DOCSLIB.ORG

Identification of Copy Number Variants Associated with Renal Agenesis Using Array-Based Comparative Genomic Hybridization

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Identification of Copy Number Variants Associated with Renal Agenesis Using Array-Based Comparative Genomic Hybridization - Identification of copy number variants associated with renal agenesis using array-based comparative genomic hybridization Chen, Beichen https://iro.uiowa.edu/discovery/delivery/01IOWA_INST:ResearchRepository/12730670610002771?l#13730820860002771 Chen, B. (2010). Identification of copy number variants associated with renal agenesis using array-based comparative genomic hybridization [University of Iowa]. https://doi.org/10.17077/etd.noml5jhf https://iro.uiowa.edu Copyright 2010 Beichen Chen Downloaded on 2021/10/06 12:15:40 -0500 - IDENTIFICATION OF COPY NUMBER VARIANTS ASSOCIATED WITH RENAL AGENESIS USING ARRAY-BASED COMPARATIVE GENOMIC HYBRIDIZATION by Beichen Chen A thesis submitted in partial fulfillment of the requirements for the Master of Science degree in Biology in the Graduate College of The University of Iowa July 2010 Thesis Supervisor: Assistant Professor John R. Manak Graduate College The University of Iowa Iowa City, Iowa CERTIFICATE OF APPROVAL ___________________________________ MASTER’S THESIS ________________ This is to certify that the Master’s thesis of Beichen Chen has been approved by the Examining Committee for the thesis requirement for the Master of Science degree in Biology at the July 2010 graduation. Thesis Committee: __________________________________ John Manak, Thesis Supervisor __________________________________ Sarit Smolikove __________________________________ Polly Ferguson ACKNOWLEDGMENTS I would like to thank all members in Dr. Manak’s lab, especially to Steven Butcher, Xiaojing Hong and Riley Boland who help me for numerous times in my experiments. Also, thanks to Dr. Brophy and Jason Clarke who provide patients’ DNA samples and useful information for my projects. Thanks to Song Yi and Nidhi Sahni for their nice help in thesis preparation and writing. Thanks to my advisor, Dr. Manak, for his insightful instructions and profound experience in research during my 2-year study in the lab. And in the end, to my parents who always support me under any circumstances. For the love and help from all of you. ii ABSTRACT Copy Number Variants (CNVs) are defined as DNA segments of 1kb or more in length and present in a variable number of copies in the human genome. It has been recently shown that many human genetic diseases including organ malformations are caused by CNVs in a patient’s genome. However, the genetic and molecular basis for Renal Agenesis (RA), which is a medical condition whereby unilateral or bilateral fetal kidneys fail to develop, has not yet been extended to CNV studies. By using array-based Comparative Genomic Hybridization, we are analyzing DNA from patients who have RA in order to identify CNVs that are causative for RA; genes within the CNVs will then be assessed for their potential involvement in RA by altering their dose in Xenopus embryos. iii TABLE OF CONTENTS LIST OF TABLES……………………………………………...………………………... v LIST OF FIGURES………………………………………………………………………vi INTRODUCTION………………………….……………...……………………………...1 MATERIALS AND METHODS………………………………………………………….6 Genomic DNA preparation………………………………………………………..6 DNA labeling………………….…….………………………………………….....6 Array-based CGH………………………..………………………………...……...7 NimbleScan 2.5 Analysis..……………….………………………………...……...7 RESULTS AND DISCUSSION…………………………………………...……………...8 CONCLUSION AND FUTURE STUDIES……………………………………………..44 REFERENCES………………………………………….……………………………….45 iv LIST OF TABLES Table 1. Novel amplifications and deletions detected in RA patients ....................................12 2. 27 CNVs which contain genes or part of gene .........................................................13 3. Genes and their functions contained within the 27 novel CNVs..............................14 4. RA Candidate Genes.................................................................................................26 5. Novel CNVs that do not cover genes and their regulatory elements, ETSs andConservedregions................................................................................................30 6. Novel CNVs with regulatory elements or adjacent genes that are involvedin renal diseases ............................................................................................................34 7. Genes involved in kidney development....................................................................35 8. Race and origin of members who share similar deletion on chromosome 13 ..........39 v LIST OF FIGURES Figure 1. Copy Number Variants. ..............................................................................................4 2. Non-allelic homologous recombination can generate duplications and deletions......................................................................................................................5 3. 