DOCSLIB.ORG

Faculty of Graduate Studies and Scientific Research Molecular

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Faculty of Graduate Studies and Scientific Research Molecular Republic of Sudan Ministry of Higher Education and Scientific Research Shendi University Faculty of Graduate Studies and Scientific Research Molecular Identification of Genetic Markers of Susceptibility to Essential Hypertension Using Whole Exome Sequencing among Sudanese Patients from Afro- Asiatic and Nilo-Saharan ethnic groups A Thesis Submitted in Fulfillment for the Requirements of PhD Degree in Biochemistry By: Wesal Ahmed ELHanbli Babiker MBBS- MSc Medical Biochemistry Supervisor: Dr: Dina Ahmed Hassan Associate professor of Biochemistry (2020) سورة الفاتحة I Bibliographic Entry Author: Wesal Ahmed ELHanbli Babiker Thesis: Molecular Identification of Genetic Markers of Susceptibility to Essential Hypertension Using Whole Exome Sequencing among Sudanese Patients from Afro-asiatic and Nilo-Saharan ethnic groups Degree program: PhD Faculty: Faculty of Medicine Field of study: Biochemistry Supervisor: Dr: Dina Ahmed Hassan Duration: (from 2015 to 2020) Key words: Essential hypertension, whole exome sequencing, bioinformatics tools, GPCR, MTHFR, ADM, Real-time PCR. II PhD Examination Committee Members Thesis Title: Molecular Identification of Genetic Markers of Susceptibility to Essential Hypertension Using Whole Exome Sequencing among Sudanese Patients from Afro-asiatic and Nilo-Saharan ethnic groups Supervisor: Dr: Dina Ahmed Hassan Signature …………………………… date ……………………………. Internal Examiner: Prof. Rashid Eltayeb Abdalla Signature …………………………….. date …………………………… External Examiner: Prof. Mamoun Makki EL Manna Signature …………………………….. date ……………………………. III Statement I Wesal Ahmed ELHanbli Babiker, declare that the study of Molecular Identification of Genetic Markers of Susceptibility to Essential Hypertension Using Whole Exome Sequencing among Sudanese Patients from Afro-asiatic and Nilo- Saharan ethnic groups, is my own original work and submitted in fulfillment for the requirements of PhD degree in biochemistry. I have followed all ethical and technical principles in the preparation, data collection, data analysis and compilation of this study. I declare that it has not been presented to any other university for a similar or any degree award, and any sources used are indicated as references. Signature ...................................................................................... Date ……………………………………………………………… IV DEDEICATION To soul of my dear father, To my kind dear mother, To my supportive lovely little family, To my sisters and brother, To my friends, To all whom I love ,,,,, V Acknowledgments I would like to express my profound appreciation and gratitude to my supervisor Dr. Dina Ahmed Hassan Ibrahim Associate Professor of Biochemistry, director of Central Laboratory, Ministry of Higher Education and Scientific Research for her supervision and continuous encouragement and support throughout the course of this study. I would like to appreciate the contribution of both: Dr. Mutaz Amin and Dr. Mahmoud Koko for their informative knowledge and help in Bioinformatics tools. I specifically thank the two family members for their generous participation in this study. Further thanks to the patients, the healthy volunteers