Mapping Our Genes—Genome Projects: How Big? How Fast?
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Mouse Germ Line Mutations Due to Retrotransposon Insertions Liane Gagnier1, Victoria P
Gagnier et al. Mobile DNA (2019) 10:15 https://doi.org/10.1186/s13100-019-0157-4 REVIEW Open Access Mouse germ line mutations due to retrotransposon insertions Liane Gagnier1, Victoria P. Belancio2 and Dixie L. Mager1* Abstract Transposable element (TE) insertions are responsible for a significant fraction of spontaneous germ line mutations reported in inbred mouse strains. This major contribution of TEs to the mutational landscape in mouse contrasts with the situation in human, where their relative contribution as germ line insertional mutagens is much lower. In this focussed review, we provide comprehensive lists of TE-induced mouse mutations, discuss the different TE types involved in these insertional mutations and elaborate on particularly interesting cases. We also discuss differences and similarities between the mutational role of TEs in mice and humans. Keywords: Endogenous retroviruses, Long terminal repeats, Long interspersed elements, Short interspersed elements, Germ line mutation, Inbred mice, Insertional mutagenesis, Transcriptional interference Background promoter and polyadenylation motifs and often a splice The mouse and human genomes harbor similar types of donor site [10, 11]. Sequences of full-length ERVs can TEs that have been discussed in many reviews, to which encode gag, pol and sometimes env, although groups of we refer the reader for more in depth and general infor- LTR retrotransposons with little or no retroviral hom- mation [1–9]. In general, both human and mouse con- ology also exist [6–9]. While not the subject of this re- tain ancient families of DNA transposons, none view, ERV LTRs can often act as cellular enhancers or currently active, which comprise 1–3% of these genomes promoters, creating chimeric transcripts with genes, and as well as many families or groups of retrotransposons, have been implicated in other regulatory functions [11– which have caused all the TE insertional mutations in 13]. -
Medical Advisory Board September 1, 2006–August 31, 2007
hoWard hughes medical iNstitute 2007 annual report What’s Next h o W ard hughes medical i 4000 oNes Bridge road chevy chase, marylaNd 20815-6789 www.hhmi.org N stitute 2007 a nn ual report What’s Next Letter from the president 2 The primary purpose and objective of the conversation: wiLLiam r. Lummis 6 Howard Hughes Medical Institute shall be the promotion of human knowledge within the CREDITS thiNkiNg field of the basic sciences (principally the field of like medical research and education) and the a scieNtist 8 effective application thereof for the benefit of mankind. Page 1 Page 25 Page 43 Page 50 seeiNg Illustration by Riccardo Vecchio Südhof: Paul Fetters; Fuchs: Janelia Farm lab: © Photography Neurotoxin (Brunger & Chapman): Page 3 Matthew Septimus; SCNT images: by Brad Feinknopf; First level of Rongsheng Jin and Axel Brunger; iN Bruce Weller Blake Porch and Chris Vargas/HHMI lab building: © Photography by Shadlen: Paul Fetters; Mouse Page 6 Page 26 Brad Feinknopf (Tsai): Li-Huei Tsai; Zoghbi: Agapito NeW Illustration by Riccardo Vecchio Arabidopsis: Laboratory of Joanne Page 44 Sanchez/Baylor College 14 Page 8 Chory; Chory: Courtesy of Salk Janelia Farm guest housing: © Jeff Page 51 Ways Illustration by Riccardo Vecchio Institute Goldberg/Esto; Dudman: Matthew Szostak: Mark Wilson; Evans: Fred Page 10 Page 27 Septimus; Lee: Oliver Wien; Greaves/PR Newswire, © HHMI; Mello: Erika Larsen; Hannon: Zack Rosenthal: Paul Fetters; Students: Leonardo: Paul Fetters; Riddiford: Steitz: Harold Shapiro; Lefkowitz: capacity Seckler/AP, © HHMI; Lowe: Zack Paul Fetters; Map: Reprinted by Paul Fetters; Truman: Paul Fetters Stewart Waller/PR Newswire, Seckler/AP, © HHMI permission from Macmillan Page 46 © HHMI for Page 12 Publishers, Ltd.: Nature vol. -
Capr-Toc 3..4