2.1M segMNT plot of an amplification on chromosome 14 51,005,999- 54,929,999 in patient JCA27II.1A............................................................................27 4. SignalMap Analysis of the amplification region in Patient JCA27II.1A.. ...............28 5. Regulatory elements, ESTs, Conserved region and repeated sequences within chr13: 57,054,000-57,090,000..................................................................................40 6. Regulatory elements, ESTs, Conserved region and repeated sequences within chr5: 109,301,999-109,385,999................................................................................42 vi 1 INTRODUCTION Renal agenesis (RA) is a congenital kidney malformation disease in which one (unilateral RA) or both (bilateral RA) kidneys fail to develop in a fetus. In children, RA is one of the leading causes of end stage renal disease (ESRD), which alone accounts for $15 billion of annual health care expenditure in the U.S. (USRDS, 1999). Occurrence of Unilateral Renal Agenesis (URA) is 1/1000, while Bilateral Renal Agenesis (BRA) occurs at a frequency of 1/3000-1/5000 (Norwood and Chevalier, 2003; Yalavarthy and Parikh, 2003); the latter is almost always fatal at birth because of the presence of the oligohydramnios sequence in which lack of amniotic fluid results in fatal problems for the fetus (Potter, 1965; Potter 1946). Combining our pedigree analysis (Clarke and Brophy, unpublished data) with current literature, BRA appears to have both autosomal dominant and autosomal recessive hereditary forms (Simone, 2007). Moreover, more than 70 different clinical conditions exist where RA has been identified as a component (Sanna-Cherchi et al., 2007; Kerecuk et al., 2008), and phenotypes of RA, particularly URA, are widely heterogeneous (Yalavarthy and Parikh, 2003). Despite the importance and complexity of RA, researchers still lack an understanding of the precise genetic process leading to RA. There are some genes that have been shown to be associated with RA or pediatric congenital anomalies of the kidney and urinary tract (CAKUT), which is a larger category of renal diseases including RA. These genes, including PAX2, RET, EYA1, PBX1, SIX2, are either derived from animal studies or have been found mutated in human renal syndrome patients (Torres et al., 1995, Schuchardt et al., 1994, Johnson et al.,1999, Schnabel et al., 2003, Simone, 2007). However, due to its complexity, other genes are likely to play a role in RA. Furthermore, human RA has been characterized as a multifactorial disorder with an apparent genetic contribution (Yalavarthy and Parikh, 2003). By understanding its genetic basis, medications and therapy for RA could be improved. Copy number variants (CNVs) are defined as abnormal DNA segments of 1kb or greater that are present in a variable number of copies in the human genome; they are likely to be one of 2 the major factors which induce RA (Fanciulli et al., 2009) (Figure 1). CNVs could either be inherited or de novo genomic rearrangements such as deletions, amplifications and translocations. These amplifications and deletions are usually caused by Non-Allelic Homologous Recombination (NAHR) in which non-allelic repeat sequences pair with each other and recombination takes place between the repeated sequences (Figure 2). Regardless of origin, genomic regions encompassed by CNVs can contain one to hundreds of genes, as well as other functional elements (Redon, 2006). If CNVs contain genes that have important biological functions, their presence could potentially lead to disease. In the last 5 years, the number of diseases identified as being induced by CNVs include various cancers (Kallioniemi, 2008; Lenz et al., 2008), nervous system diseases (Walsh et al., 2008; Dibbens et al., 2009; Glessner et al., 2009; Mefford et al., 2009a, b), and congenital malformation and birth defects (Greenway et al., 2009; Lu et al., 2008; Osoegawa et al., 2008; Shi et al., 2009). One study predicts that at least 10% of sporadic cases of tetralogy of Fallot, a severe