC FTLD-U p value FC ALS FTLD-U ALS Cytochrome b-c1 complex P14927 UQCRB 1.534E-03 -1.591E+00 6.005E-04 -1.639E+00 subunit 7 NADH dehydrogenase O95182 NDUFA7 4.127E-04 -9.471E-01 3.467E-05 -1.643E+00 [ubiquinone] 1 alpha subcomplex subunit 7 NADH dehydrogenase O43678 NDUFA2 3.230E-04 -9.145E-01 2.113E-04 -1.450E+00 [ubiquinone] 1 alpha subcomplex subunit 2 NADH dehydrogenase O43920 NDUFS5 1.769E-04 -8.829E-01 3.235E-05 -1.007E+00 [ubiquinone] iron-sulfur protein 5 ARF GTPase-activating A0A0C4DGN6 GIT1 1.306E-03 -8.810E-01 1.115E-03 -7.228E-01 protein GIT1 Methylglutaconyl-CoA Q13825 AUH 6.097E-04 -7.666E-01 5.619E-06 -1.178E+00 hydratase, mitochondrial ADP/ATP translocase 1 P12235 SLC25A4 6.068E-03 -6.095E-01 3.595E-04 -1.011E+00 MIC J3QTA6 CHCHD6 1.090E-04 -5.913E-01 2.124E-03 -5.948E-01 MIC J3QTA6 CHCHD6 1.090E-04 -5.913E-01 2.124E-03 -5.948E-01 Protein kinase C and casein Q9BY11 PACSIN1 3.837E-03 -5.863E-01 3.680E-06 -1.824E+00 kinase substrate in neurons protein 1 Tubulin polymerization- O94811 TPPP 6.466E-03 -5.755E-01 6.943E-06 -1.169E+00 promoting protein MIC C9JRZ6 CHCHD3 2.912E-02 -6.187E-01 2.195E-03 -9.781E-01 Mitochondrial 2-
    [Show full text]
  • Genomics and Risk Assessment | Mini-Monograph
    Genomics and Risk Assessment | Mini-Monograph Database Development in Toxicogenomics: Issues and Efforts William B. Mattes,1 Syril D. Pettit,2 Susanna-Assunta Sansone,3 Pierre R. Bushel,4 and Michael D. Waters4 1Pfizer Inc, Groton, Connecticut, USA; 2ILSI Health and Environmental Sciences Institute, Washington, DC, USA; 3European Molecular Biology Laboratory–European Bioinformatics Institute, Hinxton, United Kingdom; 4National Center for Toxicogenomics, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA thousands of defined probes, each of which The marriage of toxicology and genomics has created not only opportunities but also novel infor- is intended to detect a single mRNA mole- matics challenges. As with the larger field of gene expression analysis, toxicogenomics faces the cule. The mRNA sample is labeled and problems of probe annotation and data comparison across different array platforms. hybridized to the microarray such that the Toxicogenomics studies are generally built on standard toxicology studies generating biological end signal at a given probe is related to the point data, and as such, one goal of toxicogenomics is to detect relationships between changes in amount of that particular mRNA in the sam- gene expression and in those biological parameters. These challenges are best addressed through ple. This readout characteristic makes data collection into a well-designed toxicogenomics database. A successful publicly accessible toxi- microarray-based transcript profiling particu- cogenomics database will serve as a repository for data sharing and as a resource for analysis, data larly appealing because the identities of the mining, and discussion.
