A Review on the Population Genomics of Transposable Elements
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CENTRE for POPULATION GENOMICS Strategic Plan 2021-2022 CENTRE for POPULATION GENOMICS Strategic Plan 2021-2022
CENTRE FOR POPULATION GENOMICS Strategic Plan 2021-2022 CENTRE FOR POPULATION GENOMICS Strategic Plan 2021-2022 • Plan-on-a-page page 3 • Vision page 4 • Purpose page 5 • Goals page 6 • Objectives page 7 • Goal 1 detail page 8 - 10 • Goal 2 detail page 11 - 13 • Goal 3 detail page 14 - 16 • Goal 4 detail page 17 - 19 • Principles page 20 • Operating model page 21 - 25 • Operational plan page 26 • Monitoring & evaluation plan page 27 – 28 • Team values page 29 CENTRE FOR POPULATION GENOMICS Strategic Plan-on-a-page 2021-2022 Vision: A world in which genomic information enables comprehensive disease prediction, accurate diagnosis and effective therapeutics for all people Purpose: To establish respectful partnerships with diverse communities, collect and analyse genomic data at transformative scale and drive genomic discovery and equitable genomic medicine in Australia Goals: Community Computational Genomic Scientific & medical partnerships infrastructure datasets knowledge Principles: Respect Diversity Openness Scalability Connectedness 3 CENTRE FOR POPULATION GENOMICS Strategic Plan 2021-2022 Vision: A world in which genomic information enables comprehensive disease prediction, accurate diagnosis and effective therapeutics for all people • The next decade will see a transformation of medicine and biology, driven in part by an explosion in our understanding of the connections between human genetic variation and individuals’ traits. This knowledge will allow the dissection of the biological basis of human traits, improve the prediction and diagnosis of disease, and accelerate the discovery and validation of new therapeutic targets. Key to these discoveries will be population genomics: the generation and analysis of massive-scale data sets of human genetic variation, combined with information on health and clinical outcomes. -
Copy Number of P Elements, KP/Full-Sized P Element Ratio and Their Relationships with Environmental Factors in Brazilian Drosophila Melanogaster Populations
Heredity (2003) 91, 570–576 & 2003 Nature Publishing Group All rights reserved 0018-067X/03 $25.00 www.nature.com/hdy Copy number of P elements, KP/full-sized P element ratio and their relationships with environmental factors in Brazilian Drosophila melanogaster populations MT Ruiz and CMA Carareto Departamento de Biologia, IBILCE, Universidade Estadual Paulista, Rua Cristo´va˜o Colombo, 2265, Jardim Nazare´,Sa˜o Jose´ do Rio Preto 15054-000, SP, Brazil The P transposable element copy numbers and the KP/full- and the strains from less extreme latitudes had many sized P element ratios were determined in eight Brazilian more full-sized P than KP elements. However, no clinal strains of Drosophila melanogaster. Strains from tropical variation was observed. Strains from different localities, regions showed lower overall P element copy numbers previously classified as having P cytotype, displayed a higher than did strains from temperate regions. Variable numbers of or a lower proportion of KP elements than of full-sized full-sized and defective elements were detected, but the P elements, as well as an equal number of the two element full-sized P and KP elements were the predominant classes types, showing that the same phenotype may be produced of elements in all strains. The full-sized P and KP element by different underlying genomic components of the P–M ratios were calculated and compared with latitude. The system. northernmost and southernmost Brazilian strains showed Heredity (2003) 91, 570–576, advance online publication, fewer full-sized elements than KP elements per genome, 17 September 2003; doi:10.1038/sj.hdy.6800360 Keywords: P transposable elements; KP elements; KP/full-sized P elements; P–M systems; Drosophila melanogaster Introduction elements, allows P element transposition (Engels, 1983). -
"Evolutionary Emergence of Genes Through Retrotransposition"