congenital organ malformation, are caused by CNVs (Greenway et al., 2009). However, to date, relevant studies for human RA focused either on single nucleotide polymorphisms, gene mutations or linkage analysis, whereas studies of the role of CNVs in RA have been absent. We are seeking to identify causative CNVs in RA patients in order to ultimately identify the genes within CNVs that are associated with RA. To identify CNVs, we use microarray-based Comparative Genomic Hybridization (aCGH). aCGH has identified CNVs associated with diseases such as immunodeficiency virus (HIV), auto immune disease and a spectrum of neuropsychiatric disorders (Gonzales, 2005; Aitman, 2006; Fanciulli, 2007; Willcocks, 2008) as well as the various diseases/disorders
Load more

Recommended publications
  • Genetic Variations in the PSMA6 and PSMC6 Proteasome Genes Are Associated with Multiple Sclerosis and Response to Interferon‑Β Therapy in Latvians
    EXPERIMENTAL AND THERAPEUTIC MEDICINE 21: 478, 2021 Genetic variations in the PSMA6 and PSMC6 proteasome genes are associated with multiple sclerosis and response to interferon‑β therapy in Latvians NATALIA PARAMONOVA1, JOLANTA KALNINA1, KRISTINE DOKANE1, KRISTINE DISLERE1, ILVA TRAPINA1, TATJANA SJAKSTE1 and NIKOLAJS SJAKSTE1,2 1Genomics and Bioinformatics, Institute of Biology of The University of Latvia; 2Department of Medical Biochemistry of The University of Latvia, LV‑1004 Riga, Latvia Received July 8, 2020; Accepted December 8, 2020 DOI: 10.3892/etm.2021.9909 Abstract. Several polymorphisms in genes related to the Introduction ubiquitin‑proteasome system exhibit an association with pathogenesis and prognosis of various human autoimmune Multiple sclerosis (MS) is a lifelong demyelinating disease of diseases. Our previous study reported the association the central nervous system. The clinical onset of MS tends to between multiple sclerosis (MS) and the PSMA3‑rs2348071 be between the second and fourth decade of life. Similarly to polymorphism in the Latvian population. The current study other autoimmune diseases, women are affected 3‑4 times more aimed to evaluate the PSMA6 and PSMC6 genetic variations, frequently than men (1). About 10% of MS patients experience their interaction between each other and with the rs2348071, a primary progressive MS form characterized by the progres‑ on the susceptibility to MS risk and response to therapy in sion of neurological disability from the onset. In about 90% the Latvian population. PSMA6‑rs2277460, ‑rs1048990 and of MS patients, the disease undergoes the relapse‑remitting PSMC6‑rs2295826, ‑rs2295827 were genotyped in the MS MS course (RRMS); in most of these patients, the condition case/control study and analysed in terms of genotype‑protein acquires secondary progressive course (SPMS) (2).
    [Show full text]
  • TRANSCRIPTIONAL REGULATION of Hur in RENAL STRESS
    TRANSCRIPTIONAL REGULATION OF HuR IN RENAL STRESS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Sudha Suman Govindaraju Graduate Program in Biochemistry The Ohio State University 2014 Dissertation Committee: Dr. Beth S. Lee, Ph.D., Advisor Dr. Kathleen Boris-Lawrie, Ph.D. Dr. Sissy M. Jhiang, Ph.D. Dr. Arthur R. Strauch, Ph.D Abstract HuR is a ubiquitously expressed RNA-binding protein that affects the post- transcriptional life of thousands of cellular mRNAs by regulating transcript stability and translation. HuR can post-transcriptionally regulate gene expression and modulate cellular responses to stress, differentiation, proliferation, apoptosis, senescence, inflammation, and the immune response. It is an important mediator of survival during cellular stress, but when inappropriately expressed, can promote oncogenic transformation. Not surprisingly, the expression of HuR itself is tightly regulated at multiple transcriptional and post-transcriptional levels. Previous studies demonstrated the existence of two alternate HuR transcripts that differ in their 5’ untranslated regions and have markedly different translatabilities. These forms were also found to be reciprocally expressed following cellular stress in kidney proximal tubule cell lines, and the shorter, more readily translatable variant was shown to be regulated by Smad 1/5/8 pathway and bone morphogenetic protein-7 (BMP-7) signaling. In this study, the factors that promote transcription of the longer alternate form were identified. NF-κB was shown to be important for expression of the long HuR mRNA, as was a newly identified region with potential for binding the Sp/KLF families of transcription factors.