    [Show full text]
  • Gene Expression Specification
    Gene Expression Specification October 2003 Version 1.1 formal/03-10-01 An Adopted Specification of the Object Management Group, Inc. Copyright © 2002, EMBL-EBI (European Bioinformatics Institute) Copyright © 2003 Object Management Group Copyright © 2002, Rosetta Inpharmatics USE OF SPECIFICATION - TERMS, CONDITIONS & NOTICES The material in this document details an Object Management Group specification in accordance with the terms, conditions and notices set forth below. This document does not represent a commitment to implement any portion of this specification in any company's products. The information contained in this document is subject to change without notice. LICENSES The companies listed above have granted to the Object Management Group, Inc. (OMG) a nonexclusive, royalty-free, paid up, worldwide license to copy and distribute this document and to modify this document and distribute copies of the modified version. Each of the copyright holders listed above has agreed that no person shall be deemed to have infringed the copyright in the included material of any such copyright holder by reason of having used the specification set forth herein or having conformed any computer software to the specification. Subject to all of the terms and conditions below, the owners of the copyright in this specification hereby grant you a fully-paid up, non-exclusive, nontransferable, perpetual, worldwide license (without the right to sublicense), to use this specification to create and distribute software and special purpose specifications that are based upon this specification, and to use, copy, and distribute this specification as provided under the Copyright Act; provided that: (1) both the copyright notice identified above and this permission notice appear on any copies of this specification; (2) the use of the specifications is for informational purposes and will not be copied or posted on any network computer or broadcast in any media and will not be otherwise resold or transferred for commercial purposes; and (3) no modifications are made to this specification.
    [Show full text]
  • UC Irvine UC Irvine Electronic Theses and Dissertations
    UC Irvine UC Irvine Electronic Theses and Dissertations Title Generation and application of a chimeric model to examine human microglia responses to amyloid pathology Permalink https://escholarship.org/uc/item/38g5s0sj Author Hasselmann, Jonathan Publication Date 2021 Supplemental Material https://escholarship.org/uc/item/38g5s0sj#supplemental Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA, IRVINE Generation and application of a chimeric model to examine human microglia responses to amyloid pathology DISSERTATION Submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY In Biological Sciences By Jonathan Hasselmann Dissertation Committee: Associate Professor Mathew Blurton-Jones, Chair Associate Professor Kim Green Professor Brian Cummings 2021 Portions of the Introduction and Chapter 2 © 2020 Wiley Periodicals, Inc. Chapter 1 and a portion of Chapter 2 © 2019 Elsevier Inc. All other materials © 2021 Jonathan Hasselmann DEDICATION To Nikki and Isla: During this journey, I have been fortunate enough to have the love and support of two of the strongest ladies I have ever met. I can say without a doubt that I would not have made it here without the two of you standing behind me. I love you both with all my heart and this achievement belongs to the two of you just as much as it belongs to me. Thank you for always having my back. ii TABLE OF CONTENTS LIST OF FIGURES .......................................................................................................................v
    [Show full text]
  • Neurofibromatosis I and Multiple Sclerosis Christina Bergqvist1,2, François Hemery3, Salah Ferkal2,4 and Pierre Wolkenstein1,2,4*
    Bergqvist et al. Orphanet Journal of Rare Diseases (2020) 15:186 https://doi.org/10.1186/s13023-020-01463-z LETTER TO THE EDITOR Open Access Neurofibromatosis I and multiple sclerosis Christina Bergqvist1,2, François Hemery3, Salah Ferkal2,4 and Pierre Wolkenstein1,2,4* Abstract Neurofibromatosis 1 (NF1) is one of the most common autosomal dominant genetic disorders with a birth incidence as high as 1:2000. It is caused by mutations in the NF1 gene on chromosome 17 which encodes neurofibromin, a regulator of neuronal differentiation. While NF1 individuals are predisposed to develop benign and malignant nervous system tumors, various non-tumoral neurological conditions including multiple sclerosis (MS) have also been reported to occur more frequently in NF1. The number of epidemiologic studies on MS in NF1 individuals is very limited. The aim of this study was to determine the estimated population proportion of MS in NF1 patients followed in our Referral Centre for Neurofibromatosis using the Informatics for Integrated Biology and the Bedside (i2b2) platform to extract information from the hospital’s electronic health records. We found a total 1507 patients with confirmed NF1, aged 18 years (y) and above (mean age 39.2y, range 18-88y; 57% women). Five NF1 individuals were found to have MS, yielding an estimated population proportion of 3.3 per 1000 (0.0033, 95% Confidence Interval 0.0014–0.0077). The median age at diagnosis was 45 y (range 28–49 y). Three patients had relapsing-remitting MS and two patients had secondary progressive MS. Patients with NF1 were found to be twice more likely to develop MS than the general population in France (odds ratio 2.2), however this result was not statistically significant (95% Confidence Interval 0.91–5.29).
