DNA Sequence Insertion and Evolutionary Variation in Gene Regulation (Mobile Elements/Long Terminal Repeats/Alu Sequences/Factor-Binding Sites) Roy J
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An Alu Element-Based Model of Human Genome Instability George Wyndham Cook, Jr
Louisiana State University LSU Digital Commons LSU Doctoral Dissertations Graduate School 2013 An Alu element-based model of human genome instability George Wyndham Cook, Jr. Louisiana State University and Agricultural and Mechanical College, [email protected] Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_dissertations Recommended Citation Cook, Jr., George Wyndham, "An Alu element-based model of human genome instability" (2013). LSU Doctoral Dissertations. 2090. https://digitalcommons.lsu.edu/gradschool_dissertations/2090 This Dissertation is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Doctoral Dissertations by an authorized graduate school editor of LSU Digital Commons. For more information, please [email protected]. AN ALU ELEMENT-BASED MODEL OF HUMAN GENOME INSTABILITY A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of the requirements for the degree of Doctor of Philosophy in The Department of Biological Sciences by George Wyndham Cook, Jr. B.S., University of Arkansas, 1975 May 2013 TABLE OF CONTENTS LIST OF TABLES ...................................................................................................... iii LIST OF FIGURES .................................................................................................... iv LIST OF ABBREVIATIONS ...................................................................................... -
DNA Insertion Mutations Can Be Predicted by a Periodic Probability
Research article DNA insertion mutations can be predicted by a periodic probability function Tatsuaki Tsuruyama1 1Department of Pathology, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan Running title: Probability prediction of mutation Correspondence to: Tatsuaki Tsuruyama Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan Tel.: +81-75-751-3488; Fax: +81-75-761-9591 E-mail: [email protected] 1 Abstract It is generally difficult to predict the positions of mutations in genomic DNA at the nucleotide level. Retroviral DNA insertion is one mode of mutation, resulting in host infections that are difficult to treat. This mutation process involves the integration of retroviral DNA into the host-infected cellular genomic DNA following the interaction between host DNA and a pre-integration complex consisting of retroviral DNA and integrase. Here, we report that retroviral insertion sites around a hotspot within the Zfp521 and N-myc genes can be predicted by a periodic function that is deduced using the diffraction lattice model. In conclusion, the mutagenesis process is described by a biophysical model for DNA–DNA interactions. Keywords: Insertion, mutagenesis, palindromic sequence, retroviral DNA 2 Text Introduction Extensive research has examined retroviral insertions to further our understanding of DNA mutations. Retrovirus-related diseases, including leukemia/lymphoma and AIDS, develop after retroviral genome insertion into the genomic DNA of the infected host cell. Retroviral DNA insertion is one of the modes of insertional mutation. After reverse-transcription of the retroviral genomic RNA into DNA, the retroviral DNA forms a pre-insertion complex (PIC) with the integrase enzyme, which catalyzes the insertion reaction. -
Transcriptome-Wide Effects of Inverted Sines on Gene Expression And
Tajaddod et al. Genome Biology (2016) 17:220 DOI 10.1186/s13059-016-1083-0 RESEARCH Open Access Transcriptome-wide effects of inverted SINEs on gene expression and their impact on RNA polymerase II activity Mansoureh Tajaddod1†, Andrea Tanzer3†, Konstantin Licht2†, Michael T. Wolfinger2,3, Stefan Badelt3, Florian Huber1,4, Oliver Pusch2, Sandy Schopoff1, Michael Janisiw2, Ivo Hofacker3 and Michael F. Jantsch2,5* Abstract Background: Short interspersed elements (SINEs) represent the most abundant group of non-long-terminal repeat transposable elements in mammalian genomes. In primates, Alu elements are the most prominent and homogenous representatives of SINEs. Due to their frequent insertion within or close to coding regions, SINEs have been suggested to play a crucial role during genome evolution. Moreover, Alu elements within mRNAs have also been reported to control gene expression at different