    [Show full text]
  • NPI-0052 and Γ-Radiation Induce a Synergistic Apoptotic Effect In
    Frisira et al. Cell Death and Disease (2019) 10:785 https://doi.org/10.1038/s41419-019-2026-y Cell Death & Disease ARTICLE Open Access NPI-0052 and γ-radiation induce a synergistic apoptoticeffectinmedulloblastoma Eleni Frisira1, Fatima Rashid1,SwastinaNathVarma2,SaraBadodi1, Valentine Ayodele Benjamin-Ombo1, David Michod 2 and Maria Victoria Niklison-Chirou 1 Abstract Medulloblastoma (MB) is the most common malignant solid paediatric brain tumour. The standard treatment for MB is surgical resection of the tumour, radiation and chemotherapy. This therapy is associated with high morbidity and adverse side effects. Hence, more targeted and less toxic therapies are vitally needed to improve the quality of life of survivors. NPI-0052 is a novel proteasome inhibitor that irreversibly binds the 20S proteasome subunit. This compound has anti-tumour activity in metastatic solid tumours, glioblastoma and multiple myeloma with a good safety profile. Importantly, NPI-0052 has a lipophilic structure and can penetrate the blood–brain barrier, making it a suitable treatment for brain tumours. In the present study, we performed an in silico gene expression analysis to evaluate the proteasome subunit expression in MB. To evaluate the anticancer activity of NPI-0052, we used a range of MB patient- derived MB cells and cell lines. The synergistic cell death of NPI-0052 with γ-radiation was evaluated in tumour organoids derived from patient-derived MB cells. We show that high expression of proteasome subunits is a poor prognostic factor for MB patients. Also, our preclinical work demonstrated that NPI-0052 can inhibit proteasome activity and activate apoptosis in MB cells. Moreover, we observe that NPI-0052 has a synergistic apoptotic effect with γ-radiation, a component of the current MB therapy.
    [Show full text]
  • Transcriptional Control of Tissue-Resident Memory T Cell Generation
    Transcriptional control of tissue-resident memory T cell generation Filip Cvetkovski Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2019 © 2019 Filip Cvetkovski All rights reserved ABSTRACT Transcriptional control of tissue-resident memory T cell generation Filip Cvetkovski Tissue-resident memory T cells (TRM) are a non-circulating subset of memory that are maintained at sites of pathogen entry and mediate optimal protection against reinfection. Lung TRM can be generated in response to respiratory infection or vaccination, however, the molecular pathways involved in CD4+TRM establishment have not been defined. Here, we performed transcriptional profiling of influenza-specific lung CD4+TRM following influenza infection to identify pathways implicated in CD4+TRM generation and homeostasis. Lung CD4+TRM displayed a unique transcriptional profile distinct from spleen memory, including up-regulation of a gene network induced by the transcription factor IRF4, a known regulator of effector T cell differentiation. In addition, the gene expression profile of lung CD4+TRM was enriched in gene sets previously described in tissue-resident regulatory T cells. Up-regulation of immunomodulatory molecules such as CTLA-4, PD-1, and ICOS, suggested a potential regulatory role for CD4+TRM in tissues. Using loss-of-function genetic experiments in mice, we demonstrate that IRF4 is required for the generation of lung-localized pathogen-specific effector CD4+T cells during acute influenza infection. Influenza-specific IRF4−/− T cells failed to fully express CD44, and maintained high levels of CD62L compared to wild type, suggesting a defect in complete differentiation into lung-tropic effector T cells.
