The Origin, Evolution, and Functional Impact of Short Insertion–Deletion Variants Identified in 179 Human Genomes
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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. -
Frameshift Indels Generate Highly Immunogenic Tumor Neoantigens Tumor-Specifi C Neoantigens Are the Targets of T Cells in the Neoantigens
Published OnlineFirst July 21, 2017; DOI: 10.1158/2159-8290.CD-RW2017-135 RESEARCH WATCH Apoptosis Major finding: An NMR-based fragment Mechanism: BIF-44 binds to a deep hy- Impact: Allosteric BAX sensitization screen identified a BAX-interacting com- drophobic pocket to induce conformation may represent a therapeutic strategy pound, BIF-44, that enhances BAX activity . changes that sensitize BAX activation . to promote apoptosis of cancer cells . BAX CAN BE ALLOSTERICALLY SENSITIZED TO PROMOTE APOPTOSIS The proapoptotic BAX protein is comprised of BH3 motif of the BIM protein. BIF-44 bound nine α-helices (α1–α9) and is a critical regulator competitively to the same region as vMIA, in a of the mitochondrial apoptosis pathway. In the deep hydrophobic pocket formed by the junction conformationally inactive state, BAX is primar- of the α3–α4 and α5–α6 hairpins that normally ily cytosolic and can be activated by BH3-only maintain BAX in an inactive state. Binding of BIF- activator proteins, which bind to ab α6/α6 “trig- 44 induced a structural change that resulted in ger site” to induce a conformational change that allosteric mobilization of the α1–α2 loop, which activates BAX and promotes its oligomerization. is involved in BH3-mediated activation, and the Conversely, antiapoptotic BCL2 proteins or the cytomeg- BAX BH3 helix, which is involved in propagating BAX oli- alovirus vMIA protein can bind to and inhibit BAX. Efforts gomerization, resulting in sensitization of BAX activation. In to therapeutically enhance apoptosis have largely focused addition to identifying a BAX allosteric sensitization site and on inhibiting antiapoptotic proteins. -
DNA Sequence Insertion and Evolutionary Variation in Gene Regulation (Mobile Elements/Long Terminal Repeats/Alu Sequences/Factor-Binding Sites) Roy J
Proc. Natl. Acad. Sci. USA Vol. 93, pp. 9374-9377, September 1996 Colloquium Paper This paper was presented at a colloquium entitled "Biology of Developmental Transcription Control, " organized by Eric H. Davidson, Roy J. Britten, and Gary Felsenfeld, held October 26-28, 1995, at the National Academy of Sciences in Irvine, CA. DNA sequence insertion and evolutionary variation in gene regulation (mobile elements/long terminal repeats/Alu sequences/factor-binding sites) RoY J. BRITrEN Division of Biology, California Institute of Technology, 101 Dahlia Avenue, Corona del Mar, CA 92625 ABSTRACT Current evidence on the long-term evolution- 3 and 4). Sequence change, obscuring the original structure, ary effect of insertion of sequence elements into gene regions has occurred in the long history, and the underlying rate of is reviewed, restricted to cases where a sequence derived from base substitution that is responsible is known (5). a past insertion participates in the regulation of expression of The requirements for a convincing example are: (i) that a useful gene. Ten such examples in eukaryotes demonstrate there be a trace of a known class of elements present in gene that segments of repetitive DNA or mobile elements have been region; (ii) that there is evidence that it has been there long inserted in the past in gene regions, have been preserved, enough to not just be a transient mutation; (iii) that some sometimes modified by selection, and now affect control of sequence residue of the mobile element or repeat participates transcription ofthe adjacent gene. Included are only examples in regulation of expression of the gene; (iv) that the gene have in which transcription control was modified by the insert. -
Small Variants Frequently Asked Questions (FAQ) Updated September 2011
Small Variants Frequently Asked Questions (FAQ) Updated September 2011 Summary Information for each Genome .......................................................................................................... 3 How does Complete Genomics map reads and call variations? ........................................................................... 3 How do I assess the quality of a genome produced by Complete Genomics?................................................ 4 What is the difference between “Gross mapping yield” and “Both arms mapped yield” in the summary file? ............................................................................................................................................................................. 5 What are the definitions for Fully Called, Partially Called, Half-Called and No-Called?............................ 5 In the summary-[ASM-ID].tsv file, how is the number of homozygous SNPs calculated? ......................... 5 In the summary-[ASM-ID].tsv file, how is the number of heterozygous SNPs calculated? ....................... 5 In the summary-[ASM-ID].tsv file, how is the total number of SNPs calculated? .......................................... 5 In the summary-[ASM-ID].tsv file, what regions of the genome are included in the “exome”? .............. 6 In the summary-[ASM-ID].tsv file, how is the number of SNPs in the exome calculated? ......................... 6 In the summary-[ASM-ID].tsv file, how are variations in potentially redundant regions of the genome counted? ..................................................................................................................................................................... -