Cancer Prevention Contents Research January 2011 Volume 4 Number 1 PERSPECTIVES 51 Interleukin 6, but Not T Helper 2 Cytokines, Promotes Lung Carcinogenesis 1 The Search for Unaffected Individuals Cesar E. Ochoa, with Lynch Syndrome: Do the Ends Seyedeh Golsar Mirabolfathinejad, Justify the Means? Ana Ruiz Venado, Scott E. Evans, Heather Hampel and Albert de la Chapelle Mihai Gagea, Christopher M. Evans, See article by Dinh et al., p. 9 Burton F. Dickey, and Seyed Javad Moghaddam 6 Time to Think Outside the (Genetic) Box 65 Cannabinoid Receptors, CB1 and CB2, Jean-Pierre J. Issa and Judy E. Garber as Novel Targets for Inhibition of See article by Wong et al., p. 23 Non–Small Cell Lung Cancer Growth and Metastasis RESEARCH ARTICLES Anju Preet, Zahida Qamri, Mohd W Nasser, Anil Prasad, Konstantin Shilo, Xianghong Zou, Jerome E. Groopman, 9 Health Benefits and Cost-Effectiveness and Ramesh K. Ganju of Primary Genetic Screening for Lynch Syndrome in the General Population 76 MicroRNAs 221/222 and Tuan A. Dinh, Benjamin I. Rosner, Genistein-Mediated Regulation of James C. Atwood, C. Richard Boland, ARHI Tumor Suppressor Gene in Sapna Syngal, Hans F. A. Vasen, Prostate Cancer Stephen B. Gruber, and Randall W. Burt Yi Chen, Mohd Saif Zaman, Guoren Deng, See perspective p. 1 Shahana Majid, Shranjot Saini, Jan Liu, Yuichiro Tanaka, and Rajvir Dahiya 23 Constitutional Methylation of the BRCA1 Promoter Is Specifically 87 Naftopidil, a Selective Associated with BRCA1 Mutation- a1-Adrenoceptor Antagonist, Associated Pathology in Early-Onset Suppresses Human Prostate Tumor Breast Cancer Growth by Altering Interactions Ee Ming Wong, Melissa C. -
Department of Energy Office of Health and Environmental Research SEQUENCING the HUMAN GENOME Summary Report of the Santa Fe Workshop March 3-4, 1986
Department of Energy Office of Health and Environmental Research SEQUENCING THE HUMAN GENOME Summary Report of the Santa Fe Workshop March 3-4, 1986 Los Alamos National Laboratory Los Alamos Los Alamos, New Mexico 87545 Los Alamos National Laboratory is operated by the University of California for the United States Department of Energy under contract W-7405-ENG-36. DEPARTMENT OF ENERGY OFFICE OF HEALTH AND ENVIRONMENTAL RESEARCH SEQUENCING THE HUMAN GENOME SUMMARY REPORT ON THE SANTA FE WORKSHOP (MARCH 3-4, 1986) Executive Summary. The following is a summary of the Santa Fe Workshop held on March 3 and 4, 1986. The workshop was sponsored by the Office of Health and Environmental Research (OHER) and Los Alamos National Laboratory (LANL) and dedicated to examining the feasibility, advisability, and approaches to sequencing the human genome. The workshop considered four principal topics: I. Technologies to be employed. II. Expected benefits. III. Architecture of the enterprise. IV. Participants and funding. I . Technology The participants of the workshop foresaw extraordinary and continuing progress in the efficiency and accuracy of mapping, ordering , and sequencing technologies. They suggested that a coordinated analysis of the human genome begin with the task of ordering overlapping recombinant DNA fragments obtained from purified human chromosomes that would provide an infrastructure for sequencing activity. At the same time, they support in-depth evaluation of current and developing strategies for sequencing including possible applications of automation and robotics that would minimize the time and cost of sequencing. II. Benefits The socio-political and health benefits, and the benefit:cost ratio were seen as highly favorable not only for human health, but in addition for the development of new diagnostic, preventative and therapeutic tools, jobs, and industries. -
Biallelic MUTYH Mutations Can Mimic Lynch Syndrome
European Journal of Human Genetics (2014) 22, 1334–1337 & 2014 Macmillan Publishers Limited All rights reserved 1018-4813/14 www.nature.com/ejhg SHORT REPORT Biallelic MUTYH mutations can mimic Lynch syndrome Monika Morak1,2, Barbara Heidenreich1, Gisela Keller3, Heather Hampel4, Andreas Laner2, Albert de la Chapelle4 and Elke Holinski-Feder*,1,2 The hallmarks of Lynch syndrome (LS) include a positive family history of colorectal cancer (CRC), germline mutations in the DNA mismatch repair (MMR) genes, tumours with high microsatellite instability (MSI-H) and loss of MMR protein expression. However, in B10–15% of clinically suspected LS cases, MMR mutation analyses cannot explain MSI-H and abnormal immunohistochemistry (IHC) results. The highly variable phenotype of MUTYH-associated polyposis (MAP) can overlap with the LS phenotype, but is inherited recessively. We analysed the MUTYH gene in 85 ‘unresolved’ patients with tumours showing IHC MMR-deficiency without detectable germline mutation. Biallelic p.(Tyr179Cys) MUTYH germline mutations were found in one patient (frequency 1.18%) with CRC, urothelial carcinoma and a sebaceous gland carcinoma. LS was suspected due to a positive family history of CRC and because of MSI-H and MSH2–MSH6 deficiency on IHC in the sebaceous gland carcinoma. Sequencing of this tumour revealed two somatic MSH2 mutations, thus explaining MSI-H and IHC results, and mimicking LS-like histopathology. This is the first report of two somatic MSH2 mutations leading to an MSI-H tumour lacking MSH2–MSH6 protein expression in a patient with MAP. In addition to typical transversion mutations in KRAS and APC, MAP can also induce tumourigenesis via the MSI-pathway. -