    [Show full text]
  • PB #ISAG2017 1 @Isagofficial #ISAG2017 #ISAG2017
    Bioinformatics · Comparative Genomics · Computational Biology Epigenetics · Functional Genomics · Genome Diversity · Geno Genome Sequencing · Immunogenetics · Integrative Geno · Microbiomics · Population Genomics · Systems Biolog Genetic Markers and Selection · Genetics and Dis Gene Editing · Bioinformatics · Comparative Computational Biology · Epigenetics · Fun Genome Diversity · Genome Sequeng Integrative Genomics · Microbiom Population Genomics · Syste Genetic Markers and Sel Genetics and Disease Gene Editing · Bi O’Brien Centre for Science Bioinformati and O’Reilly Hall, University College Dublin, Dublin, Ireland ABSTRACTMINI PROGRAMME BOOK www.isag.us/2017 PB #ISAG2017 1 @isagofficial #ISAG2017 #ISAG2017 Contents ORAL PRESENTATIONS 1 Animal Forensic Genetics Workshop 1 Applied Genetics and Genomics in Other Species of Economic Importance 3 Domestic Animal Sequencing and Annotation 5 Genome Edited Animals 8 Horse Genetics and Genomics 9 Avian Genetics and Genomics 12 Comparative MHC Genetics: Populations and Polymorphism 16 Equine Genetics and Thoroughbred Parentage Testing Workshop 19 Genetics of Immune Response and Disease Resistance 20 ISAG-FAO Genetic Diversity 24 Ruminant Genetics and Genomics 28 Animal Epigenetics 31 Cattle Molecular Markers and Parentage Testing 33 Companion Animal Genetics and Genomics 34 Microbiomes 37 Pig Genetics and Genomics 40 Novel, Groundbreaking Research/Methodology Presentation 44 Applied Genetics of Companion Animals 44 Applied Sheep and Goat Genetics 45 Comparative and Functional Genomics 47 Genetics
    [Show full text]
  • (NF1) As a Breast Cancer Driver
    INVESTIGATION Comparative Oncogenomics Implicates the Neurofibromin 1 Gene (NF1) as a Breast Cancer Driver Marsha D. Wallace,*,† Adam D. Pfefferle,‡,§,1 Lishuang Shen,*,1 Adrian J. McNairn,* Ethan G. Cerami,** Barbara L. Fallon,* Vera D. Rinaldi,* Teresa L. Southard,*,†† Charles M. Perou,‡,§,‡‡ and John C. Schimenti*,†,§§,2 *Department of Biomedical Sciences, †Department of Molecular Biology and Genetics, ††Section of Anatomic Pathology, and §§Center for Vertebrate Genomics, Cornell University, Ithaca, New York 14853, ‡Department of Pathology and Laboratory Medicine, §Lineberger Comprehensive Cancer Center, and ‡‡Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27514, and **Memorial Sloan-Kettering Cancer Center, New York, New York 10065 ABSTRACT Identifying genomic alterations driving breast cancer is complicated by tumor diversity and genetic heterogeneity. Relevant mouse models are powerful for untangling this problem because such heterogeneity can be controlled. Inbred Chaos3 mice exhibit high levels of genomic instability leading to mammary tumors that have tumor gene expression profiles closely resembling mature human mammary luminal cell signatures. We genomically characterized mammary adenocarcinomas from these mice to identify cancer-causing genomic events that overlap common alterations in human breast cancer. Chaos3 tumors underwent recurrent copy number alterations (CNAs), particularly deletion of the RAS inhibitor Neurofibromin 1 (Nf1) in nearly all cases. These overlap with human CNAs including NF1, which is deleted or mutated in 27.7% of all breast carcinomas. Chaos3 mammary tumor cells exhibit RAS hyperactivation and increased sensitivity to RAS pathway inhibitors. These results indicate that spontaneous NF1 loss can drive breast cancer. This should be informative for treatment of the significant fraction of patients whose tumors bear NF1 mutations.