and all the study participants for contributing to this effort. I am grateful to all members in Central Lab with special thanks to Dr. Khalid Enan, Dalia Mursi and Raya Osman for their counseling and Kind support. My appreciation is also extended to my dear friends and colleagues in Shendi University for their continuous support. VI Abstract Background: Essential hypertension (EH) is one of most important risk factors for CVDs, stroke and end stage renal disease and a major cause of premature deaths worldwide. It is a multigene complex disorder with no known single gene playing a major role, but rather many genes each with mild effects reacting to different environmental stimuli contribute to BP. This study we hypothesized that a block of specific single nucleotide polymorphisms (SNPs) and insertion /deletion mutations (InDels) in genes controlling pathways of BP regulation is associated with susceptibility to EH among Sudanese taking the Afro-asiatic ethnic group as a model. Aim of study: To identify the genetic markers of EH among Sudanese patients. Study design: Prospective laboratory case control study Duration: (from 2015 to 2020) Site of work: Central laboratory, Ministry of Higher Education and Scientific Research. Methods and Results: Whole exome sequencing (WES) was used to analyze genomic DNA of (15) members (13 hypertensive cases and 2 normotensive controls) of two families of strong family history of EH. The 2 families belong to the Afro-asiatic ethnic group. In silico analysis and data filtration with bioinformatics tools identified set of genes which function in different metabolic pathways; mainly lipid and lipoproteins metabolism as well as signal transduction, informational and immune system pathways. Screening for MTHFR rs1801133 and ADM rs5005 was performed using real time PCR for a total of (221) samples (107 hypertensive cases and 114 VII normotensive controls). Results showed high frequency of the 2 variants among Sudanese especially among Nilo-Saharan ethnic group. Unlike ADM, MTHFR variant is associated with EH (P value 0.04) and this association is significant among females. Conclusions: WES is a molecular method used to identify novel variants associated with polygenetic complex diseases. In silico analysis applied highlighted the importance of G-protein coupled receptors (GPCRs) as an important pathway in regulating blood pressure via its role in activation of calcium release. Screening of population for the identified variants is required to determine alleles associated with susceptibility to EH and BP regulation. VIII المستخلص ارتفاع ضغط الدم اﻷساسي (EH) هو واحد من أهم عوامل الخطر ﻷمراض القلب واﻷوعية الدموية ، والسكتة الدماغية والمرض الكلوي في المرحلة النهائية وسبب رئيسي للوفاة المبكرة في جميع أنحاء العالم . إنه اضطراب معقد متعدد الجينات مع عدم وجود جين واحد معروف يلعب دو ًرا رئيسيًا ، ولكن العديد من الجينات ذات اﻵثار الخفيفة التي تتفاعل مع المنبهات البيئية المختلفة تساهم في ضغط الدم .في هذه الدراسة افترضنا أن كتلة من تعدد أشكال النوكليوتيدات الفردية (SNPs) وطفرات الحذف اﻹدراج (InDels) في الجينات التي تتحكم في مسارات تنظيم ضغط الدم ترتبط بارتفاع ضغط الدم اﻷساسي بين السودانيين وتم اخذ مجموعة عرقية أفرواسيوية كنموزج. تم استخدام تسلسل اﻹكسوم الكامل (WES) لتحليل الحمض النووي الجينومي لـ 15 عض ًوا - 13 حالة ارتفاع ضغط الدم و 2 ضوابط معيارية - لضغط الدم لعائلتين من تاريخ عائلي قوي ﻻرتفاع ضغط الدم اﻷساسي. تنتمي العائلتان إلى المجموعة اﻹثنية اﻷفرو آسيوية .