Evolutionary Emergence of Advanced article Genes Through Article Contents . Introduction Retrotransposition . Gene Alteration Following Retrotransposon Insertion . Retrotransposon Recruitment by Host Genome . Retrotransposon-mediated Gene Duplication Richard Cordaux, University of Poitiers, Poitiers, France . Conclusion Mark A Batzer, Department of Biological Sciences, Louisiana State University, Baton Rouge, doi: 10.1002/9780470015902.a0020783 Louisiana, USA Variation in the number of genes among species indicates that new genes are continuously generated over evolutionary times. Evidence is accumulating that transposable elements, including retrotransposons (which account for about 90% of all transposable elements inserted in primate genomes), are potent mediators of new gene origination. Retrotransposons have fostered genetic innovation during human and primate evolution through: (i) alteration of structure and/or expression of pre-existing genes following their insertion, (ii) recruitment (or domestication) of their coding sequence by the host genome and (iii) their ability to mediate gene duplication via ectopic recombination, sequence transduction and gene retrotransposition. Introduction genes, respectively, and de novo origination from previ- ously noncoding genomic sequence. Genome sequencing Variation in the number of genes among species indicates projects have also highlighted that new gene structures can that new genes are continuously generated over evolution- arise as a result of the activity of transposable elements ary times. Although the emergence of new genes and (TEs), which are mobile genetic units or ‘jumping genes’ functions is of central importance to the evolution of that have been bombarding the genomes of most species species, studies on the formation of genetic innovations during evolution. For example, there are over three million have only recently become possible. -
Interspecific DNA Transformation in Drosophila (Drosophila Melanogaster/Drosophila Simulans/Rosy Gene/P Element/Transposable Element) NANCY J
Proc. Nati. Acad. Sci. USA Vol. 81, pp. 7515-7519, December 1984 Genetics Interspecific DNA transformation in Drosophila (Drosophila melanogaster/Drosophila simulans/rosy gene/P element/transposable element) NANCY J. SCAVARDA AND DANIEL L. HARTL Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110 Communicated by Peter H. Raven, August 7, 1984 ABSTRACT A DNA fragment that includes the wild-type (4). Use of an average rate of synonymous substitutions in rosy (ry+) gene of Drosophila melanogaster has been intro- coding regions of 5.1 + 0.3 x 10-9 per nucleotide site per yr duced by microinjection into the germ line of the reproductive- (9, 10) results in an estimated time since separation of 4.1 + ly isolated species Drosophila simulans and incorporated into 0.2 million yr, but analogous estimates based on rates of nu- the D. simulans genome. Transformation was mediated by the cleotide substitution in intervening sequences range from 3.8 transposable element P, which occurs in the genome of most to 6.8 million yr. These estimates are uncertain because av- natural populations ofD. melanogaster but not in D. simulans. erage rates of substitution in other organisms may have little Rubin and Spradling [Rubin, G. M. & Spradling, A. C. relevance to insects, and because evolutionary change in the (1982) Science 218, 348-353] have previously shown that the gene coding for alcohol dehydrogenase may be atypical. ry' DNA fragment, which is flanked by recognition sequences Although D. melanogaster and D. simulans are reproduc- of P element, can transform the germ line ofD. -
Advances in Genomics for Drug Development
G C A T T A C G G C A T genes Review Advances in Genomics for Drug Development Roberto Spreafico , Leah B. Soriaga, Johannes Grosse, Herbert W. Virgin and Amalio Telenti * Vir Biotechnology, Inc., San Francisco, CA 94158, USA; Rspreafi[email protected] (R.S.); [email protected] (L.B.S.); [email protected] (J.G.); [email protected] (H.W.V.) * Correspondence: [email protected] Received: 24 July 2020; Accepted: 13 August 2020; Published: 15 August 2020 Abstract: Drug development (target identification, advancing drug leads to candidates for preclinical and clinical studies) can be facilitated by genetic and genomic knowledge. Here, we review the contribution of population genomics to target identification, the value of bulk and single cell gene expression analysis for understanding the biological relevance of a drug target, and genome-wide CRISPR editing for the prioritization of drug targets. In genomics, we discuss the different scope of genome-wide association studies using genotyping arrays, versus exome and whole genome sequencing. In transcriptomics, we discuss the information from drug perturbation and the selection of biomarkers. For CRISPR screens, we discuss target discovery, mechanism of action and the concept of