Transcriptional Profile Analysis of RPGRORF15 Frameshift Mutation Identifies Novel Genes Associated with Retinal Degeneration
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BMC Genomics BioMed Central Research article Open Access Differential gene expression in ADAM10 and mutant ADAM10 transgenic mice Claudia Prinzen1, Dietrich Trümbach2, Wolfgang Wurst2, Kristina Endres1, Rolf Postina1 and Falk Fahrenholz*1 Address: 1Johannes Gutenberg-University, Institute of Biochemistry, Mainz, Johann-Joachim-Becherweg 30, 55128 Mainz, Germany and 2Helmholtz Zentrum München – German Research Center for Environmental Health, Institute for Developmental Genetics, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany Email: Claudia Prinzen - [email protected]; Dietrich Trümbach - [email protected]; Wolfgang Wurst - [email protected]; Kristina Endres - [email protected]; Rolf Postina - [email protected]; Falk Fahrenholz* - [email protected] * Corresponding author Published: 5 February 2009 Received: 19 June 2008 Accepted: 5 February 2009 BMC Genomics 2009, 10:66 doi:10.1186/1471-2164-10-66 This article is available from: http://www.biomedcentral.com/1471-2164/10/66 © 2009 Prinzen et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: In a transgenic mouse model of Alzheimer disease (AD), cleavage of the amyloid precursor protein (APP) by the α-secretase ADAM10 prevented amyloid plaque formation, and alleviated cognitive deficits. Furthermore, ADAM10 overexpression increased the cortical synaptogenesis. These results suggest that upregulation of ADAM10 in the brain has beneficial effects on AD pathology. Results: To assess the influence of ADAM10 on the gene expression profile in the brain, we performed a microarray analysis using RNA isolated from brains of five months old mice overexpressing either the α-secretase ADAM10, or a dominant-negative mutant (dn) of this enzyme. -
Comparative Analysis of the Domestic Cat Genome Reveals Genetic Signatures Underlying Feline Biology and Domestication
Comparative analysis of the domestic cat genome reveals genetic signatures underlying feline biology and domestication Michael J. Montaguea,1, Gang Lib,1, Barbara Gandolfic, Razib Khand, Bronwen L. Akene, Steven M. J. Searlee, Patrick Minxa, LaDeana W. Hilliera, Daniel C. Koboldta, Brian W. Davisb, Carlos A. Driscollf, Christina S. Barrf, Kevin Blackistonef, Javier Quilezg, Belen Lorente-Galdosg, Tomas Marques-Bonetg,h, Can Alkani, Gregg W. C. Thomasj, Matthew W. Hahnj, Marilyn Menotti-Raymondk, Stephen J. O’Brienl,m, Richard K. Wilsona, Leslie A. Lyonsc,2, William J. Murphyb,2, and Wesley C. Warrena,2 aThe Genome Institute, Washington University School of Medicine, St. Louis, MO 63108; bDepartment of Veterinary Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843; cDepartment of Veterinary Medicine & Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO 65201; dPopulation Health & Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616; eWellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom; fNational Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20886; gCatalan Institution for Research and Advanced Studies, Institute of Evolutionary Biology, Pompeu Fabra University, 08003 Barcelona, Spain; hCentro de Analisis Genomico 08028, Barcelona, Spain; iDepartment of Computer Engineering, Bilkent University, Ankara 06800, Turkey; jDepartment of Biology, Indiana University, Bloomington, -
Content Based Search in Gene Expression Databases and a Meta-Analysis of Host Responses to Infection
Content Based Search in Gene Expression Databases and a Meta-analysis of Host Responses to Infection A Thesis Submitted to the Faculty of Drexel University by Francis X. Bell in partial fulfillment of the requirements for the degree of Doctor of Philosophy November 2015 c Copyright 2015 Francis X. Bell. All Rights Reserved. ii Acknowledgments I would like to acknowledge and thank my advisor, Dr. Ahmet Sacan. Without his advice, support, and patience I would not have been able to accomplish all that I have. I would also like to thank my committee members and the Biomed Faculty that have guided me. I would like to give a special thanks for the members of the bioinformatics lab, in particular the members of the Sacan lab: Rehman Qureshi, Daisy Heng Yang, April Chunyu Zhao, and Yiqian Zhou. Thank you for creating a pleasant and friendly environment in the lab. I give the members of my family my sincerest gratitude for all that they have done for me. I cannot begin to repay my parents for their sacrifices. I am eternally grateful for everything they have done. The support of my sisters and their encouragement gave me the strength to persevere to the end. iii Table of Contents LIST OF TABLES.......................................................................... vii LIST OF FIGURES ........................................................................ xiv ABSTRACT ................................................................................ xvii 1. A BRIEF INTRODUCTION TO GENE EXPRESSION............................. 1 1.1 Central Dogma of Molecular Biology........................................... 1 1.1.1 Basic Transfers .......................................................... 1 1.1.2 Uncommon Transfers ................................................... 3 1.2 Gene Expression ................................................................. 4 1.2.1 Estimating Gene Expression ............................................ 4 1.2.2 DNA Microarrays ...................................................... -
Genetics of Abca4-Associated Diseases and Retinitis Pigmentosa
GENETICS OF ABCA4-ASSOCIATED DISEASES AND RETINITIS PIGMENTOSA Yajing (Angela) Xie Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2016 © 2016 Yajing (Angela) Xie All rights reserved ABSTRACT Genetics of ABCA4-Associated Diseases and Retinitis Pigmentosa Yajing (Angela) Xie Inherited retinal dystrophies encompass a broad group of genetic disorders affecting visual functions in as high as 1 in 3,000 individuals around the world. Common symptoms include loss of central, periphery, or night visions, and in severe cases progression to complete blindness. Syndromic forms also exist involving abnormalities in other parts of the body. Currently, more than 250 genes representing a wide variety of functional roles have been shown to be responsible for the disease phenotypes. Moreover, mutations in the same gene sometimes cause different phenotypes while mutations in multiple genes can give rise to the same clinical subtype, further demonstrating the level of complexity in these disorders. Such genetic heterogeneity has substantially complicated the process of pinpointing precise genetic causes underlying these conditions. The goal of my thesis research is to clarify the genetic causes underlying retinal dystrophies, with a primary focus on phenotypes resembling ABCA4-associated diseases and retinitis pigmentosa in both syndromic and non-syndromic forms. Recent advances in the next-generation sequencing (NGS), the high-throughput, ‘deep’ sequencing technology, have enabled several novel genes to be identified, or found new mutations in known genes. Nevertheless, a substantial fraction of unsolved cases still remain. The primary work in this thesis involves utilizing NGS, particularly whole- exome sequencing, to identify disease-causal mutations in families where at least one parent and affected or unaffected siblings are available. -
Genetic Analysis of Rare Eye Disorders in Pakistani Families
GENETIC ANALYSIS OF RARE EYE DISORDERS IN PAKISTANI FAMILIES By MUHAMMAD ARIF NADEEM SAQIB Department of Biochemistry Faculty of Biological Sciences Quaid-i-Azam University Islamabad, Pakistan 2015 GENETIC ANALYSIS OF RARE EYE DISORDERS IN PAKISTANI FAMILIES A thesis Submitted in the partial fulfillment of the Requirements for the degree of DOCTOR OF PHILOSOPHY In BIOCHEMISTRY/MOLECULAR BIOLOGY By MUHAMMAD ARIF NADEEM SAQIB Department of Biochemistry Faculty of Biological Sciences Quaid-i-Azam University Islamabad, Pakistan 2015 CERTIFICATE A thesis submitted in the partial fulfillment of the requirements for the degree of the Doctor of Philosophy. We accept this dissertation as conforming to the required standard. 1 _________________ 2________________ Dr. Muhammad Ansar External Examiner (Supervisor) 3 ____________________ Dr. Muhammad Ansar (Chairperson) Dated: February 09, 2015 DECLARATION I hereby declare that the work presented in the following thesis is my own efforts and that the thesis is my own composition. No part of the thesis has been previously presented for any other degree. Muhammad Arif Nadeem Saqib Dedicated To Muhammad Romman Khan (Late) My Son, who died during the journey of my PhD ACKNOWLEDGEMENT All praise to Allah Almighty, the most beneficent, the most merciful, Who gave me strength and enabled me to undertake and execute this research task. Countless salutations upon the Holy Prophet Hazrat Muhammad (Sallallaho Allaihe Waalahe Wassalum), the city of knowledge for enlightening with the essence of faith in Allah and guiding the mankind, the true path of life. I would like to extend my appreciation to those people, who helped me in one way or another to finish the thesis. -
