In Silico Candidate Variant and Gene Identification Using Inbred Mouse Strains
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PARSANA-DISSERTATION-2020.Pdf
DECIPHERING TRANSCRIPTIONAL PATTERNS OF GENE REGULATION: A COMPUTATIONAL APPROACH by Princy Parsana A dissertation submitted to The Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland July, 2020 © 2020 Princy Parsana All rights reserved Abstract With rapid advancements in sequencing technology, we now have the ability to sequence the entire human genome, and to quantify expression of tens of thousands of genes from hundreds of individuals. This provides an extraordinary opportunity to learn phenotype relevant genomic patterns that can improve our understanding of molecular and cellular processes underlying a trait. The high dimensional nature of genomic data presents a range of computational and statistical challenges. This dissertation presents a compilation of projects that were driven by the motivation to efficiently capture gene regulatory patterns in the human transcriptome, while addressing statistical and computational challenges that accompany this data. We attempt to address two major difficulties in this domain: a) artifacts and noise in transcriptomic data, andb) limited statistical power. First, we present our work on investigating the effect of artifactual variation in gene expression data and its impact on trans-eQTL discovery. Here we performed an in-depth analysis of diverse pre-recorded covariates and latent confounders to understand their contribution to heterogeneity in gene expression measurements. Next, we discovered 673 trans-eQTLs across 16 human tissues using v6 data from the Genotype Tissue Expression (GTEx) project. Finally, we characterized two trait-associated trans-eQTLs; one in Skeletal Muscle and another in Thyroid. Second, we present a principal component based residualization method to correct gene expression measurements prior to reconstruction of co-expression networks. -
Genetic Epidemiology
Received: 10 May 2019 | Revised: 31 July 2019 | Accepted: 28 August 2019 DOI: 10.1002/gepi.22260 RESEARCH ARTICLE Population‐wide copy number variation calling using variant call format files from 6,898 individuals Grace Png1,2,3 | Daniel Suveges1,4 | Young‐Chan Park1,2 | Klaudia Walter1 | Kousik Kundu1 | Ioanna Ntalla5 | Emmanouil Tsafantakis6 | Maria Karaleftheri7 | George Dedoussis8 | Eleftheria Zeggini1,3* | Arthur Gilly1,3,9* 1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Abstract Kingdom Copy number variants (CNVs) play an important role in a number of human 2Department of Medical Genetics, diseases, but the accurate calling of CNVs remains challenging. Most current University of Cambridge, Cambridge, approaches to CNV detection use raw read alignments, which are computationally United Kingdom intensive to process. We use a regression tree‐based approach to call germline CNVs 3Institute of Translational Genomics, Helmholtz Zentrum München—German from whole‐genome sequencing (WGS, >18x) variant call sets in 6,898 samples Research Center for Environmental across four European cohorts, and describe a rich large variation landscape Health, Neuherberg, Germany comprising 1,320 CNVs. Eighty‐one percent of detected events have been previously 4European Bioinformatics Institute, ‐ ‐ Wellcome Genome Campus, Hinxton, reported in the Database of Genomic Variants. Twenty three percent of high quality United Kingdom deletions affect entire genes, and we recapitulate known events such as the GSTM1 5William Harvey Research Institute, Barts and RHD gene deletions. We test for association between the detected deletions and and The London School of Medicine and 275 protein levels in 1,457 individuals to assess the potential clinical impact of the Dentistry, Queen Mary University of London, London, United Kingdom detected CNVs. -
Genomic Correlates of Relationship QTL Involved in Fore- Versus Hind Limb Divergence in Mice
