Instability of the Pseudoautosomal Boundary in House Mice
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Causal Varian Discovery in Familial Congenital Heart Disease - an Integrative -Omic Approach Wendy Demos Marquette University
Marquette University e-Publications@Marquette Master's Theses (2009 -) Dissertations, Theses, and Professional Projects Causal Varian discovery in Familial Congenital Heart Disease - An Integrative -Omic Approach Wendy Demos Marquette University Recommended Citation Demos, Wendy, "Causal Varian discovery in Familial Congenital Heart Disease - An Integrative -Omic Approach" (2012). Master's Theses (2009 -). 140. https://epublications.marquette.edu/theses_open/140 CAUSAL VARIANT DISCOVERY IN FAMILIAL CONGENITAL HEART DISEASE – AN INTEGRATIVE –OMIC APPROACH by Wendy M. Demos A Thesis submitted to the Faculty of the Graduate School, Marquette University, in Partial Fulfillment of the Requirements for the Degree of Master of Science Milwaukee, Wisconsin May 2012 ABSTRACT CAUSAL VARIANT DISCOVERY IN FAMILIAL CONGENITAL HEART DISEASE – AN INTEGRATIVE –OMIC APPROACH Wendy M. Demos Marquette University, 2012 Background : Hypoplastic left heart syndrome (HLHS) is a congenital heart defect that leads to neonatal death or compromised quality of life for those affected and their families. This syndrome requires extensive medical intervention for the affected to survive. It is characterized by significant underdevelopment or non-existence of the components of the left heart and the aorta, including the left ventricular cavity and mass. There are many factors ranging from genetics to environmental relationships hypothesized to lead to the development of the syndrome, including recent studies suggesting a link between hearing impairment and congenital heart defects (CHD). Although broadly characterized those factors remain poorly understood. The goal of this project is to systematically utilize bioinformatics tools to determine the relationships of novel mutations found in exome sequencing to a familial congenital heart defect. Methods A systematic genomic and proteomic approach involving exome sequencing, pathway analysis, and protein modeling was implemented to examine exome sequencing data of a patient with HLHS. -
Analysis of HIV-1 Intersubtype Recombination Breakpoints
Jia et al. Virology Journal (2016) 13:156 DOI 10.1186/s12985-016-0616-1 RESEARCH Open Access Analysis of HIV-1 intersubtype recombination breakpoints suggests region with high pairing probability may be a more fundamental factor than sequence similarity affecting HIV-1 recombination Lei Jia, Lin Li, Tao Gui, Siyang Liu, Hanping Li, Jingwan Han, Wei Guo, Yongjian Liu* and Jingyun Li* Abstract Background: With increasing data on HIV-1, a more relevant molecular model describing mechanism details of HIV-1 genetic recombination usually requires upgrades. Currently an incomplete structural understanding of the copy choice mechanism along with several other issues in the field that lack elucidation led us to perform an analysis of the correlation between breakpoint distributions and (1) the probability of base pairing, and (2) intersubtype genetic similarity to further explore structural mechanisms. Methods: Near full length sequences of URFs from Asia, Europe, and Africa (one sequence/patient), and representative sequences of worldwide CRFs were retrieved from the Los Alamos HIV database. Their recombination patterns were analyzed by jpHMM in detail. Then the relationships between breakpoint distributions and (1) the probability of base pairing, and (2) intersubtype genetic similarities were investigated. Results: Pearson correlation test showed that all URF groups and the CRF group exhibit the same breakpoint distribution pattern. Additionally, the Wilcoxon two-sample test indicated a significant and inexplicable limitation of recombination in regions with high pairing probability. These regions have been found to be strongly conserved across distinct biological states (i.e., strong intersubtype similarity), and genetic similarity has been determined to be a very important factor promoting recombination. -
Approaches to Maximize Sgrna-Barcode Coupling in Perturb-Seq Screens