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. -
Mutational Landscape of Spontaneous Base Substitutions and Small Indels in Experimental Caenorhabditis Elegans Populations of Differing Size
| INVESTIGATION Mutational Landscape of Spontaneous Base Substitutions and Small Indels in Experimental Caenorhabditis elegans Populations of Differing Size Anke Konrad, Meghan J. Brady, Ulfar Bergthorsson, and Vaishali Katju1 Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77845 ORCID IDs: 0000-0003-3994-460X (A.K.); 0000-0003-1419-1349 (U.B.); 0000-0003-4720-9007 (V.K.) ABSTRACT Experimental investigations into the rates and fitness effects of spontaneous mutations are fundamental to our understanding of the evolutionary process. To gain insights into the molecular and fitness consequences of spontaneous mutations, we conducted a mutation accumulation (MA) experiment at varying population sizes in the nematode Caenorhabditis elegans, evolving 35 lines in parallel for 409 generations at three population sizes (N = 1, 10, and 100 individuals). Here, we focus on nuclear SNPs and small insertion/deletions (indels) under minimal influence of selection, as well as their accrual rates in larger populations under greater selection efficacy. The spontaneous rates of base substitutions and small indels are 1.84 (95% C.I. 6 0.14) 3 1029 substitutions and 6.84 (95% C.I. 6 0.97) 3 10210 changes/site/generation, respectively. Small indels exhibit a deletion bias with deletions exceeding insertions by threefold. Notably, there was no correlation between the frequency of base substitutions, nonsynonymous substitutions, or small indels with population size. These results contrast with our previous analysis of mitochondrial DNA mutations and nuclear copy-number changes in these MA lines, and suggest that nuclear base substitutions and small indels are under less stringent purifying selection compared to the former mutational classes. -
Indelible Markers the Recruitment of Modified Histones by the RITS Complex
RESEARCH HIGHLIGHTS IN BRIEF EPIGENETICS Argonaute slicing is required for heterochromatic silencing and spreading. HUMAN GENETICS Irvine, D. V. et al. Science 313, 1134–1137 (2006) It has been proposed that small interfering RNA (siRNA)- guided histone H3 dimethylation on lysine 9 (H3K9me2) might be caused by an interaction of siRNA with DNA and INDELible markers the recruitment of modified histones by the RITS complex. Alternatively, siRNAs might guide histone modification by Over 10 million unique SNPs, some comprised about 30% of the base-pairing with RNA. Working in fission yeast, Irvine et al. of which influence human traits and total. Another ~30% consisted of provide support for the second mechanism. They show that disease susceptibilities, have been expansions of either monomeric the endonucleolytic cleavage motif of Argonaute is required identified in the human genome. base-pair repeats or multi-base for heterochromatic silencing and for ‘slicing’ mRNAs that are Now, another type of natural genetic repeats. Approximately 40% of indels complementary to siRNAs. They also show that spreading of variation, which involves insertion included insertions of apparently ran- silencing requires read-through transcription, as well as slicing. and deletion polymorphisms (indels), dom DNA sequences. Transposons has been systematically studied and accounted for only a small proportion TECHNOLOGY mapped for the first time. (less than 1%) of the polymorphisms Trans-kingdom transposition of the maize Dissociation Understanding more about indels that were identified. element. is important because they are known Indels were spread throughout Emelyanov, A. et al. Genetics 1 September 2006 (doi:10.1534/ to contribute to human disease. -
Pervasive Indels and Their Evolutionary Dynamics After The
MBE Advance Access published April 24, 2012 Pervasive Indels and Their Evolutionary Dynamics after the Fish-Specific Genome Duplication Baocheng Guo,1,2 Ming Zou,3 and Andreas Wagner*,1,2 1Institute of Evolutionary Biology and Environmental Studies, University of Zurich, Zurich, Switzerland 2The Swiss Institute of Bioinformatics, Quartier Sorge-Batiment Genopode, Lausanne, Switzerland 3Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, People’s Republic of China *Corresponding author: E-mail: [email protected]. Associate editor: Herve´ Philippe Abstract Research article Insertions and deletions (indels) in protein-coding genes are important sources of genetic variation. Their role in creating new proteins may be especially important after gene duplication. However, little is known about how indels affect the divergence of duplicate genes. We here study thousands of duplicate genes in five fish (teleost) species with completely sequenced genomes. The ancestor of these species has been subject to a fish-specific genome duplication (FSGD) event Downloaded from that occurred approximately 350 Ma. We find that duplicate genes contain at least 25% more indels than single-copy genes. These indels accumulated preferentially in the first 40 my after the FSGD. A lack of widespread asymmetric indel accumulation indicates that both members of a duplicate gene pair typically experience relaxed selection. Strikingly, we observe a 30–80% excess of deletions over insertions that is consistent for indels of various lengths and across the five genomes. We also find that indels preferentially accumulate inside loop regions of protein secondary structure and in http://mbe.oxfordjournals.org/ regions where amino acids are exposed to solvent. -