gene to drug mapping. Harnessing genetic support increases the probability of drug developability and approval. Keywords: druggability; loss-of-function; CRISPR 1. Introduction For over 20 years, genomics has been used as a tool for accelerating drug development. Various conceptual approaches and techniques assist target identification, target prioritization and tractability, as well as the prediction of outcomes from pharmacological perturbations. These basic premises are now supported by a rapid expansion of population genomics initiatives (sequencing or genotyping of hundreds of thousands of individuals), in-depth understanding of disease and drug perturbation at the tissue and single-cell level as measured by transcriptome analysis, and by the capacity to screen for loss of function or activation of genes, genome-wide, using CRISPR technologies. -
Evolution of Pogo, a Separate Superfamily of IS630-Tc1-Mariner
Gao et al. Mobile DNA (2020) 11:25 https://doi.org/10.1186/s13100-020-00220-0 RESEARCH Open Access Evolution of pogo, a separate superfamily of IS630-Tc1-mariner transposons, revealing recurrent domestication events in vertebrates Bo Gao, Yali Wang, Mohamed Diaby, Wencheng Zong, Dan Shen, Saisai Wang, Cai Chen, Xiaoyan Wang and Chengyi Song* Abstracts Background: Tc1/mariner and Zator, as two superfamilies of IS630-Tc1-mariner (ITm) group, have been well-defined. However, the molecular evolution and domestication of pogo transposons, once designated as an important family of the Tc1/mariner superfamily, are still poorly understood. Results: Here, phylogenetic analysis show that pogo transposases, together with Tc1/mariner,DD34E/Gambol,and Zator transposases form four distinct monophyletic clades with high bootstrap supports (> = 74%), suggesting that they are separate superfamilies of ITm group. The pogo superfamily represents high diversity with six distinct families (Passer, Tigger, pogoR, Lemi, Mover,andFot/Fot-like) and wide distribution with an expansion spanning across all the kingdoms of eukaryotes. It shows widespread occurrences in animals and fungi, but restricted taxonomic distribution in land plants. It has invaded almost all lineages of animals—even mammals—and has been domesticated repeatedly in vertebrates, with 12 genes, including centromere-associated protein B (CENPB), CENPB DNA-binding domain containing 1 (CENPBD1), Jrk helix–turn–helix protein (JRK), JRK like (JRKL), pogo transposable element derived with KRAB domain (POGK), and with ZNF domain (POGZ), and Tigger transposable element-derived 2 to 7 (TIGD2–7), deduced as originating from this superfamily. Two of them (JRKL and TIGD2) seem to have been co-domesticated, and the others represent independent domestication events. -
Genome of Drosophila Guanche WOLFGANG J
Proc. Nati. Acad. Sci. USA Vol. 89, pp. 4018-4022, May 1992 Genetics P-element homologous sequences are tandemly repeated in the genome of Drosophila guanche WOLFGANG J. MILLER*, SYLVIA HAGEMANNt, ELEONORE REITERt, AND WILHELM PINSKERtt *Institut fur Botanik, Abteilung Cytologie und Genetik, Rennweg 14, A-1030 Vienna, Austria; and tInstitut fur Allgemeine Biologie, Abteilung Genetik, Wahringerstrasse 17, A-1090 Vienna, Austria Communicated by Bruce Wallace, December 23, 1991 ABSTRACT In Drosophila guanche, P-homologous se- In germ-line cells, the copy number of P elements is quences were found to be located in a tandem repetitive array genetically regulated by a complex mixture of chromosomal (copy number: 20-50) at a single genomic site. The cytological and cytoplasmic factors (11). At least two mechanisms can be position on the polytene chromosomes was determined by in situ distinguished: the maternally transmitted cytotype (12) and a hybridization (chromosome 0: 85C). Sequencing of one com- chromosomally inherited control system (13). In the P cyto- plete repeat unit (3.25 kilobases) revealed high sequence simi- type, the cytoplasmic state of P-strain individuals, transpo- larity between the central coding region comprising exons 0 to sition is repressed in somatic cells and in the germ line. In 2 and the corresponding section of the Drosophila melanogaster general the P cytotype develops gradually as a result of the P element. The rest of the sequence has diverged considerably. increasing number of P-element copies. M-strains, on the Exon 3 has no coding function and the inverted repeats have other hand, have genomes devoid of P elements. -
Retrotransposon Long Interspersed Nucleotide Element1 (LINE1) Is