bioRxiv preprint doi: https://doi.org/10.1101/298349; this version posted April 11, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Approaches to maximize sgRNA-barcode coupling in Perturb-seq screens Britt Adamson1-4, Thomas M. Norman1-4, Marco Jost1-5, Jonathan S. Weissman1-4, † 1 Department of Cellular & Molecular Pharmacology, 2 Howard Hughes Medical Institute, 3 California Institute for Quantitative Biomedical Research, 4 Center for RNA Systems Biology, 5 Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA † Lead contact; Correspondence should be addressed to [email protected] ABSTRACT Perturb-seq is a platform for single-cell gene expression profiling of pooled CRISPR screens. Like many functional genomics platforms, Perturb-seq relies on lentiviral transduction to introduce perturbation libraries to cells. On this platform, these are barcoded sgRNA libraries. A critical consideration for performing Perturb-seq experiments is uncoupling of barcodes from linked sgRNA expression cassettes, which can occur during lentiviral transduction of co-packaged libraries due to reverse transcriptase-mediated template switching. This problem is common to lentiviral libraries designed with linked variable regions. Here, we demonstrate that recombination between Perturb-seq vectors scrambles linked variable regions separated by 2 kb. This predicts information loss in Perturb-seq screens performed with co-packaged libraries. We also demonstrate ways to address this problem and discuss best practices for single-cell screens with transcriptional readouts. -
X-Linked Microtubule-Associated Protein, Mid1, Regulates Axon Development
X-linked microtubule-associated protein, Mid1, regulates axon development Tingjia Lua,b,1, Renchao Chena,b,1,2, Timothy C. Coxc,d, Randal X. Moldriche, Nyoman Kurniawanf, Guohe Tana, Jo K. Perryg, Alan Ashworthg, Perry F. Bartlette,LiXua, Jing Zhanga, Bin Lua, Mingyue Wua,b, Qi Shena, Yuanyuan Liua,b, Linda J. Richardse,h, and Zhiqi Xionga,2 aInstitute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; bUniversity of Chinese Academy of Sciences, Shanghai 200031, China; cDepartment of Pediatrics, University of Washington, Seattle, WA 98105; dDepartment of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia; eQueensland Brain Institute, fCentre for Advanced Imaging, and hSchool of Biomedical Sciences, University of Queensland, Brisbane, QLD 4072, Australia; and gBreakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW7 3RP, United Kingdom Edited by Yuh Nung Jan, Howard Hughes Medical Institute, University of California, San Francisco, CA, and approved October 8, 2013 (received for review March 25, 2013) Opitz syndrome (OS) is a genetic neurological disorder. The gene axonal growth and branch formation whereas down-regulation of responsible for the X-linked form of OS, Midline-1 (MID1), encodes Mid1 in the developing cortex accelerated callosal axon growth an E3 ubiquitin ligase that regulates the degradation of the cata- and altered the projection pattern of callosal axons. In addition, lytic subunit of protein phosphatase 2A (PP2Ac). However, how a similar defect of axon development was observed in Mid1 Mid1 functions during neural development is largely unknown. knockout (KO) mice. -
Rnai and Heterochromatin Repress Centromeric Meiotic Recombination
RNAi and heterochromatin repress centromeric meiotic recombination Chad Ellermeiera,1, Emily C. Higuchia, Naina Phadnisa, Laerke Holma,b, Jennifer L. Geelhooda, Genevieve Thonb, and Gerald R. Smitha,2 aDivision of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; and bDepartment of Molecular Biology, University of Copenhagen Biocenter, DK-2200 Copenhagen, Denmark Edited* by Paul Nurse, The Rockefeller University, New York, NY, and approved April 2, 2010 (received for review December 9, 2009) During meiosis, the formation of viable haploid gametes from diploid correlated with birth defects resulting from chromosome mis- precursors requires that each homologous chromosome pair be segregation (2). (Here and subsequently, “centromeric” is meant to properly segregated toproduce anexact haploid set ofchromosomes. include “pericentromeric.”) Thus, repression of recombination spe- Genetic recombination, which provides a physical connection be- cifically in the centromere is crucial for the proper segregation of tween homologous chromosomes, is essential in most species for meiotic chromosomes, but the mechanism by which centromeric proper homologue segregation. Nevertheless, recombination is re- recombination is repressed during meiosis has been largely unknown. pressed specifically in and around the centromeres of chromosomes, Centromeric heterochromatin in many species represses apparently because rare centromeric (or pericentromeric) recombina- within its domain the abundance of transcripts and the expres- tion events, when they do occur, can disrupt proper segregation and sion of genes inserted into the heterochromatic region (4). In the lead to genetic disabilities, including birth defects. The basis by which fission yeast Schizosaccharomyces pombe, the formation of cen- centromeric meiotic recombination is repressed has been largely tromeric heterochromatin is facilitated by RNAi functions, which unknown. -