حددت تصفية البيانات باستخدام أدوات المعلوماتية الحيوية مجموعة من الجينات التي تعمل في مسارات التمثيل الغذائي المختلفة ؛ بشكل رئيسي استقﻻب الدهون والبروتينات الدهنية وكذلك تحويل اﻹشارة ، ومسارات المعلومات ونظام المناعة . تم إجراء الفحص لـ MTHFR rs1801133 و ADM rs5005 باستخدام PCR في الوقت الفعلي لمجموعه 221 عينة - 107 حاﻻت ارتفاع ضغط الدم و 114 ضوابط معيارية . أظهرت النتائج توات ًرا عاليًا للمتغيرين بين السودانيين خاصة بين مجموعة النيلو الصحراوية العرقية .على عكس ADM ، يرتبط متغير MTHFRبارتفاع ضغط الدم اﻷساسي- P 0.04 - وهذا اﻻرتباط مهم خاصة عند اﻻناث. تسلسل اﻹكسوم الكامل هي طريقة جذابة لتحديد المتغيرات الجديدة المرتبطة باﻷمراض الوراثية المعقدة . يسلط تحليلنا في السليكو الضوء على أهمية المستقبﻻت المقترنة بالبروتين GPCRs) G) كمسار مهم في تنظيم ضغط الدم من خﻻل دوره في تنشيط إطﻻق الكالسيوم .مطلوب فحص السكان للمتغيرات المحددة لتحديد اﻷليﻻت المرتبطة بقابلية التأثر بالصحة وتنظيم ضغط الدم. IX Table of Contents I اﻻيه Bibliographic Entry II PhD Examination Committee Members III Statement IV Dedication V Acknowledgements VI English Abstract VII Arabic Abstract IX Table of Contents X List of Tables XIV List of Figures XVI List of Abbreviations XVII Glossary XXV CHAPTER ONE: INTRODUCTION 1.1 Definition 1 1.2 Classification 2 1.3 Pathogenesis of essential hypertension 3 1.4 Genetic role in EH 6 1.5 Methods of mapping human disease genes 6 1.6 Molecular study of hypertension in Sudan 7 1.7 Justification 9 1.8 Objectives 11 X CHAPTER TWO: LITERATURE REVIEW 2.1 Prevalence of essential hypertension 12 2.2 Genetics of hypertension 13 2.3 Clinical application of genomic sequencing to the detection of germ-line mutations 14 2.3.1 Sanger sequencing 14 2.3.2 Next generation sequencing 14 2.3.3 Whole genome sequencing 15 2.3.4 Whole exome sequencing 15 2.4 Development of genetic hypotheses in essential hypertension 16 2.4.1 Renin-angiotensin aldosterone system 17 2.4.2 G protein B3 subunit 20 2.4.3 α-adducin 21 2.4.4 Other genetic polymorphisms 22 CHAPTER THREE: MATERIALS AND METHODS 3.1 Study design 32 3.2 Study area and population 32 3.3 Inclusion criteria 32 3.4 Exclusion criteria 32 3.5 Sample size 32 3.6 Data tools 32 3.7 Study description and protocol 33 3.7.1 Phase 1: Whole exome sequencing 33 3.7.1.1 Preparation of WES sample 33 3.7.1.2 In-silico bioinformatics analysis 36 3.7.2 Phase II: Screening of the population 36 XI 3.7.2.1 DNA extraction. 36 3.7.2.2 Primer Design 37 3.7.2.3 Real-time PCR assay 37 3.8 Statistical analysis 39 3.9 Ethical consideration 39 CHAPTER FOUR: RESULTS Phase 1: Whole Exome Sequencing 4.1 Demographic characterization of the (2 ) families members 40 4.2 Whole exome sequencing results 41 4.2.1 In silico analysis 41 4.2.2 Identification of variants related to hypertension 42 4.2.3 Individual family analysis 43 4.2.4 Pathways and interactions of the selected genes 58 Phase II: Screening of the population 4.3 Case-control study results 61 4.3.1 MTHFR gene variant rs1801133 (G/A) 61 4.3.2 ADM gene variant rs5005 (C/G) 63
Load more

Recommended publications
  • Ejercicio Físico En La Patogenia De La Artritis Inducida Por Proteoglicano En Ratón