Loyola University Chicago Loyola eCommons Biology: Faculty Publications and Other Works Faculty Publications 2013 Genomic Correlates of Relationship QTL Involved in Fore- Versus Hind Limb Divergence in Mice Mihaela Palicev Gunter P. Wagner James P. Noonan Benedikt Hallgrimsson James M. Cheverud Loyola University Chicago, [email protected] Follow this and additional works at: https://ecommons.luc.edu/biology_facpubs Part of the Biology Commons Recommended Citation Palicev, M, GP Wagner, JP Noonan, B Hallgrimsson, and JM Cheverud. "Genomic Correlates of Relationship QTL Involved in Fore- Versus Hind Limb Divergence in Mice." Genome Biology and Evolution 5(10), 2013. This Article is brought to you for free and open access by the Faculty Publications at Loyola eCommons. It has been accepted for inclusion in Biology: Faculty Publications and Other Works by an authorized administrator of Loyola eCommons. For more information, please contact [email protected]. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License. © Palicev et al., 2013. GBE Genomic Correlates of Relationship QTL Involved in Fore- versus Hind Limb Divergence in Mice Mihaela Pavlicev1,2,*, Gu¨ nter P. Wagner3, James P. Noonan4, Benedikt Hallgrı´msson5,and James M. Cheverud6 1Konrad Lorenz Institute for Evolution and Cognition Research, Altenberg, Austria 2Department of Pediatrics, Cincinnati Children‘s Hospital Medical Center, Cincinnati, Ohio 3Yale Systems Biology Institute and Department of Ecology and Evolutionary Biology, Yale University 4Department of Genetics, Yale University School of Medicine 5Department of Cell Biology and Anatomy, The McCaig Institute for Bone and Joint Health and the Alberta Children’s Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, Canada 6Department of Anatomy and Neurobiology, Washington University *Corresponding author: E-mail: [email protected]. -
Identification of the Binding Partners for Hspb2 and Cryab Reveals
Brigham Young University BYU ScholarsArchive Theses and Dissertations 2013-12-12 Identification of the Binding arP tners for HspB2 and CryAB Reveals Myofibril and Mitochondrial Protein Interactions and Non- Redundant Roles for Small Heat Shock Proteins Kelsey Murphey Langston Brigham Young University - Provo Follow this and additional works at: https://scholarsarchive.byu.edu/etd Part of the Microbiology Commons BYU ScholarsArchive Citation Langston, Kelsey Murphey, "Identification of the Binding Partners for HspB2 and CryAB Reveals Myofibril and Mitochondrial Protein Interactions and Non-Redundant Roles for Small Heat Shock Proteins" (2013). Theses and Dissertations. 3822. https://scholarsarchive.byu.edu/etd/3822 This Thesis is brought to you for free and open access by BYU ScholarsArchive. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of BYU ScholarsArchive. For more information, please contact [email protected], [email protected]. Identification of the Binding Partners for HspB2 and CryAB Reveals Myofibril and Mitochondrial Protein Interactions and Non-Redundant Roles for Small Heat Shock Proteins Kelsey Langston A thesis submitted to the faculty of Brigham Young University in partial fulfillment of the requirements for the degree of Master of Science Julianne H. Grose, Chair William R. McCleary Brian Poole Department of Microbiology and Molecular Biology Brigham Young University December 2013 Copyright © 2013 Kelsey Langston All Rights Reserved ABSTRACT Identification of the Binding Partners for HspB2 and CryAB Reveals Myofibril and Mitochondrial Protein Interactors and Non-Redundant Roles for Small Heat Shock Proteins Kelsey Langston Department of Microbiology and Molecular Biology, BYU Master of Science Small Heat Shock Proteins (sHSP) are molecular chaperones that play protective roles in cell survival and have been shown to possess chaperone activity. -
Fine–Mapping Identifies NAD–ME1 As a Candidate Underlying a Major
bioRxiv preprint doi: https://doi.org/10.1101/2020.09.07.285429; this version posted September 9, 2020. 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. 1 Fine–mapping identifies NAD–ME1 as a candidate underlying 2 a major locus controlling temporal variation in primary and 3 specialized metabolism in Arabidopsis 4 5 Marta Francisco1, Daniel J. Kliebenstein2,3, Víctor M. Rodríguez1, Pilar Soengas1, 6 Rosaura Abilleira1, María E. Cartea1 7 1Misión Biológica de Galicia, (MBG-CSIC), P.O. Box 28, 36080, Pontevedra, Spain 8 2Department of Plant Sciences, University of California at Davis, Davis, CA 95616, 9 USA. 10 3DynaMo Center of Excellence, University of Copenhagen, Thorvaldsensvej 40, DK- 11 1871 Frederiksberg C, Denmark. 12 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.07.285429; this version posted September 9, 2020. 