levels. Results: Here, we undertake a genome-wide analysis of insertion patterns of human Alus within transcribed portions of the genome. Multiple, nearby insertions of SINEs within one transcript are more abundant in tandem orientation than in inverted orientation. Indeed, analysis of transcriptome-wide expression levels of 15 ENCODE cell lines suggests a cis-repressive effect of inverted Alu elements on gene expression. Using reporter assays, we show that the negative effect of inverted SINEs on gene expression is independent of known sensors of double-stranded RNAs. Instead, transcriptional elongation seems impaired, leading to reduced mRNA levels. Conclusions: Our study suggests that there is a bias against multiple SINE insertions that can promote intramolecular base pairing within a transcript. Moreover, at a genome-wide level, mRNAs harboring inverted SINEs are less expressed than mRNAs harboring single or tandemly arranged SINEs. -
Insertion Element (IS1 Insertion Sequence/Chloramphenicol Resistance Transposon Tn9/Integrative Recombination) L
Proc. Nati. Acad. Sci. USA Vol. 75, No. 3, pp. 1490-1494, March 1978 Genetics Chromosomal integration of phage X by means of a DNA insertion element (IS1 insertion sequence/chloramphenicol resistance transposon Tn9/integrative recombination) L. A. MACHATTIE AND J. A. SHAPIRO Department of Microbiology, University of Chicago, Chicago, Illinois 60637 Communicated by Albert Dorfman, January 10, 1978 ABSTRACT Phage Xcamll2, which contains the chlor- carries a deletion of the gal-attB-bio region of the Escherichia amphenicol resistance transposon Tn9 and has a deletion of attP coil chromosome. MGBO is a gal+bio+ transductant of and the int gene, will lysogenize Escherichia coli K-12. Pro- phage integration occurs at different chromosomal sites, in- MADO. MS6 is a galE indicator for detection of XgalE + T- cluding lacYand maiB, but not at attB. All Xcamll2 prophages transducing particles and S1653 is a gal deletion strain for de- are excised from the chromosome after induction but with tection of Xgal + particles (3). Strain 200PS is a thi lacY strain various efficiencies for different locations. Heteroduplex from the Pasteur collection. Strain QL carries a complete lac analysis of XplacZ transducing phages isolated from a lacY:: deletion, strain X9003 carries the nonpolar M15 lacZ deletion, Xcamll2 prophage reveals an insertion sequence 1 (IS1) element and either will serve as indicator for XplacZ phage in a blue at theloint of viral and chromosomal DNA. Two lines of evi- dencekdicate that Xcamll2 encodes an excision activity that plaque assay (8). recognizes the ISI element: (i) prophage derepression increases Media. Our basic minimal medium and complete TYE the frequency of excision from IacYto yield lac+ revertants, and medium have been described (9). -
Gene Therapy Glossary of Terms
GENE THERAPY GLOSSARY OF TERMS A • Phase 3: A phase of research to describe clinical trials • Allele: one of two or more alternative forms of a gene that that gather more information about a drug’s safety and arise by mutation and are found at the same place on a effectiveness by studying different populations and chromosome. different dosages and by using the drug in combination • Adeno-Associated Virus: A single stranded DNA virus that has with other drugs. These studies typically involve more not been found to cause disease in humans. This type of virus participants.7 is the most frequently used in gene therapy.1 • Phase 4: A phase of research to describe clinical trials • Adenovirus: A member of a family of viruses that can cause occurring after FDA has approved a drug for marketing. infections in the respiratory tract, eye, and gastrointestinal They include post market requirement and commitment tract. studies that are required of or agreed to by the study • Adeno-Associated Virus Vector: Adeno viruses used as sponsor. These trials gather additional information about a vehicles for genes, whose core genetic material has been drug’s safety, efficacy, or optimal use.8 removed and replaced by the FVIII- or FIX-gene • Codon: a sequence of three nucleotides in DNA or RNA • Amino Acids: building block of a protein that gives instructions to add a specific amino acid to an • Antibody: a protein produced by immune cells called B-cells elongating protein in response to a foreign molecule; acts by binding to the • CRISPR: a family of DNA sequences that can be cleaved by molecule and often making it inactive or targeting it for specific enzymes, and therefore serve as a guide to cut out destruction and insert genes. -