Evidence of Functional Redundancy Between MID Proteins: Implications for the Presentation of Opitz Syndrome
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Developmental Biology 277 (2005) 417–424 www.elsevier.com/locate/ydbio Evidence of functional redundancy between MID proteins: implications for the presentation of Opitz syndrome Alessandra Granata, Dawn Savery, Jamile Hazan, Billy M.F. Cheung, Andrew Lumsden, Nandita A. Quaderi* MRC Centre for Developmental Neurobiology, King’s College London, Guy’s Hospital Campus, London, SE1 1UL, UK Received for publication 30 April 2004, revised 17 July 2004, accepted 8 September 2004 Available online 27 October 2004 Abstract Opitz G/BBB syndrome (OS) is a congenital defect characterized by hypertelorism and hypospadias, but additional midline malformations are also common in OS patients. X-linked OS is caused by mutations in the ubiquitin ligase MID1. In chick, MID1 is involved in left–right determination: a mutually repressive relationship between Shh and cMid1 in Hensen’s node plays a key role in establishing the avian left–right axis. We have utilized our existing knowledge of the molecular basis of avian L/R determination to investigate the possible existence of functional redundancy between MID1 and its close homologue MID2. The expression of cMid2 overlaps with that of cMid1 in the node, and we demonstrate that MID2 can both mimic MID1 function as a right side determinant and rescue the laterality defects caused by knocking down endogenous MID proteins in the node. Our results show that MID2 is able to compensate for an absence in MID1 during chick left–right determination and may explain why OS patients do not suffer laterality defects despite the association between midline and L/R development. -
The E3-Ubiquitin Ligase MID1 Catalyzes Ubiquitination and Cleavage of Fu
Repository of the Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Association http://edoc.mdc-berlin.de/14376 The E3-ubiquitin ligase MID1 catalyzes ubiquitination and cleavage of Fu Schweiger, S. and Dorn, S. and Fuchs, M. and Koehler, A. and Matthes, F. and Mueller, E.C. and Wanker, E. and Schneider, R. and Krauss, S. This is a copy of the original article. This research was originally published in Journal of Biological Chemistry. Schweiger, S. and Dorn, S. and Fuchs, M. and Koehler, A. and Matthes, F. and Mueller, E.C. and Wanker, E. and Schneider, R. and Krauss, S. The E3-ubiquitin ligase MID1 catalyzes ubiquitination and cleavage of Fu. J Biol Chem. 2014; 289: 31805-31817. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Journal of Biological Chemistry 2014 NOV 14 ; 289(46): 31805-31817 Doi: 10.1074/jbc.M113.541219 American Society for Biochemistry and Molecular Biology Cell Biology: The E3 Ubiquitin Ligase MID1 Catalyzes Ubiquitination and Cleavage of Fu Susann Schweiger, Stephanie Dorn, Melanie Fuchs, Andrea Köhler, Frank Matthes, Eva-Christina Müller, Erich Wanker, Rainer Downloaded from Schneider and Sybille Krauß J. Biol. Chem. 2014, 289:31805-31817. doi: 10.1074/jbc.M113.541219 originally published online October 2, 2014 http://www.jbc.org/ Access the most updated version of this article at doi: 10.1074/jbc.M113.541219 Find articles, minireviews, Reflections and Classics on similar topics on the JBC Affinity Sites. at MAX DELBRUECK CENTRUM FUE on November 17, 2014 Alerts: • When this article is cited • When a correction for this article is posted Click here to choose from all of JBC's e-mail alerts This article cites 40 references, 10 of which can be accessed free at http://www.jbc.org/content/289/46/31805.full.html#ref-list-1 THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. -
Sonic Hedgehog Repression Underlies Gigaxonin Mutation– Induced Motor Deficits in Giant Axonal Neuropathy