    [Show full text]
  • Suppression of Cytokine Signaling by SOCS3: Characterization of the Mode of Inhibition and the Basis of Its Specificity
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Immunity Article Suppression of Cytokine Signaling by SOCS3: Characterization of the Mode of Inhibition and the Basis of Its Specificity Jeffrey J. Babon,1,2,5,* Nadia J. Kershaw,1,3,5 James M. Murphy,1,2,5 Leila N. Varghese,1,2 Artem Laktyushin,1 Samuel N. Young,1 Isabelle S. Lucet,4 Raymond S. Norton,1,2,6 and Nicos A. Nicola1,2,* 1Walter and Eliza Hall Institute of Medical Research, 1G Royal Pde, Parkville, 3052, VIC, Australia 2The University of Melbourne, Royal Parade, Parkville, 3050, VIC, Australia 3Ludwig Institute for Cancer Research, Royal Pde, Parkville, 3050, VIC, Australia 4Monash University, Wellington Rd, Clayton, 3800, VIC, Australia 5These authors contributed equally to this work 6Present address: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Australia *Correspondence: [email protected] (J.J.B.), [email protected] (N.A.N.) DOI 10.1016/j.immuni.2011.12.015 SUMMARY Genetic deletion of each individual JAK leads to various immunological and hematopoietic defects; however, aberrant Janus kinases (JAKs) are key effectors in controlling activation of JAKs can be likewise pathological. Three myelopro- immune responses and maintaining hematopoiesis. liferative disorders (polycythemia vera, essential thrombocythe- SOCS3 (suppressor of cytokine signaling-3) is a mia, and primary myelofibrosis) are caused by a single point major regulator of JAK signaling and here we investi- mutation in JAK2 (JAK2V617F)(James et al., 2005; Levine et al., gate the molecular basis of its mechanism of action.
    [Show full text]
  • Low Dose and Low Dose-Rate Radiation Effects and Models
    Forty-Fourth Annual Meeting Program Low Dose and Low Dose-Rate Radiation Effects and Models April 14–15, 2008 Bethesda North Marriott Hotel & Conference Center 5701 Marinelli Road North Bethesda, MD 20852 On the cover: • top: Two nuclei have each been “hit” by three alpha particles from a microbeam and show activated γH2AX foci at the site of the traversal. • center: Chromosome painting technology makes it possible to identify each human chromosome and characterize the number, location and types of aberrations produced by ionizing radiation. • bottom: Measuring the frequency of micronuclei provides a rapid measure of cytogenetic damage, which increases as a function of radiation dose. Introduction Low Dose and Low Dose-Rate Radiation Effects and Models Forty-Fourth Annual Meeting of the National Council on Radiation Protection and Measurements (NCRP) Potential human health effects of low doses of ionizing models of the biological responses and human health radiation such as those experienced in occupational impacts of exposure to low doses of radiation. The and medical exposures are of great contemporary meeting will feature presentations by international interest. Considerable debate exists over the applica- experts on the topics of (1) molecular, cellular, tissue, bility of a linear-nonthreshold model for characterizing and laboratory animal studies on the effects of expo- the biological responses and health effects of expo- sure to low dose and low dose-rate radiation, (2) sure to low radiation doses, and alternative models results of epidemiological studies on human health have been proposed. A related subject of interest and effects of low radiation doses in occupational, medical debate is the effect of the rate of delivery of radiation and other exposure scenarios, (3) potential impacts of doses on the biological and health outcomes of expo- these findings on future regulatory guidance and pub- sure.