Sequences Enriched in Alu Repeats Drive Nuclear Localization of Long Rnas in Human Cells
bioRxiv preprint doi: https://doi.org/10.1101/189746; this version posted September 16, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Sequences enriched in Alu repeats drive nuclear localization of long RNAs in human cells Yoav Lubelsky and Igor Ulitsky* Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel * - Corresponding author, [email protected] +972-8-9346421 Abstract Long noncoding RNAs (lncRNAs) are emerging as key players in multiple cellular pathways, but their modes of action, and how those are dictated by sequence remain elusive. While lncRNAs share most molecular properties with mRNAs, they are more likely to be enriched in the nucleus, a feature that is likely to be crucial for function of many lncRNAs, but whose molecular underpinnings remain largely unclear. In order identify elements that can force nuclear localization we screened libraries of short fragments tiled across nuclear RNAs, which were cloned into the untranslated regions of an efficiently exported mRNA. The screen identified a short sequence derived from Alu elements and found in many mRNAs and lncRNAs that increases nuclear accumulation and reduces overall expression levels. Measurements of the contribution of individual bases and short motifs to the element functionality identified a combination of RCCTCCC motifs that are bound by the abundant nuclear protein HNRNPK. Increased HNRNPK binding and C-rich motifs are predictive of substantial nuclear enrichment in both lncRNAs and mRNAs, and this mechanism is conserved across species. Our results thus detail a novel pathway for regulation of RNA accumulation and subcellular localization that has been co-opted to regulate the fate of transcripts that integrated Alu elements. -
Isolation, Characterization, and Mapping of Four Novel Polymorphic Markers and an H3.3B Pseudogene to Chromosome 9P21-22
348J Hum Genet (1999) 44:348–349 © Jpn Soc Hum Genet and Springer-Verlag 1999 BRIEF REPORT — CASE REPORT Elias Aliprandis · Juliette Harris · Barney Yoo Bruce D. Gelb · John A. Martignetti Isolation, characterization, and mapping of four novel polymorphic markers and an H3.3B pseudogene to chromosome 9p21-22 Received: April 16, 1999 / Accepted: May 20, 1999 Abstract Alterations in chromosomal region 9p21-22 are (Cannon-Albright et al. 1994), and multiple familial trich- among the most frequently encountered cytogenetic changes oepithelioma (Harada et al. 1996). We describe the isola- present in a number of human malignancies. In addition, the tion, characterization, fine mapping, and ordering of four causative genes of a number of hereditary cancers have been novel polymorphic markers, the previously identified genetically mapped to this region. We describe the isolation marker D9S1846, and a processed replacement histone and precise localization of four novel polymorphic markers H3.3B pseudogene and its flanking L1 and Alu elements. and a previously identified marker, D9S1846, from this re- gion. Moreover, we have identified a retroposon-rich area within this oncogenic region containing a processed H3.3B pseudogene flanked by an L1 sequence and an Alu element. Source and isolation of polymorphic DNA markers and Together, these finely mapped and ordered reagents should an H3.3B pseudogene prove useful for genetic mapping, sequencing, and loss of heterozygosity studies of the 9p21-22 region. Two P1 clones and one PAC clone (731, 232, and 160 8P, respectively; Research Genetics, Huntsville, AL, USA) from Key words Chromosome 9p21-22 · Polymorphic markers · the region were restriction enzyme digested and the resulting Histone H3.3B Pseudogene · Loss of heterozygosity · fragments were separated electrophoretically and transferred to Retroposon a nylon membrane (NEN, Boston, MA, USA) using standard methods (Maniatis et al. -
Generation of Deletion Derivatives by Targeted Transformation of Human