The Role of the Retinoids in Schizophrenia: Genomic and Clinical Perspectives
Molecular Psychiatry (2020) 25:706–718 https://doi.org/10.1038/s41380-019-0566-2 REVIEW ARTICLE The role of the retinoids in schizophrenia: genomic and clinical perspectives 1,2 1,2 William R. Reay ● Murray J. Cairns Received: 17 April 2019 / Revised: 23 September 2019 / Accepted: 17 October 2019 / Published online: 30 October 2019 © The Author(s) 2019. This article is published with open access Abstract Signalling by retinoid compounds is vital for embryonic development, with particular importance for neurogenesis in the human brain. Retinoids, metabolites of vitamin A, exert influence over the expression of thousands of transcripts genome wide, and thus, act as master regulators of many important biological processes. A significant body of evidence in the literature now supports dysregulation of the retinoid system as being involved in the aetiology of schizophrenia. This includes mechanistic insights from large-scale genomic, transcriptomic and, proteomic studies, which implicate disruption of disparate aspects of retinoid biology such as transport, metabolism, and signalling. As a result, retinoids may present a valuable clinical opportunity in schizophrenia via novel pharmacotherapies and dietary intervention. Further work, fi 1234567890();,: 1234567890();,: however, is required to expand on the largely observational data collected thus far and con rm causality. This review will highlight the fundamentals of retinoid biology and examine the evidence for retinoid dysregulation in schizophrenia. Introduction neural connectivity [8–10]. While early investigation of this hypothesis was focused around the dopamine system, Schizophrenia is a psychiatric disorder likely influenced by because of its clear role in psychosis, it now seems likely that an array of genetic and environmental factors [1–4]. -
The Lrat−/− Rat: CRISPR/Cas9 Construction and Phenotyping of a New Animal Model for Retinitis Pigmentosa
International Journal of Molecular Sciences Article The Lrat−/− Rat: CRISPR/Cas9 Construction and Phenotyping of a New Animal Model for Retinitis Pigmentosa Céline Koster 1 , Koen T. van den Hurk 1, Colby F. Lewallen 2, Mays Talib 3, Jacoline B. ten Brink 1 , Camiel J. F. Boon 3,4 and Arthur A. Bergen 1,4,5,* 1 Department of Human Genetics Amsterdam, Section of Ophthalmogenetics, Amsterdam University Medical Centers (AUMC), University of Amsterdam (UvA), Location Meibergdreef, 1105 AZ Amsterdam, The Netherlands; [email protected] (C.K.); [email protected] (K.T.v.d.H.); [email protected] (J.B.t.B.) 2 Georgia Institute of Technology, G.W. Woodruff School of Mechanical Engineering, Atlanta, GA 30313, USA; [email protected] 3 Department of Ophthalmology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; [email protected] (M.T.); [email protected] (C.J.F.B.) 4 Department of Ophthalmology, Amsterdam University Medical Centers (AUMC), University of Amsterdam (UvA), Location Meibergdreef, 1105 AZ Amsterdam, The Netherlands 5 The Netherlands Institute for Neuroscience (NIN-KNAW), 1105 BA Amsterdam, The Netherlands * Correspondence: [email protected] Abstract: Purpose: We developed and phenotyped a pigmented knockout rat model for lecithin retinol acyltransferase (LRAT) using CRISPR/Cas9. The introduced mutation (c.12delA) is based on a patient group harboring a homologous homozygous frameshift mutation in the LRAT gene (c.12delC), Citation: Koster, C.; van den Hurk, causing a dysfunctional visual (retinoid) cycle. Methods: The introduced mutation was confirmed by K.T.; Lewallen, C.F.; Talib, M.; ten DNA and RNA sequencing. -
Identification of Significantly Mutated Subnetworks in the Breast Cancer Genome