    UNIVERSIDAD AUTÓNOMA DE CHIHUAHUA FACULTAD DE CIENCIAS DE LA CULTURA FÍSICA SECRETARÍA DE INVESTIGACIÓN Y POSGRADO EJERCICIO FÍSICO EN LA PATOGENIA DE LA ARTRITIS INDUCIDA POR PROTEOGLICANO EN RATÓN TESIS QUE PARA OBTENER EL GRADO DE: DOCTORA EN CIENCIAS DE LA CULTURA FÍSICA PRESENTA: M. EN C. SUSANA AIDEÉ GONZÁLEZ CHÁVEZ DIRECTOR DE TESIS: DR. CÉSAR FRANCISCO PACHECO TENA CHIHUAHUA, CHIH., MÉXICO, SEPTIEMBRE DE 2017 UNIVERSIDAD AUTÓNOMA DE CHIHUAHUA FACULTAD DE CIENCIAS DE LA CULTURA FÍSICA SECRETARÍA DE INVESTIGACIÓN Y POSGRADO El que suscribe, integrante del Núcleo Complementario del Programa de Doctorado Interinstitucional en Ciencias de la Cultura Física de la Facultad de Ciencias de la Cultura Física de la Universidad Autónoma de Chihuahua. CERTIFICA Que el presente trabajo titulado “Ejercicio físico en la patogenia de la artritis inducida por proteoglicano en ratón”, ha sido realizado bajo mi dirección en el Laboratorio de Investigación PABIOM de la Facultad de Medicina y Ciencias Biomédicas de la Universidad Autónoma de Chihuahua, por la M. en C. Susana Aideé González Chávez para optar por el grado de: DOCTORA EN CIENCIAS DE LA CULTURA FÍSICA Esta es una investigación original que ha sido realizada con rigor ético y científico, por lo que autorizo su presentación ante el grupo de sinodales correspondiente. Para los fines que haya lugar, se extiende la presente a los doce días del mes de Septiembre del dos mil diecisiete. Atentamente Dr. César Francisco Pacheco Tena Doctor en Ciencias Médicas Facultad de Medicina y Ciencias Biomédicas, UACH i UNIVERSIDAD AUTÓNOMA DE CHIHUAHUA FACULTAD DE CIENCIAS DE LA CULTURA FÍSICA SECRETARÍA DE INVESTIGACIÓN Y POSGRADO El presente trabajo “Ejercicio físico en la patogenia de la artritis inducida por proteoglicano en ratón” realizado por la M.
    [Show full text]
  • A Novel Type of SYT/SSX Fusion
    A Novel Type of SYT/SSX Fusion: Methodological and Biological Implications Maria Törnkvist, M.Sc., Bertha Brodin, Ph.D., Armando Bartolazzi, M.D., Ph.D., Olle Larsson, M.D., Ph.D. Department of Cellular and Molecular Tumor Pathology, Cancer Centrum Karolinska, Karolinska Hospital (MT, BB, AB, OL), Stockholm, Sweden; and Department of Pathology, Regina Elena Cancer Institute (AB), Rome, Italy the presence of SYT/SSX transcripts in two cases Synovial sarcoma (SS) is a rare soft-tissue tumor using the proposed RT-PCR approach. Applications that affects children and young adults. It is charac- of optimized RT-PCR can contribute to reduce false- terized by the chromosomal translocation t(X; negative SYT/SSX SS cases reported in literature. 18)(p11.2;q11.2), which results in the fusion of the SYT gene on chromosome 18 with a SSX gene on KEY WORDS: RT-PCR, Synovial sarcoma, SYT/SSX chromosome X. In the majority of cases, SYT is fusion gene, SYT/SSX variants. fused to exon 5 of SSX1 (64%), SSX2 (36%), or, Mod Pathol 2002;15(6):679–685 rarely, SSX4. A novel fusion transcript variant deriv- ing from the fusion of SYT to exon 6 of SSX4 gene Synovial sarcomas (SS) account for 7 to 10% of all (SYT/SSX4v) was found coexpressed in one of the human soft-tissue sarcomas and are mainly located previously reported SYT/SSX4 cases. In the present in the extremities in the vicinity of large joints (1). investigation, we describe a new SS case that was Depending on histomorphological appearance, SSs previously shown to be negative for SYT/SSX1 and are usually subdivided into two major forms, bipha- SYT/SSX2 expression by conventional reverse tran- sic and monophasic.