Proc. Natl. Acad. Sci. USA Vol. 87, pp. 1300-1304, February 1990 Genetics Generation of deletion derivatives by targeted transformation of human-derived yeast artificial chromosomes (yeast artificial chromosome fragmentation/homologous recombination/repetitive DNA/macrorestriction map) WILLIAM J. PAVAN*, PHILIP HIETERt, AND ROGER H. REEVES*t Departments of *Physiology and tMolecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 Communicated by John W. Littlefield, November 27, 1989 ABSTRACT Mammalian DNA 'segments cloned as yeast homologous recombination (HR)-based methods have in- artificial chromosomes (YACs) can be manipulated by DNA- volved DNA segments of about several hundred base pairs mediated transformation when placed in an appropriate yeast (bp) or more in length that are completely homologous to the genetic background. A "fragmenting vector" has been devel- genomic target sequence. The length of homologous se- oped that can introduce a yeast telomere and selectable marker quence required to target recombination, the degree of mis- into human-derived YACs at specific sites by means of homol- match tolerated, and the effects of these variables on the ogous recombination, deleting all sequences distal to the re- frequency of HR are not known. combination site. A powerful application of the method uses a Repetitive sequences are distributed throughout the ge- human Alu family repeat sequence to target recombination to nomes of mammals. The human genome contains -500,000 multiple independent sites on a human-derived YAC. Sets of copies of Alu family repetitive elements (8). Individual Alu deletion derivatives generated by this procedure greatly facil- elements are tandem direct repeats totaling "300 bp in itate restriction mapping oflarge genomic segments. -
The Origin, Evolution, and Functional Impact of Short Insertion–Deletion Variants Identified in 179 Human Genomes
Downloaded from genome.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Research The origin, evolution, and functional impact of short insertion–deletion variants identified in 179 human genomes Stephen B. Montgomery,1,2,3,14,16 David L. Goode,3,14,15 Erika Kvikstad,4,13,14 Cornelis A. Albers,5,6 Zhengdong D. Zhang,7 Xinmeng Jasmine Mu,8 Guruprasad Ananda,9 Bryan Howie,10 Konrad J. Karczewski,3 Kevin S. Smith,2 Vanessa Anaya,2 Rhea Richardson,2 Joe Davis,3 The 1000 Genomes Pilot Project Consortium, Daniel G. MacArthur,5,11 Arend Sidow,2,3 Laurent Duret,4 Mark Gerstein,8 Kateryna D. Makova,9 Jonathan Marchini,12 Gil McVean,12,13 and Gerton Lunter13,16 1–13[Author affiliations appear at the end of the paper.] Short insertions and deletions (indels) are the second most abundant form of human genetic variation, but our un- derstanding of their origins and functional effects lags behind that of other types of variants. Using population-scale sequencing, we have identified a high-quality set of 1.6 million indels from 179 individuals representing three diverse human populations. We show that rates of indel mutagenesis are highly heterogeneous, with 43%–48% of indels occurring in 4.03% of the genome, whereas in the remaining 96% their prevalence is 16 times lower than SNPs. Polymerase slippage can explain upwards of three-fourths of all indels, with the remainder being mostly simple de- letions in complex sequence. However, insertions do occur and are significantly associated with pseudo-palindromic sequence features compatible with the fork stalling and template switching (FoSTeS) mechanism more commonly as- sociated with large structural variations. -
Active Alu Element “A-Tails”: Size Does Matter
Letter Active Alu Element “A-Tails”: Size Does Matter Astrid M. Roy-Engel,1 Abdel-Halim Salem,2,3 Oluwatosin O. Oyeniran,1 Lisa Deininger,1 Dale J. Hedges,2 Gail E. Kilroy,2 Mark A. Batzer,2 and Prescott L. Deininger1,4,5 1Tulane Cancer Center, SL-66, Department of Environmental Health Sciences, Tulane University–Health Sciences Center, NewOrleans, Louisiana 70112, USA; 2Department of Biological Sciences, Biological Computation and Visualization Center, Louisiana State University, Baton Rouge, Louisiana 70803, USA; 3Department of Anatomy, Faculty of Medicine, Suez Canal University, Ismailia, Egypt; 4Laboratory of Molecular Genetics, Alton Ochsner Medical Foundation, New Orleans, Louisiana 70121, USA. Long and short interspersed elements (LINEs and SINEs) are retroelements that make up almost half of the human genome. L1 and Alu represent the most prolific human LINE and SINE families, respectively. Only a few Alu elements are able to retropose, and the factors determining their retroposition capacity are poorly understood. The data presented in this paper indicate that the length of Alu “A-tails” is one of the principal factors in determining the retropositional capability of an Alu element. The A stretches of the Alu subfamilies analyzed, both old (Alu S and J) and young (Ya5), had a Poisson distribution of A-tail lengths with a mean size of 21 and 26, respectively. In contrast, the A-tails of very recent Alu insertions (disease causing) were all between 40 and 97 bp in length. The L1 elements analyzed displayed a similar tendency, in which the “disease”-associated elements have much longer A-tails (mean of 77) than do the elements even from the young Ta subfamily (mean of 41). -