www.nature.com/scientificreports OPEN Identifcation of signifcantly mutated subnetworks in the breast cancer genome Rasif Ajwad1,2, Michael Domaratzki2, Qian Liu1, Nikta Feizi1 & Pingzhao Hu1,2,3* Recent studies showed that somatic cancer mutations target genes that are in specifc signaling and cellular pathways. However, in each patient only a few of the pathway genes are mutated. Current approaches consider only existing pathways and ignore the topology of the pathways. For this reason, new eforts have been focused on identifying signifcantly mutated subnetworks and associating them with cancer characteristics. We applied two well-established network analysis approaches to identify signifcantly mutated subnetworks in the breast cancer genome. We took network topology into account for measuring the mutation similarity of a gene-pair to allow us to infer the signifcantly mutated subnetworks. Our goals are to evaluate whether the identifed subnetworks can be used as biomarkers for predicting breast cancer patient survival and provide the potential mechanisms of the pathways enriched in the subnetworks, with the aim of improving breast cancer treatment. Using the copy number alteration (CNA) datasets from the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) study, we identifed a signifcantly mutated yet clinically and functionally relevant subnetwork using two graph-based clustering algorithms. The mutational pattern of the subnetwork is signifcantly associated with breast cancer survival. The genes in the subnetwork are signifcantly enriched in retinol metabolism KEGG pathway. Our results show that breast cancer treatment with retinoids may be a potential personalized therapy for breast cancer patients since the CNA patterns of the breast cancer patients can imply whether the retinoids pathway is altered. -
ABSTRACT Using a Bioinformatics Approach to Identify Genes That
ABSTRACT Using a bioinformatics approach to identify genes that have possible candidacy of association with retinitis pigmentosa: GeneWeaver Natasha Lie Director: Erich J. Baker, Ph.D. Retinitis pigmentosa (RP) is a retinal degenerative disorder that affects about 1 in 3,000 people. The disease is genetic in cause, and currently there is no cure. The genetic cause of the disease may be contributed to one of several different genes, underscoring the complex genetic underpinnings of this disease. The information required to determine which genes are potentially causative for RP may exist, but it is difficult to determine which genes are most suitable for study because of the immense wealth and breadth of available information. In other words, large-scale heterogeneous species-specific data often obfuscates the true causative genetic background of RP. In this study we describe a method of identifying genes that may contribute to RP using the bioinformatics techniques of graph theory and database utilization. We report a potential ranked list of genes in which disruptions are likely causative of RP. APPROVED BY DIRECTOR OF HONORS THESIS: ___________________________________________________ Dr. Erich Baker, School of Engineering and Computer Science APPROVED BY THE HONORS PROGRAM: ______________________________________________ Dr. Elizabeth Corey, Director DATE: _________________________ USING A BIOINFORMATICS APPROACH TO IDENTIFY GENES THAT HAVE POSSIBLE CANDIDACY OF ASSOCIATION WITH RETINITIS PIGMENTOSA: GENEWEAVER A Thesis Submitted to the -
A New Strategy to Identify and Annotate Human RPE-Specific Gene Expression
A New Strategy to Identify and Annotate Human RPE-Specific Gene Expression Judith C. Booij1, Jacoline B. ten Brink1, Sigrid M. A. Swagemakers2,3, Annemieke J. M. H. Verkerk2, Anke H. W. Essing1, Peter J. van der Spek2, Arthur A. B. Bergen1,4,5* 1 Department of Clinical and Molecular Ophthalmogenetics, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands, 2 Department of Bioinformatics and Genetics, Erasmus Medical Center, Rotterdam, The Netherlands, 3 Cancer Genomics Centre, Erasmus Medical Center, Rotterdam, The Netherlands, 4 Clinical Genetics Academic Medical Centre Amsterdam, University of Amsterdam, The Netherlands, 5 Department of Ophthalmology, Academic Medical Centre Amsterdam, University of Amsterdam, The Netherlands Abstract Background: To identify and functionally annotate cell type-specific gene expression in the human retinal pigment epithelium (RPE), a key tissue involved in age-related macular degeneration and retinitis pigmentosa. Methodology: RPE, photoreceptor and choroidal cells were isolated from selected freshly frozen healthy human donor eyes using laser microdissection. RNA isolation, amplification and hybridization to 44 k microarrays was carried out according to Agilent specifications. Bioinformatics was carried out using Rosetta Resolver, David and Ingenuity software. Principal Findings: Our previous 22 k analysis of the RPE transcriptome showed that the RPE has high levels of protein synthesis, strong energy demands, is exposed to high levels of oxidative stress and a variable degree of inflammation. We currently use a complementary new strategy aimed at the identification and functional annotation of RPE-specific expressed transcripts. This strategy takes advantage of the multilayered cellular structure of the retina and overcomes a number of limitations of previous studies. -
Network Mining Approach to Cancer Biomarker Discovery
NETWORK MINING APPROACH TO CANCER BIOMARKER DISCOVERY THESIS Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University By Praneeth Uppalapati, B.E. Graduate Program in Computer Science and Engineering The Ohio State University 2010 Thesis Committee: Dr. Kun Huang, Advisor Dr. Raghu Machiraju Copyright by Praneeth Uppalapati 2010 ABSTRACT With the rapid development of high throughput gene expression profiling technology, molecule profiling has become a powerful tool to characterize disease subtypes and discover gene signatures. Most existing gene signature discovery methods apply statistical methods to select genes whose expression values can differentiate different subject groups. However, a drawback of these approaches is that the selected genes are not functionally related and hence cannot reveal biological mechanism behind the difference in the patient groups. Gene co-expression network analysis can be used to mine functionally related sets of genes that can be marked as potential biomarkers through survival analysis. We present an efficient heuristic algorithm EigenCut that exploits the properties of gene co- expression networks to mine functionally related and dense modules of genes. We apply this method to brain tumor (Glioblastoma Multiforme) study to obtain functionally related clusters. If functional groups of genes with predictive power on patient prognosis can be identified, insights on the mechanisms related to metastasis in GBM can be obtained and better therapeutical plan can be developed. We predicted potential biomarkers by dividing the patients into two groups based on their expression profiles over the genes in the clusters and comparing their survival outcome through survival analysis. -
The Impact of Cytoplasmic Capping on Transcriptome Complexity Dissertation Presented in Partial Fulfillment of the Requirements
The impact of cytoplasmic capping on transcriptome complexity Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Daniel E. del Valle-Morales, B.S. Graduate Program in Molecular, Cellular, and Developmental Biology The Ohio State University 2020 Dissertation Committee Daniel R. Schoenberg, Advisor Dawn S. Chandler Ralf Bundschuh Guramrit Singh Copyrighted by Daniel E. del Valle-Morales 2020 Abstract The 5’ cap is an essential modification of mRNAs that is needed for the functionality and lifespan of an mRNA. The cap is added almost immediately after the first nucleotide is transcribed, coordinated by RNGTT and RNMT-RAM bound to the C-terminal tail of RNA Pol II. This process of capping was thought to exclusively occur in the nucleus and loss of the cap was irreversible, leading to the rapid degradation of the mRNA. However, not all mRNAs share this fate. Over the last decade, the Schoenberg lab has characterized cytoplasmic capping, a process where the cap can be restored to previously decapped mRNAs. Cytoplasmic capping is catalyzed by a complex that consists of a cytoplasmic pool of both RNGTT and RNMT-RAM bound to the adapter protein NCK1 along with an unknown 5’ monophosphate kinase. mRNAs that undergo cytoplasmic capping can cycle from being in a decapped state to a recapped state as a way to fine tune gene expression, a process called cap homeostasis. The recapping targets were initially identified using a catalytically inactive and cytoplasmically restricted form of RNGTT termed K294A. Overexpression of K294A resulted in an accumulation of uncapped mRNAs in non-translating mRNPs.