    [Show full text]
  • Cellular and Molecular Signatures in the Disease Tissue of Early
    Cellular and Molecular Signatures in the Disease Tissue of Early Rheumatoid Arthritis Stratify Clinical Response to csDMARD-Therapy and Predict Radiographic Progression Frances Humby1,* Myles Lewis1,* Nandhini Ramamoorthi2, Jason Hackney3, Michael Barnes1, Michele Bombardieri1, Francesca Setiadi2, Stephen Kelly1, Fabiola Bene1, Maria di Cicco1, Sudeh Riahi1, Vidalba Rocher-Ros1, Nora Ng1, Ilias Lazorou1, Rebecca E. Hands1, Desiree van der Heijde4, Robert Landewé5, Annette van der Helm-van Mil4, Alberto Cauli6, Iain B. McInnes7, Christopher D. Buckley8, Ernest Choy9, Peter Taylor10, Michael J. Townsend2 & Costantino Pitzalis1 1Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Departments of 2Biomarker Discovery OMNI, 3Bioinformatics and Computational Biology, Genentech Research and Early Development, South San Francisco, California 94080 USA 4Department of Rheumatology, Leiden University Medical Center, The Netherlands 5Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology & Immunology Center, Amsterdam, The Netherlands 6Rheumatology Unit, Department of Medical Sciences, Policlinico of the University of Cagliari, Cagliari, Italy 7Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK 8Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), University of Birmingham, Birmingham B15 2WB, UK 9Institute of
    [Show full text]
  • The “Melanoma-Enriched” Microrna Mir-4731-5P Acts As a Tumour Suppressor
    www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 31 Research Paper The “melanoma-enriched” microRNA miR-4731-5p acts as a tumour suppressor Mitchell S. Stark1,2, Lisa N. Tom1, Glen M. Boyle2, Vanessa F. Bonazzi3, H. Peter Soyer1, Adrian C. Herington3, Pamela M. Pollock3, Nicholas K. Hayward2 1Dermatology Research Centre, The University of Queensland, School of Medicine, Translational Research Institute, Brisbane, QLD, Australia 2QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD, Australia 3School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, at The Translational Research Institute, Brisbane, QLD, Australia Correspondence to: Mitchell S. Stark, email: [email protected] Keywords: SSX, microRNA, melanoma, PMP22, miR-4731 Received: May 02, 2015 Accepted: June 01, 2016 Published: June 16, 2016 ABSTRACT We previously identified miR-4731-5p (miR-4731) as a melanoma-enriched microRNA following comparison of melanoma with other cell lines from solid malignancies. Additionally, miR-4731 has been found in serum from melanoma patients and expressed less abundantly in metastatic melanoma tissues from stage IV patients relative to stage III patients. As miR-4731 has no known function, we used biotin-labelled miRNA duplex pull-down to identify binding targets of miR- 4731 in three melanoma cell lines (HT144, MM96L and MM253). Using the miRanda miRNA binding algorithm, all pulled-down transcripts common to the three cell lines (n=1092) had potential to be targets of miR-4731 and gene-set enrichment analysis of these (via STRING v9.1) highlighted significantly associated genes related to the ‘cell cycle’ pathway and the ‘melanosome’. Following miR-4731 overexpression, a selection (n=81) of pull-down transcripts underwent validation using a custom qRT-PCR array.
    [Show full text]
  • Molecular Analyses of Malignant Pleural Mesothelioma
    Molecular Analyses of Malignant Pleural Mesothelioma Shir Kiong Lo National Heart and Lung Institute Imperial College Dovehouse Street London SW3 6LY A thesis submitted for MD (Res) Faculty of Medicine, Imperial College London 2016 1 Abstract Malignant pleural mesothelioma (MPM) is an aggressive cancer that is strongly associated with asbestos exposure. Majority of patients with MPM present with advanced disease and the treatment paradigm mainly involves palliative chemotherapy and best supportive care. The current chemotherapy options are limited and ineffective hence there is an urgent need to improve patient outcomes. This requires better understanding of the genetic alterations driving MPM to improve diagnostic, prognostic and therapeutic strategies. This research aims to gain further insights in the pathogenesis of MPM by exploring the tumour transcriptional and mutational profiles. We compared gene expression profiles of 25 MPM tumours and 5 non-malignant pleura. This revealed differentially expressed genes involved in cell migration, invasion, cell cycle and the immune system that contribute to the malignant phenotype of MPM. We then constructed MPM-associated co-expression networks using weighted gene correlation network analysis to identify clusters of highly correlated genes. These identified three distinct molecular subtypes of MPM associated with genes involved in WNT and TGF-ß signalling pathways. Our results also revealed genes involved in cell cycle control especially the mitotic phase correlated significantly with poor prognosis. Through exome analysis of seven paired tumour/blood and 29 tumour samples, we identified frequent mutations in BAP1 and NF2. Additionally, the mutational profile of MPM is enriched with genes encoding FAK, MAPK and WNT signalling pathways.