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. 13 Summary 14 Plant metabolism is modulated by a complex interplay between internal signals and 15 external cues. A major goal of all quantitative metabolomic studies is to clone the 16 underlying genes to understand the mechanistic basis of this variation. Using fine-scale 17 genetic mapping, in this work we report the identification and initial characterization of 18 NAD-DEPENDENT MALIC ENZYME 1 (NAD-ME1) as the candidate gene underlying 19 the pleiotropic network Met.II.15 QTL controlling variation in plant metabolism and 20 circadian clock outputs in the Bay × Sha Arabidopsis population. -
Meta-Analysis of Nasopharyngeal Carcinoma
BMC Genomics BioMed Central Research article Open Access Meta-analysis of nasopharyngeal carcinoma microarray data explores mechanism of EBV-regulated neoplastic transformation Xia Chen†1,2, Shuang Liang†1, WenLing Zheng1,3, ZhiJun Liao1, Tao Shang1 and WenLi Ma*1 Address: 1Institute of Genetic Engineering, Southern Medical University, Guangzhou, PR China, 2Xiangya Pingkuang associated hospital, Pingxiang, Jiangxi, PR China and 3Southern Genomics Research Center, Guangzhou, Guangdong, PR China Email: Xia Chen - [email protected]; Shuang Liang - [email protected]; WenLing Zheng - [email protected]; ZhiJun Liao - [email protected]; Tao Shang - [email protected]; WenLi Ma* - [email protected] * Corresponding author †Equal contributors Published: 7 July 2008 Received: 16 February 2008 Accepted: 7 July 2008 BMC Genomics 2008, 9:322 doi:10.1186/1471-2164-9-322 This article is available from: http://www.biomedcentral.com/1471-2164/9/322 © 2008 Chen 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: Epstein-Barr virus (EBV) presumably plays an important role in the pathogenesis of nasopharyngeal carcinoma (NPC), but the molecular mechanism of EBV-dependent neoplastic transformation is not well understood. The combination of bioinformatics with evidences from biological experiments paved a new way to gain more insights into the molecular mechanism of cancer. Results: We profiled gene expression using a meta-analysis approach. Two sets of meta-genes were obtained. Meta-A genes were identified by finding those commonly activated/deactivated upon EBV infection/reactivation. -
CD56+ T-Cells in Relation to Cytomegalovirus in Healthy Subjects and Kidney Transplant Patients
CD56+ T-cells in Relation to Cytomegalovirus in Healthy Subjects and Kidney Transplant Patients Institute of Infection and Global Health Department of Clinical Infection, Microbiology and Immunology Thesis submitted in accordance with the requirements of the University of Liverpool for the degree of Doctor in Philosophy by Mazen Mohammed Almehmadi December 2014 - 1 - Abstract Human T cells expressing CD56 are capable of tumour cell lysis following activation with interleukin-2 but their role in viral immunity has been less well studied. The work described in this thesis aimed to investigate CD56+ T-cells in relation to cytomegalovirus infection in healthy subjects and kidney transplant patients (KTPs). Proportions of CD56+ T cells were found to be highly significantly increased in healthy cytomegalovirus-seropositive (CMV+) compared to cytomegalovirus-seronegative (CMV-) subjects (8.38% ± 0.33 versus 3.29%± 0.33; P < 0.0001). In donor CMV-/recipient CMV- (D-/R-)- KTPs levels of CD56+ T cells were 1.9% ±0.35 versus 5.42% ±1.01 in D+/R- patients and 5.11% ±0.69 in R+ patients (P 0.0247 and < 0.0001 respectively). CD56+ T cells in both healthy CMV+ subjects and KTPs expressed markers of effector memory- RA T-cells (TEMRA) while in healthy CMV- subjects and D-/R- KTPs the phenotype was predominantly that of naïve T-cells. Other surface markers, CD8, CD4, CD58, CD57, CD94 and NKG2C were expressed by a significantly higher proportion of CD56+ T-cells in healthy CMV+ than CMV- subjects. Functional studies showed levels of pro-inflammatory cytokines IFN-γ and TNF-α, as well as granzyme B and CD107a were significantly higher in CD56+ T-cells from CMV+ than CMV- subjects following stimulation with CMV antigens. -
Comprehensive Sequence Analysis of Nine Usher Syndrome Genes in The