FY 1982 Submission Provided
DRAFT DOE/FE-0033 Previous No. DOE/ER-0102 ENERGY MATERIALS COORDINATING COMMITTEE (EMACC) Fiscal Year 1982 March 1983 ANNUAL TECHNICAL REPORT U.S. Department of Energy Washington, D.C. 20545 DRAFT DOE/FE-0033 Previous No. DOE/ER-0102 ENERGY MATERIALS COORDINATING COMMITTEE (EMACC) Fiscal Year 1982 March 1983 ANNUAL TECHNICAL REPORT U.S. Department of Energy TABLE OF CONTENTS Page No. INTRODUCTION ........................................................ 1 Fiscal Year 1982 Activities ....................................... 2 Materials Funding Trends in the Department of Energy .............. 6 PROGRAM DESCRIPTIONS ................................................ 11 - Office of Conservation and Renewable Systems .................... 14 * Office of Building Energy Research Development .............. 14 * Energy Conversion and Utilization Technologies .............. 15 * Division of Energy Storage Technology - Electrochemical Storage Branch .............................. 16 * Office of Vehicle and Engine R&D ............................ 17 * Office of Industrial Programs ............................... 18 * Biomass Energy Technology Division - Biological Hydrogen Program .......................................... 18 * Division of Ocean Energy Technology - Ocean Thermal Energy Conversion Program ................................. 19 * Office of Solar Energy/Photovoltaics Energy - Technology - Materials Research ........................... 20 * Wind Energy Technology Division - Large Wind Turbine Research and Technology Development ........................ -
Characterizing the Dna-Binding Site Specificities of Cis2his2 Zinc Fingers
MQP-ID-DH-UM1 C H A R A C T E RI Z IN G T H E DN A-BINDIN G SI T E SPE C I F I C I T I ES O F C IS2H IS2 Z IN C F IN G E RS A Major Qualifying Project Report Submitted to the Faculty of the WORCESTER POLYTECHNIC INSTITUTE in partial fulfillment of the requirements for the Degrees of Bachelor of Science in Biochemistry and Biology and Biotechnology by _________________________ Heather Bell April 26, 2012 APPROVED: ____________________ ____________________ ____________________ Scot Wolfe, PhD Destin Heilman, PhD David Adams, PhD Gene Function and Exp. Biochemistry Biology and Biotech UMass Medical School WPI Project Advisor WPI Project Advisor MAJOR ADVISOR A BST R A C T The ability to modularly assemble Zinc Finger Proteins (ZFPs) as well as the wide variety of DNA sequences they can recognize, make ZFPs an ideal framework to design novel DNA-binding proteins. However, due to the complexity of the interactions between residues in the ZF recognition helix and the DNA-binding site there is currently no comprehensive recognition code that would allow for the accurate prediction of the DNA ZFP binding motifs or the design of novel ZFPs for a desired target site. Through the analysis of the DNA-binding site specificities of 98 ZFP clones, determined through a bacterial one-hybrid selection system, a predictive model was created that can accurately predict the binding site motifs of novel ZFPs. 2 T A B L E O F C O N T E N TS Signature Page ««««««««««««««««««««««««««« $EVWUDFW«««««««««««««««««««««««««««««« 7DEOHRI&RQWHQWV«««««««««««««««««««««««««« $FNQRZOHGJHPHQWV««««««««««««««««««««««««« %DFNJURXQG«««««««««««««««««««««««««««« Project Purpose «««««««««««««««««««««««««««15 0HWKRGV««««««««««««««««««««««««««««««16 5HVXOWV««««««««««««««««««««««««««««««21 'LVFXVVLRQ«««««««««««««««««««««««««««««28 Bibliograph\«««««««««««««««««««««««««««« 6XSSOHPHQWDO««««««««««««««««««««««««««« 3 A C K N O W L E D G E M E N TS I would like to thank Dr. -
1 Constructing the Scientific Population in the Human Genome Diversity and 1000 Genome Projects Joseph Vitti I. Introduction: P