    [Show full text]
  • Identification of Key Pathways and Genes in Dementia Via Integrated Bioinformatics Analysis
    bioRxiv preprint doi: https://doi.org/10.1101/2021.04.18.440371; this version posted July 19, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Identification of Key Pathways and Genes in Dementia via Integrated Bioinformatics Analysis Basavaraj Vastrad1, Chanabasayya Vastrad*2 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karnataka, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India bioRxiv preprint doi: https://doi.org/10.1101/2021.04.18.440371; this version posted July 19, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract To provide a better understanding of dementia at the molecular level, this study aimed to identify the genes and key pathways associated with dementia by using integrated bioinformatics analysis. Based on the expression profiling by high throughput sequencing dataset GSE153960 derived from the Gene Expression Omnibus (GEO), the differentially expressed genes (DEGs) between patients with dementia and healthy controls were identified. With DEGs, we performed a series of functional enrichment analyses. Then, a protein–protein interaction (PPI) network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network was constructed, analyzed and visualized, with which the hub genes miRNAs and TFs nodes were screened out. Finally, validation of hub genes was performed by using receiver operating characteristic curve (ROC) analysis.
    [Show full text]
  • WO 2012/174282 A2 20 December 2012 (20.12.2012) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/174282 A2 20 December 2012 (20.12.2012) P O P C T (51) International Patent Classification: David [US/US]; 13539 N . 95th Way, Scottsdale, AZ C12Q 1/68 (2006.01) 85260 (US). (21) International Application Number: (74) Agent: AKHAVAN, Ramin; Caris Science, Inc., 6655 N . PCT/US20 12/0425 19 Macarthur Blvd., Irving, TX 75039 (US). (22) International Filing Date: (81) Designated States (unless otherwise indicated, for every 14 June 2012 (14.06.2012) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, English (25) Filing Language: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, Publication Language: English DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, (30) Priority Data: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, 61/497,895 16 June 201 1 (16.06.201 1) US MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 61/499,138 20 June 201 1 (20.06.201 1) US OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, 61/501,680 27 June 201 1 (27.06.201 1) u s SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, 61/506,019 8 July 201 1(08.07.201 1) u s TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
    [Show full text]
  • Product Sheet CA1235
    SSX2 Antibody Applications: WB, IHC Detected MW: 25 kDa Cat. No. CA1235 Species & Reactivity: Human, Mouse, Rat Isotype: Rabbit IgG BACKGROUND SSX2 belongs to the family of highly homologous based immunotherapy.4 Two transcript variants synovial sarcoma X (SSX) breakpoint proteins. encoding distinct isoforms have been identified for The SSX gene family is composed of at least 9 SSX2 gene. SSX2 is thought to function in functional and highly homologous members and development and germ line cells as a repressive shown to be located on chromosome X. The gene regulator. Its control of gene expression is normal testis expresses SSX1, 2, 3, 4, 5, and 7, believed to be epigenetic in nature and to involve but not 6, 8, or 9. In tumors, SSX1, 2, and 4 are chromatin modification and remodeling. It is most expressed at varying frequencies, whereas SSX3, likely mediated by the association of SSX2 with the 5, and 6 are rarely expressed. In addition, no Polycomb gene silencing complex at the SSXRD expression of SSX8, or 9 has been observed. SSX1 domain. Polycomb silencing involves chromatin to SSX5 are also normally expressed in thyroid.1 compaction, DNA methylation, repressive histone The SSX family shares nucleotide homology modifications and inaccessibility of promoter ranging from 88% to 95%, and amino acid regions to transcription machineries. Other SSX2- homology ranging from 77% to 91%. The NH2- interacting partners include the LIM homeobox terminal moieties of the SSX proteins exhibit protein LHX4, a Ras-like GTPase Interactor, homology to the Krüppel-associated box (KRAB) RAB3IP thought to be involved in vesicular domain, a domain that is known to be involved in transport, and SSX2IP, a putative cell transcriptional repression.