    [Show full text]
  • 1714 Gene Comprehensive Cancer Panel Enriched for Clinically Actionable Genes with Additional Biologically Relevant Genes 400-500X Average Coverage on Tumor
    xO GENE PANEL 1714 gene comprehensive cancer panel enriched for clinically actionable genes with additional biologically relevant genes 400-500x average coverage on tumor Genes A-C Genes D-F Genes G-I Genes J-L AATK ATAD2B BTG1 CDH7 CREM DACH1 EPHA1 FES G6PC3 HGF IL18RAP JADE1 LMO1 ABCA1 ATF1 BTG2 CDK1 CRHR1 DACH2 EPHA2 FEV G6PD HIF1A IL1R1 JAK1 LMO2 ABCB1 ATM BTG3 CDK10 CRK DAXX EPHA3 FGF1 GAB1 HIF1AN IL1R2 JAK2 LMO7 ABCB11 ATR BTK CDK11A CRKL DBH EPHA4 FGF10 GAB2 HIST1H1E IL1RAP JAK3 LMTK2 ABCB4 ATRX BTRC CDK11B CRLF2 DCC EPHA5 FGF11 GABPA HIST1H3B IL20RA JARID2 LMTK3 ABCC1 AURKA BUB1 CDK12 CRTC1 DCUN1D1 EPHA6 FGF12 GALNT12 HIST1H4E IL20RB JAZF1 LPHN2 ABCC2 AURKB BUB1B CDK13 CRTC2 DCUN1D2 EPHA7 FGF13 GATA1 HLA-A IL21R JMJD1C LPHN3 ABCG1 AURKC BUB3 CDK14 CRTC3 DDB2 EPHA8 FGF14 GATA2 HLA-B IL22RA1 JMJD4 LPP ABCG2 AXIN1 C11orf30 CDK15 CSF1 DDIT3 EPHB1 FGF16 GATA3 HLF IL22RA2 JMJD6 LRP1B ABI1 AXIN2 CACNA1C CDK16 CSF1R DDR1 EPHB2 FGF17 GATA5 HLTF IL23R JMJD7 LRP5 ABL1 AXL CACNA1S CDK17 CSF2RA DDR2 EPHB3 FGF18 GATA6 HMGA1 IL2RA JMJD8 LRP6 ABL2 B2M CACNB2 CDK18 CSF2RB DDX3X EPHB4 FGF19 GDNF HMGA2 IL2RB JUN LRRK2 ACE BABAM1 CADM2 CDK19 CSF3R DDX5 EPHB6 FGF2 GFI1 HMGCR IL2RG JUNB LSM1 ACSL6 BACH1 CALR CDK2 CSK DDX6 EPOR FGF20 GFI1B HNF1A IL3 JUND LTK ACTA2 BACH2 CAMTA1 CDK20 CSNK1D DEK ERBB2 FGF21 GFRA4 HNF1B IL3RA JUP LYL1 ACTC1 BAG4 CAPRIN2 CDK3 CSNK1E DHFR ERBB3 FGF22 GGCX HNRNPA3 IL4R KAT2A LYN ACVR1 BAI3 CARD10 CDK4 CTCF DHH ERBB4 FGF23 GHR HOXA10 IL5RA KAT2B LZTR1 ACVR1B BAP1 CARD11 CDK5 CTCFL DIAPH1 ERCC1 FGF3 GID4 HOXA11 IL6R KAT5 ACVR2A
    [Show full text]
  • Supplementary Material DNA Methylation in Inflammatory Pathways Modifies the Association Between BMI and Adult-Onset Non- Atopic
    Supplementary Material DNA Methylation in Inflammatory Pathways Modifies the Association between BMI and Adult-Onset Non- Atopic Asthma Ayoung Jeong 1,2, Medea Imboden 1,2, Akram Ghantous 3, Alexei Novoloaca 3, Anne-Elie Carsin 4,5,6, Manolis Kogevinas 4,5,6, Christian Schindler 1,2, Gianfranco Lovison 7, Zdenko Herceg 3, Cyrille Cuenin 3, Roel Vermeulen 8, Deborah Jarvis 9, André F. S. Amaral 9, Florian Kronenberg 10, Paolo Vineis 11,12 and Nicole Probst-Hensch 1,2,* 1 Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland; [email protected] (A.J.); [email protected] (M.I.); [email protected] (C.S.) 2 Department of Public Health, University of Basel, 4001 Basel, Switzerland 3 International Agency for Research on Cancer, 69372 Lyon, France; [email protected] (A.G.); [email protected] (A.N.); [email protected] (Z.H.); [email protected] (C.C.) 4 ISGlobal, Barcelona Institute for Global Health, 08003 Barcelona, Spain; [email protected] (A.-E.C.); [email protected] (M.K.) 5 Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain 6 CIBER Epidemiología y Salud Pública (CIBERESP), 08005 Barcelona, Spain 7 Department of Economics, Business and Statistics, University of Palermo, 90128 Palermo, Italy; [email protected] 8 Environmental Epidemiology Division, Utrecht University, Institute for Risk Assessment Sciences, 3584CM Utrecht, Netherlands; [email protected] 9 Population Health and Occupational Disease, National Heart and Lung Institute, Imperial College, SW3 6LR London, UK; [email protected] (D.J.); [email protected] (A.F.S.A.) 10 Division of Genetic Epidemiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; [email protected] 11 MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, W2 1PG London, UK; [email protected] 12 Italian Institute for Genomic Medicine (IIGM), 10126 Turin, Italy * Correspondence: [email protected]; Tel.: +41-61-284-8378 Int.