Genotype-phenotype correlations J Med Genet: first published as 10.1136/jmedgenet-2011-100468 on 1 December 2011. Downloaded from ORIGINAL ARTICLE Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study Polona Le Quesne Stabej,1 Zubin Saihan,2,3 Nell Rangesh,4 Heather B Steele-Stallard,1 John Ambrose,5 Alison Coffey,5 Jenny Emmerson,5 Elene Haralambous,1 Yasmin Hughes,1 Karen P Steel,5 Linda M Luxon,4,6 Andrew R Webster,2,3 Maria Bitner-Glindzicz1,6 < Additional materials are ABSTRACT characterised by congenital, moderate to severe published online only. To view Background Usher syndrome (USH) is an autosomal hearing loss, with normal vestibular function and these files please visit the recessive disorder comprising retinitis pigmentosa, onset of RP around or after puberty; and type III journal online (http://jmg.bmj. fi com/content/49/1.toc). hearing loss and, in some cases, vestibular dysfunction. (USH3), de ned by postlingual progressive hearing 1 It is clinically and genetically heterogeneous with three loss and variable vestibular response together with Clinical and Molecular e 1 2 Genetics, Institute of Child distinctive clinical types (I III) and nine Usher genes RP. In addition there remain patients whose Health, UCL, London, UK identified. This study is a comprehensive clinical and disease does not fit into any of these three 2Institute of Ophthalmology, genetic analysis of 172 Usher patients and evaluates the subtypes, because of atypical audiovestibular or UCL, London, UK fi ‘ 3 contribution of digenic inheritance. retinal ndings, who are said to have atypical Moorfields Eye Hospital, Methods The genes MYO7A, USH1C, CDH23, PCDH15, ’ London, UK Usher syndrome . -
Multiple Roles for Unc-53/Nav2 in Cell Migration, Trafficking and Innate Immunity in Caenorhabditis Elegans
MULTIPLE ROLES FOR UNC-53/NAV2 IN CELL MIGRATION, TRAFFICKING AND INNATE IMMUNITY IN CAENORHABDITIS ELEGANS by Kristopher Lee Schmidt M.Sc., University of British Columbia, 2005 B.Sc., Trinity Western University, 2001 THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in the Department of Molecular Biology and Biochemistry Faculty of Science © Kristopher Lee Schmidt 2012 SIMON FRASER UNIVERSITY Summer 2012 All rights reserved. However, in accordance with the Copyright Act of Canada, this work may be reproduced, without authorization, under the conditions for Fair Dealing. Therefore, limited reproduction of this work for the purposes of private study, research, criticism, review and news reporting is likely to be in accordance with the law, particularly if cited appropriately [Type a quotei from the document or the summary of an interesting point. APPROVAL Name: Kristopher Lee Schmidt Degree: Doctor of Philosophy Title of Thesis: Multiple roles for UNC-53/NAV2 in cell migration, trafficking, and innate immunity in Caenorhabditis elegans. Examining Committee: Chair: Dr. Barry Honda, Ph.D. Dr. Eve Stringham, Ph.D. Professor, Department of Molecular Biology Co-Senior Supervisor and Biochemistry Professor, Department of Biology, Trinity Associate Professor, Department of Western University __________________________________ __________________________________ Dr. Nancy Hawkins, Ph.D. Dr. Christopher Beh, Ph.D. Senior Supervisor Supervisor Associate Professor, Department of Molecular Associate Professor, Department of Molecular Biology and Biochemistry Biology and Biochemistry __________________________________ __________________________________ Dr. Nicholas Harden, Ph.D. Dr. Harald Hutter, Ph.D. Supervisor Internal Examiner Associate Professor, Department of Molecular Professor, Department of Biological Sciences Biology and Biochemistry __________________________________ __________________________________ Dr. -
Profiling Cellular Processes in Adipose Tissue During Weight Loss Using Time Series Gene Expression