Sonic Hedgehog repression underlies gigaxonin mutation– induced motor deficits in giant axonal neuropathy Yoan Arribat, … , Mireille Rossel, Pascale Bomont J Clin Invest. 2019;129(12):5312-5326. https://doi.org/10.1172/JCI129788. Research Article Neuroscience Graphical abstract Find the latest version: https://jci.me/129788/pdf RESEARCH ARTICLE The Journal of Clinical Investigation Sonic Hedgehog repression underlies gigaxonin mutation–induced motor deficits in giant axonal neuropathy Yoan Arribat,1 Karolina S. Mysiak,1 Léa Lescouzères,1 Alexia Boizot,1 Maxime Ruiz,1 Mireille Rossel,2 and Pascale Bomont1 1ATIP-Avenir team, INM, INSERM, University of Montpellier, Montpellier, France. 2MMDN, University of Montpellier, EPHE, INSERM, U1198, PSL Research University, Montpellier, France. Growing evidence shows that alterations occurring at early developmental stages contribute to symptoms manifested in adulthood in the setting of neurodegenerative diseases. Here, we studied the molecular mechanisms causing giant axonal neuropathy (GAN), a severe neurodegenerative disease due to loss-of-function of the gigaxonin–E3 ligase. We showed that gigaxonin governs Sonic Hedgehog (Shh) induction, the developmental pathway patterning the dorso-ventral axis of the neural tube and muscles, by controlling the degradation of the Shh-bound Patched receptor. Similar to Shh inhibition, repression of gigaxonin in zebrafish impaired motor neuron specification and somitogenesis and abolished neuromuscular junction formation and locomotion. Shh signaling was impaired in gigaxonin-null zebrafish and was corrected by both pharmacological activation of the Shh pathway and human gigaxonin, pointing to an evolutionary-conserved mechanism regulating Shh signaling. Gigaxonin-dependent inhibition of Shh activation was also demonstrated in primary fibroblasts from patients with GAN and in a Shh activity reporter line depleted in gigaxonin. -
The Discovery of HTLV-1, the First Pathogenic Human Retrovirus John M
PERSPECTIVE PERSPECTIVE The discovery of HTLV-1, the first pathogenic human retrovirus John M. Coffin1 Tufts University School of Medicine, Boston MA 02111 Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA, and approved November 11, 2015 (received for review November 2, 2015) After the discovery of retroviral reverse transcriptase in 1970, there was a flurry of activity, sparked by the “War on Cancer,” to identify human cancer retroviruses. After many false claims resulting from various artifacts, most scientists abandoned the search, but the Gallo laboratory carried on, developing both specific assays and new cell culture methods that enabled them to report, in the accompanying 1980 PNAS paper, identification and partial characterization of human T-cell leukemia virus (HTLV; now known as HTLV-1) produced by a T-cell line from a lymphoma patient. Follow-up studies, including collaboration with the group that first identified a cluster of adult T-cell leukemia (ATL) cases in Japan, provided conclusive evidence that HTLV was the cause of this disease. HTLV-1 is now known to infect at least 4–10 million people worldwide, about 5% of whom will develop ATL. Despite intensive research, knowledge of the viral etiology has not led to improvement in treatment or outcome of ATL. However, the technology for discovery of HTLV and acknowledgment of the existence of pathogenic human retroviruses laid the technical and intellectual foundation for the discovery of the cause of AIDS soon afterward. Without this advance, our ability to diagnose and treat HIV infection most likely would have been long delayed. -
Embryonic Expression of the Human MID1 Gene and Its Mutations In
381 LETTER TO JMG J Med Genet: first published as 10.1136/jmg.2003.014829 on 30 April 2004. Downloaded from Embryonic expression of the human MID1 gene and its mutations in Opitz syndrome L Pinson, J Auge´, S Audollent, G Matte´i, H Etchevers, N Gigarel, F Razavi, D Lacombe, S Odent, M Le Merrer, J Amiel, A Munnich, G Meroni, S Lyonnet, M Vekemans, T Attie´-Bitach ............................................................................................................................... J Med Genet 2004;41:381–386. doi: 10.1136/jmg.2003.014829 pitz syndrome (G/BBB syndrome, MIM145410 and Key points MIM300000) is a midline congenital malformation Ocharacterised by hypertelorism, hypospadias and oesophagolaryngotracheal defects leading to swallowing N Opitz syndrome (G/BBB syndrome, MIM145410, and difficulties and a hoarse cry.1 