Glossary of Common Terms in Genetics
Glossary of Common Terms in Genetics Acquired mutations Gene changes genetic information. DNA is held Multiplexing A sequencing approach that that arise within individual cells and together by weak bonds between base uses several pooled samples simultaneous accumulate throughout a person's life pairs of nucleotides: adenine, guanine, ly, greatly increasing sequencing speed. span. cytosine, and thymine. Mutation Any heritable change in DNA Alleles One of a group of genes that Gene The fundamental unit of heredi sequence. occur alternatively at a given locus. A ty. A gene is an ordered sequence of single allele is inherited separately from nucleotides located in a particular posi Nucleotide A subunit of DNA or RNA each parent (e.g., at a locus for eye tion on a particular chromosome that consisting of a nitrogenous base, a phos color, the allele might result in blue or encodes a specific functional product phate molecule, and a sugar molecule. brown eyes). (i.e., a protein or RNA molecule i. Thousands of nucleotides are linked to form a DNA or RNA molecule. Base pair Two nitrogenous bases (ade Gene expression The process by which nine and thymine or guanine and cyto- a gene's coded information is converted Oncogene One or more forms of a sine) held together by weak bonds. Two into the structures present and operat gene associated with cancer. strands of DNA are held together in the ing in the cell. shape of a double helix by the bonds Polygenic disorders Genetic disorders between base pairs. Gene mapping Determination of the resulting from the combined action of relative positions of genes on a DNA alleles of more than one gene (e.g., Carrier A person who has a recessive molecule and the distance between heart disease, diabetes, and some can mutated gene along with its normal them. -
Tracking the Evolution of Mammalian Wide Interspersed Repeats Across the Mammalian Tree of Life
Master's thesis Tracking the evolution of mammalian wide interspersed repeats across the mammalian tree of life. Author Jakob Friedrich Strauß First marker Prof. Dr. Joachim Kurtz Second marker Prof. Dr. Wojciech Maka lowski November 2, 2010 Tracking the evolution of mammalian wide interspersed repeats across the mammalian tree of life. Jakob Friedrich Strauß Institute of Bioinformatics WWU M¨unster Master's thesis November 2, 2010 Abstract This work focuses on the detection of mammalian wide interspersed repeats (MIRs) within the mammalian tree of life. MIRs are retroposons that belong to the class of SINEs (short interspersed repeats). The amplification of the ancient MIR is estimated 130 ma years ago, just before the mammalian radiation and has soon become inactive. The main idea of this project is to cross detect MIR elements in orthologous loci between fully sequenced mammalian genomes. While a MIR sequence in an extant species may still have a strong resemblance to the ancient MIR element, orthologous sequences in other mammalian species may have diverged beyond recognition, e.g. in mammals with a high substitution rate as rodents. But even those strongly diverged MIR elements may be detectable when the orthologous loci of a closely related species contains a less diverged element. We analyze in which gene-families MIR elements have spread and distinguish between MIR occurrence within UTRs, introns and exons. Thus we hope to illuminate the contri- bution of MIR elements to mammalian evolution. Contents 1 Background1 1.1 Transposable Elements.............................1 1.2 Genomic impact of transposable elements...................3 1.2.1 Long interspersed nuclear elements (LINEs).............4 1.2.2 Short interspersed nuclear elements (SINEs).............4 1.3 Mammalian wide interspersed repeats (MIRs)................5 1.3.1 MIR elements and the tree of life...................7 1.4 Detection of transposable elements.......................8 1.5 Goals of this study..............................