    [Show full text]
  • The Genomics of Oral Poliovirus Vaccine
    THE GENOMICS OF ORAL POLIOVIRUS VACCINE RESPONSE IN BANGLADESHI INFANTS by Genevieve L. Wojcik, MHS A dissertation submitted to the Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland, USA October 2013 © Genevieve L. Wojcik All Rights Reserved Abstract The success of Oral Poliovirus Vaccine (OPV) in eradicating poliovirus has set an example for the immense potential of oral vaccines in preventing enteric infections. It is widely considered the standard for oral vaccines aiming to elicit a mucosal immune response. Despite being validated in diverse populations worldwide, there still remain some individuals that fail to mount an adequate response to vaccination with OPV. It has been hypothesized that this may be due to host genetics, as the heritability is estimated to be high (60%) and there have been ethnic differences in response. To address this question we conducted a genome-wide association study (GWAS) in 357 Bangladeshi children comparing individuals that fail to mount an immune response to high responders of OPV. Four different approaches were conducted to elucidate genetic risk loci: (1) a traditional GWAS analysis, (2) a correlation of the GWAS results with signatures of positive selection, (3) an application of gene-level methods to the GWAS results, and (4) an application of pathway-level methods to the GWAS results. Because there is no consensus as to the best gene- and pathway-level methods, a simulation experiment was conducted to systematically evaluate their relative performance. The traditional GWAS assessed the association of 6.6 million single nucleotide polymorphisms (SNPs) across the human genome, adjusted for stunting (height-for-age Z-score (HAZ) < -2).
    [Show full text]
  • SOCS4 Expressed by Recombinant HSV Protects Against Cytokine Storm in a Mouse Model
    ONCOLOGY REPORTS 41: 1509-1520, 2019 SOCS4 expressed by recombinant HSV protects against cytokine storm in a mouse model SHUQI REN1, XIAOQING CHEN2, RONGQUAN HUANG3, GRACE GUOYING ZHOU2,4 and ZHUQING YUAN1 1Department of Microbiology and Immunology, Guangzhou Medical University, Guangzhou, Guangdong 510182; 2Immvira Co., Ltd., Shenzhen International Institute for Biomedical Research, Shenzhen, Guangdong 518116; 3Department of Pathology; 4School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510182, P.R. China Received June 20, 2018; Accepted November 30, 2018 DOI: 10.3892/or.2018.6935 Abstract. Oncolytic viruses are genetically engineered viruses be a useful regulator to inhibit cytokine overproduction, and designed for the treatment of solid tumors, and are often coupled that HSV-SOCS4 may provide a possible solution to control with the antitumor immunity of the host. The challenge of cytokine storm and its consequences following induction by using oncolytic herpes simplex virus (oHSV) as an efficacious oncolytic virus treatment. oncolytic agent is the potential host tissue damage caused by the production of a range of cytokines following intratumoral Introduction oHSV injection. An HSV-suppressor of cytokine signaling 4 (SOCS4) recombinant virus was created to investigate whether Oncolytic viruses (OVs) are genetically engineered viruses it inhibits cytokine storm. Recombinant HSV-SOCS4 and that selectively replicate in and kill cancer cells, and represent HSV-1(F) were used to infect mice, and levels of several a novel type of antitumor therapy (1-4). This approach has representative cytokines, including monocyte chemoattractant numerous advantages as a cancer therapeutic agent due to its protein-1, interleukin (IL)-1β, tumor necrosis factor-α, IL-6 mechanism-based selectivity, potential for mediating tumor and interferon γ, in serum and bronchoalveolar lavage fluid cell death and possibility of expressing additional therapeutic (BALF) of infected mice were determined, and immune cells transgenes at the tumor site (5,6).