Constructing the Scientific Population in the Human Genome Diversity and 1000 Genome Projects Joseph Vitti I. Introduction: Populations Coming into Focus In November 2012, some eleven years after the publication of the first draft sequence of a human genome, an article published in Nature reported a new ‘map’ of the human genome – created from not one, but 1,092 individuals. For many researchers, however, what was compelling was not the number of individuals sequenced, but rather the fourteen worldwide populations they represented. Comparisons that could be made within and among these populations represented new possibilities for the scientific study of human genetic variation. The paper – which has been cited over 400 times in the subsequent year – was the output of the first phase of the 1000 Genomes Project, one of several international research consortia launched with the intent of identifying and cataloguing such variation. With the project’s phase three data release, anticipated in early spring 2014, the sample size will rise to over 2500 individuals representing twenty-six populations. Each individual’s full sequence data is made publicly available online, and is also preserved through the establishment of immortal cell lines, from which DNA can be extracted and distributed. With these developments, population-based science has been made genomic, and scientific conceptions of human populations have begun to crystallize (see appendix). Such extensive biobanking and databasing of human populations is remarkable for a number of reasons, not least among them the socially charged terrain that such an enterprise inevitably must navigate. While the 1000 Genomes Project (1000G) has been relatively uncontroversial in its reception, predecessors such as the Human Genome Diversity Project (HGDP), first conceived in 1991, faced greater difficulty. -
US Neutron Facility Development in the Last Half-Century: a Cautionary Tale
Phys. Perspect. Ó 2015 The Author(s). This article is published with open access at Springerlink.com DOI 10.1007/s00016-015-0158-8 Physics in Perspective US Neutron Facility Development in the Last Half-Century: A Cautionary Tale John J. Rush* Large multi-user facilities serve many thousands of researchers in fields from particle physics to fundamental biology. The great expense—up to billions of current-day dollars— and the complexity of such facilities required access to extensive engineering and research infrastructures, most often found at national laboratories and the largest research univer- sities. Although the development of such facilities has been largely successful and the research results unique and often spectacular, the processes for choosing, funding, and locating them were complex and not always productive. In this review, I describe the troubled efforts over the past fifty years to develop neutron research facilities in the United States. During this period, the US has moved from a preeminent position in neutron-based science to a lesser status with respect to Europe. Several major US centers of excellence have been shut down and replaced with more focused capabilities. I compare the US efforts in neutron facilities with parallel developments in Europe and Asia, discuss the reasons for this state of affairs, and make some suggestions to help prevent similar consequences in the future. Key words: neutron research; national laboratories; Department of Energy; National Institute of Standards and Technology; research reactors; spallation neutron sources; Institut Laue-Langevin; National Academy of Sciences. Introduction A major element in the great expansion both of US and international science since the Second World War has been the development of large multi-user facilities to serve many thousands of researchers around the world with applications in almost all fields, ranging from particle physics to fundamental biology. -
Ancient DNA: a History of the Science Before Jurassic Park
Contents lists available at ScienceDirect Studies in History and Philosophy of Biol & Biomed Sci journal homepage: www.elsevier.com/locate/shpsc Ancient DNA: a history of the science before Jurassic Park Elizabeth D. Jonesa,b,∗ a University College London, Department of Science and Technology Studies, Gower Street, London, WC1E 6BT, United Kingdom b University College London, Department of Genetics, Evolution and Environment, Gower Street, London, WC1E 6BT, United Kingdom 1. Introduction an array of actors from futurists and enthusiasts to scientists and the popular press contributed to ancient DNA's early history, and that what This history highlights the search for DNA from ancient and ex- we see as science often has its beginnings with ideas and individuals tinct organisms