The Japanese Society of Developmental Biologists Develop. Growth Differ. (2012) 54, 673–685 doi: 10.1111/j.1440-169X.2012.01368.x Original Article Retrotransposon long interspersed nucleotide element-1 (LINE-1) is activated during salamander limb regeneration Wei Zhu,1 Dwight Kuo,2 Jason Nathanson,3 Akira Satoh,4,5 Gerald M. Pao,1 Gene W. Yeo,3 Susan V. Bryant,5 S. Randal Voss,6 David M. Gardiner5*and Tony Hunter1* 1Molecular and Cell Biology Laboratory and Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California 92037, Departments of 2Bioengineering and 3Cellular and Molecular Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA; 4Okayama University, R.C.I.S. Okayama-city, Okayama, 700-8530, Japan; 5Department of Developmental and Cell Biology, University of California at Irvine, Irvine, California 92697, and 6Department of Biology and Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky 40506, USA Salamanders possess an extraordinary capacity for tissue and organ regeneration when compared to mam- mals. In our effort to characterize the unique transcriptional fingerprint emerging during the early phase of sala- mander limb regeneration, we identified transcriptional activation of some germline-specific genes within the Mexican axolotl (Ambystoma mexicanum) that is indicative of cellular reprogramming of differentiated cells into a germline-like state. In this work, we focus on one of these genes, the long interspersed nucleotide element-1 (LINE-1) retrotransposon, which is usually active in germ cells and silent in most of the somatic tissues in other organisms. LINE-1 was found to be dramatically upregulated during regeneration. -
History to the Rescue Pseudogenes Get Some Respect Flyin' Pain Free
RESEARCH NOTES Pseudogenes get some respect adenoviral entry is mediated by interaction between RGD motifs and integrins, they went on to engineer a virus with an RGD peptide. This Pseudogenes are the non-functional remnants of genes that have version of the modified virus specifically infected tumor cells and repli- been thought to do nothing more than take up space. A new cated more effectively than Delta-24. When injected directly into report by Shinji Hirotsune and colleagues provides evidence that human gliomas xenografted into mice, Delta-24-RGD allowed signifi- at least one such pseudogene has an essential role as a regulator of cantly longer survival than did Delta-24 or an inactivated virus control. gene expression (Nature 423, 91–96; 2003). A fortuitous insertion More impressively, 60% of mice treated with Delta-24-RGD were long- of a transgene into the Makorin1-p1 locus generated a mouse term survivors (compared with 15% of those treated with Delta-24 with a bone deformity and polycystic kidneys. Makorin1-p1 is a characterized by complete tumor regression). MH pseudogene that is normally transcribed, although no functional protein product can be produced. Strikingly, the transgene insertion reduced not only the transcription of Makorin1-p1, but RNAi on or off target? that of its functional homolog, Makorin1, as well. In vitro Two new reports examine the specificity of RNA interference (RNAi) in experiments show that an intact Makorin1-p1 locus stabilizes the human cells using genome-wide expression profiling. Targeting exoge- Makorin1 mRNA, and a rescue of the original transgenic mouse nous GFP in human embryonic kidney cells, Jen-Tsan Chi and col- with Makorin1-p1 proves that the pseudogene is required for leagues report efficient and specific knockdown using two different normal expression of Makorin1. -
Rapid Screening for CRISPR-Directed Editing of the Drosophila Genome Using White Co-Conversion
G3: Genes|Genomes|Genetics Early Online, published on August 26, 2016 as doi:10.1534/g3.116.032557 Rapid Screening for CRISPR-Directed Editing of the Drosophila Genome Using white Co-Conversion Daniel Tianfang Ge*,†,1, Cindy Tipping*,‡,1, Michael H. Brodsky§, Phillip D. Zamore*,‡,**,2 *RNA Therapeutics Institute, †Interdisciplinary Graduate Program, ‡Howard Hughes Medical Institute, §Department of Molecular, Cell and Cancer Biology, **Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA 1These authors contributed equally to this work. 2To whom correspondence should be addressed. 