G C A T T A C G G C A T genes Article Profiling Cellular Processes in Adipose Tissue during Weight Loss Using Time Series Gene Expression Samar H. K. Tareen 1,* , Michiel E. Adriaens 1,* , Ilja C. W. Arts 1,2, Theo M. de Kok 1,3, Roel G. Vink 4, Nadia J. T. Roumans 4, Marleen A. van Baak 4, Edwin C. M. Mariman 4, Chris T. Evelo 1,5,* and Martina Kutmon 1,5,* 1 Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, 6211ER Maastricht, The Netherlands; [email protected] (I.C.W.A.); [email protected] (T.M.d.K.) 2 Department of Epidemiology, CARIM School for Cardiovascular Diseases, Maastricht University, 6211ER Maastricht, The Netherlands 3 Department of Toxicogenomics, GROW School of Oncology and Developmental Biology, Maastricht University, 6211ER Maastricht, The Netherlands 4 Department of Human Biology, NUTRIM Research School, Maastricht University, 6211ER Maastricht, The Netherlands; [email protected] (R.G.V.); [email protected] (N.J.T.R.); [email protected] (M.A.v.B.); [email protected] (E.C.M.M.) 5 Department of Bioinformatics—BiGCaT, NUTRIM Research School, Maastricht University, 6211ER Maastricht, The Netherlands * Correspondence: [email protected] (S.H.K.T.); [email protected] (M.E.A.); [email protected] (C.T.E.); [email protected] (M.K.) Received: 28 September 2018; Accepted: 22 October 2018; Published: 29 October 2018 Abstract: Obesity is a global epidemic identified as a major risk factor for multiple chronic diseases and, consequently, diet-induced weight loss is used to counter obesity. -
Role and Regulation of the P53-Homolog P73 in the Transformation of Normal Human Fibroblasts
Role and regulation of the p53-homolog p73 in the transformation of normal human fibroblasts Dissertation zur Erlangung des naturwissenschaftlichen Doktorgrades der Bayerischen Julius-Maximilians-Universität Würzburg vorgelegt von Lars Hofmann aus Aschaffenburg Würzburg 2007 Eingereicht am Mitglieder der Promotionskommission: Vorsitzender: Prof. Dr. Dr. Martin J. Müller Gutachter: Prof. Dr. Michael P. Schön Gutachter : Prof. Dr. Georg Krohne Tag des Promotionskolloquiums: Doktorurkunde ausgehändigt am Erklärung Hiermit erkläre ich, dass ich die vorliegende Arbeit selbständig angefertigt und keine anderen als die angegebenen Hilfsmittel und Quellen verwendet habe. Diese Arbeit wurde weder in gleicher noch in ähnlicher Form in einem anderen Prüfungsverfahren vorgelegt. Ich habe früher, außer den mit dem Zulassungsgesuch urkundlichen Graden, keine weiteren akademischen Grade erworben und zu erwerben gesucht. Würzburg, Lars Hofmann Content SUMMARY ................................................................................................................ IV ZUSAMMENFASSUNG ............................................................................................. V 1. INTRODUCTION ................................................................................................. 1 1.1. Molecular basics of cancer .......................................................................................... 1 1.2. Early research on tumorigenesis ................................................................................. 3 1.3. Developing -
The Multifunctional Role of EMP3 in the Regulation of Membrane Receptors Associated with IDH-Wild-Type Glioblastoma
International Journal of Molecular Sciences Review The Multifunctional Role of EMP3 in the Regulation of Membrane Receptors Associated with IDH-Wild-Type Glioblastoma Antoni Andreu Martija 1,2,3 and Stefan Pusch 1,2,* 1 Clinical Cooperation Unit (CCU) Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; [email protected] 2 Department of Neuropathology, Heidelberg University Medical Center, 69120 Heidelberg, Germany 3 Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany * Correspondence: [email protected]; Tel.: +49-6221-42-1473 Abstract: Epithelial membrane protein 3 (EMP3) is a tetraspan membrane protein overexpressed in isocitrate dehydrogenase-wild-type (IDH-wt) glioblastoma (GBM). Several studies reported high EMP3 levels as a poor prognostic factor in GBM patients. Experimental findings based on glioma and non-glioma models have demonstrated the role of EMP3 in the regulation of several membrane proteins known to drive IDH-wt GBM. In this review, we summarize what is currently known about EMP3 biology. We discuss the regulatory effects that EMP3 exerts on a variety of oncogenic receptors and discuss how these mechanisms may relate to IDH-wt GBM. Lastly, we enumerate the open questions towards EMP3 function in IDH-wt GBM. Keywords: EMP3; glioblastoma; membrane receptors Citation: Martija, A.A.; Pusch, S. The Multifunctional Role of EMP3 in the Regulation of Membrane Receptors 1. Introduction Associated with IDH-Wild-Type The diagnosis of glioblastoma (GBM) is applied to highly aggressive primary central Glioblastoma. Int. J. Mol. Sci. 2021, 22, nervous system (CNS) tumors. Histologically, GBM is characterized by diffusely infiltrating 5261.