The Genomics Era: the Future of Genetics in Medicine - Glossary
The Genomics Era: the Future of Genetics in Medicine - Glossary The glossary below provides a list of key terms used throughout the course. You do not need to read them all now; we’ll be linking back to the main glossary step wherever these terms appear, so you may refer back to this list if you are unsure of the terminology being used. Term Definition The process of matching reads back to their original Alignment position in the reference genome. An allele is one of a number of alternative forms of the same gene or genetic locus. We inherit one copy Allele of our genetic code from our mother and one copy of our genetic code from our father. Each copy is known as an allele. Microarray based genomic comparative hybridisation. This is a technique used to detect chromosome imbalances by comparing patient and control DNA and comparing differences between the two sets. It is Array CGH a useful technique for detecting small chromosome deletions and duplications which would not have been detected with more traditional karyotyping techniques. A unit of DNA. There are four bases which form the Base cross links (or rungs) of the DNA double helix: adenine (A), thymine (T), guanine (G) and cytosine (C). Capture see Target enrichment. The process by which a cell becomes specialized in Cell differentiation order to perform a specific function. Centromere The point at which the sister chromatids are joined. #1 FutureLearn A structure located in the nucleus all living cells, comprised of DNA bound around proteins called histones. The normal number of chromosomes in each Chromosome human cell nucleus is 46 and is composed of 22 pairs of autosomes and a pair of sex chromosomes which determine gender: males have an X and a Y chromosome whilst females have two X chromosomes. -
Integrated Analysis of Gene Expression, SNP, Indel, and CNV
G C A T T A C G G C A T genes Article Integrated Analysis of Gene Expression, SNP, InDel, and CNV Identifies Candidate Avirulence Genes in Australian Isolates of the Wheat Leaf Rust Pathogen Puccinia triticina Long Song , Jing Qin Wu, Chong Mei Dong and Robert F. Park * Plant Breeding Institute, School of Life and Environmental Science, Faculty of Science, The University of Sydney, Sydney 2006, NSW, Australia; [email protected] (L.S.); [email protected] (J.Q.W.); [email protected] (C.M.D.) * Correspondence: [email protected]; Tel.: +61-2-9351-8806; Fax: +61-2-9351-8875 Received: 3 September 2020; Accepted: 18 September 2020; Published: 21 September 2020 Abstract: The leaf rust pathogen, Puccinia triticina (Pt), threatens global wheat production. The deployment of leaf rust (Lr) resistance (R) genes in wheat varieties is often followed by the development of matching virulence in Pt due to presumed changes in avirulence (Avr) genes in Pt. Identifying such Avr genes is a crucial step to understand the mechanisms of wheat-rust interactions. This study is the first to develop and apply an integrated framework of gene expression, single nucleotide polymorphism (SNP), insertion/deletion (InDel), and copy number variation (CNV) analysis in a rust fungus and identify candidate avirulence genes. Using a long-read based de novo genome assembly of an isolate of Pt (‘Pt104’) as the reference, whole-genome resequencing data of 12 Pt pathotypes derived from three lineages Pt104, Pt53, and Pt76 were analyzed. Candidate avirulence genes were identified by correlating virulence profiles with small variants (SNP and InDel) and CNV, and RNA-seq data of an additional three Pt isolates to validate expression of genes encoding secreted proteins (SPs). -
Comprehensive Analysis of Indels in Whole-Genome Microsatellite Regions and Microsatellite Instability Across 21 Cancer Types
Downloaded from genome.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Research Comprehensive analysis of indels in whole-genome microsatellite regions and microsatellite instability across 21 cancer types Akihiro Fujimoto,1,2,3 Masashi Fujita,1 Takanori Hasegawa,4 Jing Hao Wong,2,3 Kazuhiro Maejima,1 Aya Oku-Sasaki,1 Kaoru Nakano,1 Yuichi Shiraishi,5,6 Satoru Miyano,4,6 Go Yamamoto,7 Kiwamu Akagi,7 Seiya Imoto,4 and Hidewaki Nakagawa1 1Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Tokyo 230-0045, Japan; 2Department of Human Genetics, The University of Tokyo, Graduate School of Medicine, Tokyo 113-0033, Japan; 3Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; 4Health Intelligence Center, Institute of Medical Sciences, The University of Tokyo, Tokyo 108-8639, Japan; 5Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo 104-0045, Japan; 6Human Genome Center, Institute of Medical Sciences, The University of Tokyo, Tokyo 108-8639, Japan; 7Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama 362-0806, Japan Microsatellites are repeats of 1- to 6-bp units, and approximately 10 million microsatellites have been identified across the human genome. Microsatellites are vulnerable to DNA mismatch errors and have thus been used to detect cancers with mismatch repair deficiency. To reveal the mutational landscape of microsatellite repeat regions at the genome level, we an- alyzed approximately 20.1 billion microsatellites in 2717 whole genomes of pan-cancer samples across 21 tissue types. First, we developed a new insertion and deletion caller (MIMcall) that takes into consideration the error patterns of different types of microsatellites.