Additional defects include cleft MIM300000) is a midline congenital malformation lip with or without cleft palate, imperforate anus, anomalies characterised by hypertelorism, hypospadias and of the central nervous system (including corpus callosum oesophagolaryngotracheal defects leading to swallow- agenesis or vermis agenesis and hypoplasia),2 congenital ing difficulties and hoarse voice. This condition is heart defects (atrial and ventricular septal defects, patent genetically heterogeneous with an X-linked recessive ductus arteriosus and coarctation of the aorta),3 and form mapped to Xp22.3 and at least one autosomal developmental delay in two thirds of patients. This condition dominant form mapped to chromosome 22q11.2. is genetically heterogeneous with an X-linked recessive form Recently, mutations in MID1 have been identified mapped to Xp22.3 and at least one autosomal dominant form in the X-linked form of the disease but the gene for 4 mapped to chromosome 22q11.2. -
Rajarapu G .Genes and Genome of HIV-1. J Phylogen Evolution Biol
etics & E en vo g lu t lo i y o h n a P r f y Journal of Phylogenetics & Rajarapu, J Phylogen Evolution Biol 2014, 2:1 o B l i a o n l r o DOI: 10.4172/2329-9002.1000126 u g o y J Evolutionary Biology ISSN: 2329-9002 Review Article Open Access Genes and Genome of HIV-1 Rajarapu G* School of life sciences, University of Wolverhampton, United Kingdom Abstract There are currently various different tests for HIV infections such as HIV antibody test, P24 antigen test, Polymerase chain reaction test (PCR), Fourth generation test and Home test. Even though there is no particular treatment or therapy for HIV, very effective treatment called antiviral therapy, combination therapy, or HAART (highly active antiretroviral therapy) can retain the virus under control and permit someone with HIV to have an active, health life. Some people have acquired the side effects from their medications, such as nausea, diarrhoea, prolonged headaches, depression and mental health problems. Emergency anti-HIV medication (PEP) may stop people becoming infected, but treatment must be started within three days of coming into contact with the virus. HIV symptoms have not appeared in many of the people. Blood test is the only way to find HIV infection. We can reduce the HIV infection by using a condom during sex and reducing the number of partners. HIV regulatory, accessory proteins and envelope proteins are play a major role in vaccine development. Anti-HIV vaccines have required generating neutralizing antibodies (NAbs) and effective T-cell responses. -
Developmental Timing of Mutations Revealed by Whole-Genome Sequencing of Twins with Acute Lymphoblastic Leukemia
Developmental timing of mutations revealed by whole-genome sequencing of twins with acute lymphoblastic leukemia Yussanne Maa,1, Sara E. Dobbinsa,1, Amy L. Sherbornea,1, Daniel Chubba, Marta Galbiatib, Giovanni Cazzanigab, Concetta Micalizzic, Rick Tearled, Amy L. Lloyda, Richard Haine, Mel Greavesf,2,3, and Richard S. Houlstona,2,3 aMolecular and Population Genetics, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom; bCentro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo, 20900 Monza (Mi), Italy; cExperimental Clinical Hematology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) G. Gaslini, 16148 Genova, Italy; dComplete Genomics, Inc., Mountain View, CA 94043; ePaediatric Palliative Medicine, Children’s Hospital for Wales, University Hospital of Wales, Cardiff CF14 4XW, United Kingdom; and fHaemato-Oncology Research Unit, Division of Molecular Pathology, Institute of Cancer Research, Surrey SM2 5NG, United Kingdom Edited* by Max D. Cooper, Emory University, Atlanta, GA, and approved March 5, 2013 (received for review December 10, 2012) Acute lymphoblastic leukemia (ALL) is the major pediatric cancer. ETV6-RUNX1 fusion-negative ALL. Sequencing of matched tu- At diagnosis, the developmental timing of mutations contributing mor-normal (remission) samples from each patient was carried critically to clonal diversification and selection can be buried in the out using unchained combinatorial probe anchor ligation chem- leukemia’s covert natural history. Concordance of ALL in monozy- istry on arrays of self-assembling DNA nanoballs (11). Paired-end gotic, monochorionic twins is a consequence of intraplacental reads were aligned to the Human Genome [National Center for spread of an initiated preleukemic clone.