    [Show full text]
  • Loci for Primary Ciliary Dyskinesia Map to Chromosome 16P12.1-12.2 And
    233 LETTER TO JMG J Med Genet: first published as 10.1136/jmg.2003.014084 on 1 March 2004. Downloaded from Loci for primary ciliary dyskinesia map to chromosome 16p12.1-12.2 and 15q13.1-15.1 in Faroe Islands and Israeli Druze genetic isolates D Jeganathan*, R Chodhari*, M MeeksÀ, O Færoe, D Smyth, K Nielsen, I Amirav, A S Luder, H Bisgaard, R M Gardiner, E M K Chung, H M Mitchison ............................................................................................................................... J Med Genet 2004;41:233–240. doi: 10.1136/jmg.2003.014084 rimary ciliary dyskinesia (PCD; Immotile cilia syndrome; OMIM 242650) is an autosomal recessive disorder Key points Presulting from dysmotility of cilia and sperm flagella.1 Cilia and flagella function either to create circulation of fluid N Primary ciliary dyskinesia is an autosomal recessive over a stationary cell surface or to propel a cell through disorder characterised by recurrent sinopulmonary fluid.23 These related structures are highly complex orga- infections, bronchiectasis, and subfertility, due to nelles composed of over 200 different polypeptides.45 The dysfunction of the cilia. Fifty percent of patients with core or axoneme of cilia and flagella comprises a bundle of primary ciliary dyskinesia have defects of laterality microtubules and many associated proteins. The microtu- (situs inversus) and this association is known as bules are formed from a and b tubulin protofilaments and are Kartagener syndrome. Primary ciliary dyskinesia has arranged in a well recognised ‘9+2’ pattern: nine peripheral an estimated incidence of 1 in 20 000 live births. microtubule doublets in a ring connected around a central N pair of microtubules by radial spoke proteins.
    [Show full text]
  • The Role of Co-Deleted Genes in Neurofibromatosis Type 1
    G C A T T A C G G C A T genes Article The Role of Co-Deleted Genes in Neurofibromatosis Type 1 Microdeletions: An Evolutive Approach Larissa Brussa Reis 1,2 , Andreia Carina Turchetto-Zolet 2, Maievi Fonini 1, Patricia Ashton-Prolla 1,2,3 and Clévia Rosset 1,* 1 Laboratório de Medicina Genômica, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul 90035-903, Brazil; [email protected] (L.B.R.); [email protected] (M.F.); [email protected] (P.A.-P.) 2 Programa de Pós-Graduação em Genética e Biologia Molecular, Departamento de Genética, UFRGS, Porto Alegre, Rio Grande do Sul 91501-970, Brazil; [email protected] 3 Serviço de Genética Médica do Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul 90035-903, Brazil * Correspondence: [email protected]; Tel.: +55-51-3359-7661 Received: 28 June 2019; Accepted: 16 September 2019; Published: 24 October 2019 Abstract: Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome that results from dominant loss-of-function mutations mainly in the NF1 gene. Large rearrangements are present in 5–10% of affected patients, generally encompass NF1 neighboring genes, and are correlated with a more severe NF1 phenotype. Evident genotype–phenotype correlations and the importance of the co-deleted genes are difficult to establish. In our study we employed an evolutionary approach to provide further insights into the understanding of the fundamental function of genes that are co-deleted in subjects with NF1 microdeletions. Our goal was to access the ortholog and paralog relationship of these genes in primates and verify if purifying or positive selection are acting on these genes.
    [Show full text]