    [Show full text]
  • Serpin Peptidase Inhibitor Clade a Member 1 As a Potential Marker for Malignancy in Insulinomas
    Human Cancer Biology Serpin Peptidase Inhibitor Clade A Member 1as a Potential Marker for Malignancy in Insulinomas Sandra Vale¤ riadeSa¤ ,1, 2 Maria Lu¤ cia Corre“ a-Giannella,1, 3 Ma¤ rcio Carlos Machado,3 Karin Krogh,4 Madson Queiroz de Almeida, 3 Maria AdelaideAlbergaria Pereira,3 4 4 1 Sheila Aparecida Coelho Siqueira, RoselyAntunes Patzina, FelI¤cia Satie Ibuki, Mari Cleide Sogayar,5 Marcel Cerqueira Ce¤ sar Machado,2 and Daniel Giannella-Neto1, 3 Abstract Purpose: The biological behavior of insulinomas cannot be predicted based on histopathologic criteria in which the diagnosis of malignancy is confirmed by the presence of metastases. In this study, microarray and quantitative real-time reverse transcription-PCR were applied to identify differentially expressed genes between malignant and nonmalignant insulinomas to search for useful biomarkers to recognize the metastatic potential of insulinomas. Experimental Design: CodeLink human bioarrays were used to analyze differences in f20,000 genes between six well-differentiated endocrine tumors of benign behavior compared with one well-differentiated endocrine carcinoma (WDEC) and three metastases of endocrine carcinomas (MEC). Quantitative real-time reverse transcription-PCR was used to validate differ- ential expressions of five genes in a series of 35 sporadic insulinomas. Serpin peptidase inhibitor cladeA member1 (SERPINA1; a-1-antitrypsin) expression, identified as up-regulated in malignant insulinomas, was also evaluated by immunohistochemistry. Results: Analysis of microarray
    [Show full text]
  • Genome-Wide Transcript and Protein Analysis Reveals Distinct Features of Aging in the Mouse Heart
    bioRxiv preprint doi: https://doi.org/10.1101/2020.08.28.272260; this version posted April 21, 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. Genome-wide transcript and protein analysis reveals distinct features of aging in the mouse heart Isabela Gerdes Gyuricza1, Joel M. Chick2, Gregory R. Keele1, Andrew G. Deighan1, Steven C. Munger1, Ron Korstanje1, Steven P. Gygi3, Gary A. Churchill1 1The Jackson Laboratory, Bar Harbor, Maine 04609 USA; 2Vividion Therapeutics, San Diego, California 92121, USA; 3Harvard Medical School, Boston, Massachusetts 02115, USA Corresponding author: [email protected] Key words for online indexing: Heart Aging Transcriptomics Proteomics eQTL pQTL Stoichiometry ABSTRACT Investigation of the molecular mechanisms of aging in the human heart is challenging due to confounding factors, such as diet and medications, as well limited access to tissues. The laboratory mouse provides an ideal model to study aging in healthy individuals in a controlled environment. However, previous mouse studies have examined only a narrow range of the genetic variation that shapes individual differences during aging. Here, we analyzed transcriptome and proteome data from hearts of genetically diverse mice at ages 6, 12 and 18 months to characterize molecular changes that occur in the aging heart. Transcripts and proteins reveal distinct biological processes that are altered through the course of natural aging. Transcriptome analysis reveals a scenario of cardiac hypertrophy, fibrosis, and reemergence of fetal gene expression patterns.
    [Show full text]