1 © The Author(s) 2013. Published by the Genetics Society of America. Running title: Rapid Screening for CRISPR Editing Keywords: Cas9; Co-Conversion; Genetic Screen; Microhomology-Mediated End Joining; Homologous Recombination Corresponding author: Phillip D. Zamore Address: 368 Plantation Street, AS4-2053, Worcester, MA 01605 Tel.: 508-856-2191 E-mail: [email protected] 2 1 ABSTRACT 2 Adoption of a streamlined version of the bacterial CRISPR/Cas9 defense system has 3 accelerated targeted genome engineering. The Streptococcus pyogenes Cas9 protein, 4 directed by a simplified, CRISPR-like single guide RNA, catalyzes a double-stranded 5 DNA break at a specific genomic site; subsequent repair by end joining can introduce 6 mutagenic insertions or deletions, while repair by homologous recombination using an 7 exogenous DNA template can incorporate new sequence at the target locus. However, 8 the efficiency of Cas9-directed mutagenesis is low in Drosophila melanogaster. Here, we 9 describe a strategy that reduces the time and effort required to identify flies with 10 targeted genomic changes. -
Controlled Insertional Mutagenesis Using a LINE-1 (Orfeus) Gene-Trap
Controlled insertional mutagenesis using a LINE-1 PNAS PLUS (ORFeus) gene-trap mouse model Kathryn A. O’Donnella,b,1,2, Wenfeng Ana,b,3, Christina T. Schruma,b, Sarah J. Wheelanc, and Jef D. Boekea,b,c,1 Departments of aMolecular Biology and Genetics and cOncology, and bHigh Throughput Biology Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 Edited* by Fred H. Gage, The Salk Institute for Biological Studies, San Diego, CA, and approved May 30, 2013 (received for review February 7, 2013) A codon-optimized mouse LINE-1 element, ORFeus, exhibits dra- treated with doxycycline. We observed high levels of retro- matically higher retrotransposition frequencies compared with transposition in tissues from double-transgenic mice but not its native long interspersed element 1 counterpart. To establish in control littermates, and the amount of retrotransposition a retrotransposon-mediated mouse model with regulatable and increases with increased doxycycline dose. Induction of the tet- potent mutagenic capabilities, we generated a tetracycline (tet)- ORFeus element with high doses of doxycycline during embryo- regulated ORFeus element harboring a gene-trap cassette. Here, genesis led to a reduced number of double-transgenic mice, we show that mice expressing tet-ORFeus broadly exhibit robust likely due to a significant burden of mutations and embryonic retrotransposition in somatic tissues when treated with doxycy- lethality in these animals. Unexpectedly, a significant percentage cline. Consistent with a significant mutagenic burden, we observed of double-transgenic agouti mice developed white spots, suggest- a reduced number of double transgenic animals when treated with ing that somatic mutations occurred at different times in de- high-level doxycycline during embryogenesis. -
Transposon Insertion Mutagenesis in Mice for Modeling Human Cancers: Critical Insights Gained and New Opportunities
International Journal of Molecular Sciences Review Transposon Insertion Mutagenesis in Mice for Modeling Human Cancers: Critical Insights Gained and New Opportunities Pauline J. Beckmann 1 and David A. Largaespada 1,2,3,4,* 1 Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA; [email protected] 2 Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA 3 Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA 4 Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA * Correspondence: [email protected]; Tel.: +1-612-626-4979; Fax: +1-612-624-3869 Received: 3 January 2020; Accepted: 3 February 2020; Published: 10 February 2020 Abstract: Transposon mutagenesis has been used to model many types of human cancer in mice, leading to the discovery of novel cancer genes and insights into the mechanism of tumorigenesis. For this review, we identified over twenty types of human cancer that have been modeled in the mouse using Sleeping Beauty and piggyBac transposon insertion mutagenesis. We examine several specific biological insights that have been gained and describe opportunities for continued research. Specifically, we review studies with a focus on understanding metastasis, therapy resistance, and tumor cell of origin. Additionally, we propose further uses of transposon-based models to identify rarely mutated driver genes across many cancers, understand additional mechanisms of drug resistance and metastasis, and define personalized therapies for cancer patients with obesity as a comorbidity. Keywords: animal modeling; cancer; transposon screen 1. Transposon Basics Until the mid of 1900’s, DNA was widely considered to be a highly stable, orderly macromolecule neatly organized into chromosomes.