    [Show full text]
  • Genome-Wide Analysis of Cancer/Testis Gene Expression
    Genome-wide analysis of cancer/testis gene expression Oliver Hofmanna,b,1, Otavia L. Caballeroc, Brian J. Stevensond,e, Yao-Tseng Chenf, Tzeela Cohenc, Ramon Chuac, Christopher A. Maherb, Sumir Panjib, Ulf Schaeferb, Adele Krugerb, Minna Lehvaslaihob, Piero Carnincig,h, Yoshihide Hayashizakig,h, C. Victor Jongeneeld,e, Andrew J. G. Simpsonc, Lloyd J. Oldc,1, and Winston Hidea,b aDepartment of Biostatistics, Harvard School of Public Health, 655 Huntington Avenue, SPH2, 4th Floor, Boston, MA 02115; bSouth African National Bioinformatics Institute, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa; cLudwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; dLudwig Institute for Cancer Research, Lausanne Branch, 1015 Lausanne, Switzerland; eSwiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; fWeill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021; gGenome Exploration Research Group (Genome Network Project Core Group), RIKEN Genomic Sciences Center (GSC), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan; and hGenome Science Laboratory, Discovery Research Institute, RIKEN Wako Institute, 2-1 Hirosawa, Wako, Saitama, 3510198, Japan Contributed by Lloyd J. Old, October 28, 2008 (sent for review June 6, 2008) Cancer/Testis (CT) genes, normally expressed in germ line cells but expression profile information frequently limited to the original also activated in a wide range of cancer types, often encode defining articles. In some cases, e.g., ACRBP, the original antigens that are immunogenic in cancer patients, and present CT-restricted expression in normal tissues could not be con- potential for use as biomarkers and targets for immunotherapy.
    [Show full text]
  • Genomic and Expression Profiling of Human Spermatocytic Seminomas: Primary Spermatocyte As Tumorigenic Precursor and DMRT1 As Candidate Chromosome 9 Gene
    Research Article Genomic and Expression Profiling of Human Spermatocytic Seminomas: Primary Spermatocyte as Tumorigenic Precursor and DMRT1 as Candidate Chromosome 9 Gene Leendert H.J. Looijenga,1 Remko Hersmus,1 Ad J.M. Gillis,1 Rolph Pfundt,4 Hans J. Stoop,1 Ruud J.H.L.M. van Gurp,1 Joris Veltman,1 H. Berna Beverloo,2 Ellen van Drunen,2 Ad Geurts van Kessel,4 Renee Reijo Pera,5 Dominik T. Schneider,6 Brenda Summersgill,7 Janet Shipley,7 Alan McIntyre,7 Peter van der Spek,3 Eric Schoenmakers,4 and J. Wolter Oosterhuis1 1Department of Pathology, Josephine Nefkens Institute; Departments of 2Clinical Genetics and 3Bioinformatics, Erasmus Medical Center/ University Medical Center, Rotterdam, the Netherlands; 4Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; 5Howard Hughes Medical Institute, Whitehead Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts; 6Clinic of Paediatric Oncology, Haematology and Immunology, Heinrich-Heine University, Du¨sseldorf, Germany; 7Molecular Cytogenetics, Section of Molecular Carcinogenesis, The Institute of Cancer Research, Sutton, Surrey, United Kingdom Abstract histochemistry, DMRT1 (a male-specific transcriptional regulator) was identified as a likely candidate gene for Spermatocytic seminomas are solid tumors found solely in the involvement in the development of spermatocytic seminomas. testis of predominantly elderly individuals. We investigated these tumors using a genome-wide analysis for structural and (Cancer Res 2006; 66(1): 290-302) numerical chromosomal changes through conventional kar- yotyping, spectral karyotyping, and array comparative Introduction genomic hybridization using a 32 K genomic tiling-path Spermatocytic seminomas are benign testicular tumors that resolution BAC platform (confirmed by in situ hybridization).