from the late 1970s to the mid 1980s, uncovering the that are outside the conventional confinements of the laboratory. origination and exploration of ideas that contributed to the con- Second, this article argues that from the beginning, particularly struction of this new line of research.1 Although this is the first preceding the release of Jurassic Park,thesearchforDNAfromfossils academic historical account of ancient DNA's disciplinary develop- was closely connected to the idea of bringing back extinct organisms. ment, there are other reviews and reports that outline its history.2 Ancient DNA elicited enthusiasm and speculation across different Most cite a paper published in Nature in 1984, where researchers audiences. Some imagined using DNA to study evolutionary history. reported the discovery of DNA froma140-year-oldextinctquagga,as Others speculated about its potential to resurrect long-lost species. the beginning of ancient DNA's history. -
The Gene Wars: Science, Politics, and the Human Genome
8 Early Skirmishes | N A COMMENTARY introducing the March 7, 1986, issue of Science, I. Renato Dulbecco, a Nobel laureate and president of the Salk Institute, made the startling assertion that progress in the War on Cancer would be speedier if geneticists were to sequence the human genome.1 For most biologists, Dulbecco's Science article was their first encounter with the idea of sequencing the human genome, and it provoked discussions in the laboratories of universities and research centers throughout the world. Dul- becco was not known as a crusader or self-promoter—quite the opposite— and so his proposal attained credence it would have lacked coming from a less esteemed source. Like Sinsheimer, Dulbecco came to the idea from a penchant for thinking big. His first public airing of the idea came at a gala Kennedy Center event, a meeting organized by the Italian embassy in Washington, D.C., on Columbus Day, 1985.2 The meeting included a section on U.S.-Italian cooperation in science, and Dulbecco was invited to give a presentation as one of the most eminent Italian biologists, familiar with science in both the United States and Italy. He was preparing a review paper on the genetic approach to cancer, and he decided that the occasion called for grand ideas. In thinking through the recent past and future directions of cancer research, he decided it could be greatly enriched by a single bold stroke—sequencing the human genome. This Washington meeting marked the beginning of the Italian genome program.3 Dulbecco later made the sequencing -
A Founder Mutation of the MSH2 Gene and Hereditary Nonpolyposis Colorectal Cancer in the United States
ORIGINAL CONTRIBUTION A Founder Mutation of the MSH2 Gene and Hereditary Nonpolyposis Colorectal Cancer in the United States Henry T. Lynch, MD Context Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch Stephanie M. Coronel, MPH syndrome, is caused by mutations in the mismatch repair genes and confers an ex- Ross Okimoto, BS traordinarily high risk of colorectal, endometrial, and other cancers. However, while carriers of these mutations should be identified, counseled, and offered clinical sur- Heather Hampel, MS, CGC veillance, at present the mutations are not tested for in mutation analyses. Kevin Sweet, MS, CGC Objective To describe the prevalence of a large genomic deletion encompassing ex- Jane F. Lynch, BSN ons1to6oftheMSH2 gene that is widespread in the US population as a result of a founder effect. Ali Barrows, BS Design, Setting, and Patients Ongoing genealogical and historical study con- Juul Wijnen, PhD ducted to assess the origin and spread of an MSH2 mutation previously identified in 9 Heleen van der Klift, MS apparently unrelated families with putative HNPCC and living in widely different geo- graphic locations in the United States. Patrick Franken, HLO Main Outcome Measures Classification of family members as carriers or noncar- Anja Wagner, PhD, MD riers of the MSH2 mutation; spread of the mutation across the continental United Riccardo Fodde, PhD States. Albert de la Chapelle, MD, PhD Results To date, 566 family members of the 9 probands have been identified to be at risk and counseled; 137 of these have been tested, and 61 carry the founder mu- HE ANNUAL WORLDWIDE INCI- tation. Three families have been genealogically shown to descend from a German im- dence of colorectal cancer is es- migrant family that arrived and first settled in Pennsylvania in the early 1700s.