    [Show full text]
  • Investigating the Effect of Chronic Activation of AMP-Activated Protein
    Investigating the effect of chronic activation of AMP-activated protein kinase in vivo Alice Pollard CASE Studentship Award A thesis submitted to Imperial College London for the degree of Doctor of Philosophy September 2017 Cellular Stress Group Medical Research Council London Institute of Medical Sciences Imperial College London 1 Declaration I declare that the work presented in this thesis is my own, and that where information has been derived from the published or unpublished work of others it has been acknowledged in the text and in the list of references. This work has not been submitted to any other university or institute of tertiary education in any form. Alice Pollard The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives license. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the license terms of this work. 2 Abstract The prevalence of obesity and associated diseases has increased significantly in the last decade, and is now a major public health concern. It is a significant risk factor for many diseases, including cardiovascular disease (CVD) and type 2 diabetes. Characterised by excess lipid accumulation in the white adipose tissue, which drives many associated pathologies, obesity is caused by chronic, whole-organism energy imbalance; when caloric intake exceeds energy expenditure. Whilst lifestyle changes remain the most effective treatment for obesity and the associated metabolic syndrome, incidence continues to rise, particularly amongst children, placing significant strain on healthcare systems, as well as financial burden.
    [Show full text]
  • Structural Variant Selection for High-Altitude Adaptation Using Single-Molecule 2 Long-Read Sequencing
    bioRxiv preprint doi: https://doi.org/10.1101/2021.03.27.436702; this version posted March 27, 2021. 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 Structural variant selection for high-altitude adaptation using single-molecule 2 long-read sequencing 3 Jinlong Shi1,2,4*, Zhilong Jia1,2,3*, Xiaojing Zhao2*, Jinxiu Sun4*, Fan Liang5*, Minsung Park5*, Chenghui Zhao1, 4 Xiaoreng Wang2, Qi Chen4, Xinyu Song2,3, Kang Yu1, Qian Jia2, Depeng Wang5, Yuhui Xiao5, Yinzhe Liu5, Shijing 5 Wu1, Qin Zhong2, Jue Wu2, Saijia Cui2, Xiaochen Bo6, Zhenzhou Wu7, Manolis Kellis8,9, Kunlun He1,2# 6 1. Key Laboratory of Biomedical Engineering and Translational Medicine, Ministry of Industry and Information 7 Technology, Chinese PLA General Hospital, Beijing, China. 8 2. Beijing Key Laboratory for Precision Medicine of Chronic Heart Failure, Chinese PLA General Hospital, Beijing, 9 China. 10 3. Research Center of Medical Artificial Intelligence, Chinese PLA General Hospital, Beijing, China. 11 4. Research Center of Medical Big Data, Chinese PLA General Hospital, Beijing, China. 12 5. GrandOmics Biosciences Inc, Beijing, China. 13 6. Beijing Institute of Radiation Medicine, Beijing, China. 14 7. BioMind Inc, Beijing, China. 15 8. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, 16 MA, USA. 17 9. Broad Institute of MIT and Harvard, Cambridge, MA, USA. 18 *These authors contributed equally to this work. 19 #Corresponding author: [email protected] 20 21 Abstract: (150 words) 22 Structural variants (SVs) can be important drivers of human adaptation with strong effects, but previous studies 23 have focused primarily on common variants with weak effects.
    [Show full text]