DOCSLIB.ORG

Genetic and Phenotypic Response of Neural Tube Defect

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Genetic and Phenotypic Response of Neural Tube Defect GENETIC AND PHENOTYPIC RESPONSE OF NEURAL TUBE DEFECT MOUSE MUTANTS TO FOLIC ACID By GHUNWA A. NAKOUZI Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Adviser: Dr. Joseph H. Nadeau Department of Genetics CASE WESTERN RESERVE UNIVERSITY August, 2009 CASE WESTERN RESREVER UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of GHUNWA A. NAKOUZI _________________________________________________________ candidate for the PhD degree*. Shawn McCandless (signed)___________________________________________________ (chair of the committee) Joseph Nadeau ____________________________________________________ Mark Adams ____________________________________________________ Donald Jacobsen ____________________________________________________ Radhika Atit ____________________________________________________ June 30, 2009 (date) ________________________ *We also certify that written approval has been obtained for any proprietary material contained therein. TABLE OF CONTENTS TABLE OF CONTENTS .................................................................................................... 1 LIST OF TABLES .............................................................................................................. 3 LIST OF FIGURES ............................................................................................................ 5 ACKNOWLEDGEMENTS AND DEDICATIONS .......................................................... 6 Abstract ............................................................................................................................... 8 CHAPTER 1 ..................................................................................................................... 10 NTDs in Humans .......................................................................................................... 11 Clinical significance.................................................................................................. 11 Genetic and environmental risk factors. ................................................................... 13 Folate-Homocysteine association. ............................................................................ 14 Prevention measures. ................................................................................................ 16 Adverse effects of high levels FA. ............................................................................ 18 NTDs in Mice ............................................................................................................... 20 Mice as models for human NTDs. ............................................................................ 20 Supplementation studies and metabolic pathways. ................................................... 24 Previous response predictive profiles. ...................................................................... 29 Summary of mouse mutants selected for modeling human NTDs. .......................... 30 Research Objectives ...................................................................................................... 35 CHAPTER 2 ..................................................................................................................... 40 Abstract ......................................................................................................................... 41 Introduction ................................................................................................................... 42 Materials and Methods .................................................................................................. 45 Results ........................................................................................................................... 50 Discussion ..................................................................................................................... 58 CHAPTER 3 ..................................................................................................................... 62 Abstract ......................................................................................................................... 64 Introduction ................................................................................................................... 65 Materials and Methods .................................................................................................. 69 Results ........................................................................................................................... 76 Discussion ..................................................................................................................... 84 CHAPTER 4 ..................................................................................................................... 88 Abstract ......................................................................................................................... 90 1 Introduction ................................................................................................................... 92 Materials and Methods .................................................................................................. 94 Results ......................................................................................................................... 102 Discussion ................................................................................................................... 117 CHAPTER 5 ................................................................................................................... 121 Summary ..................................................................................................................... 122 Future Directions ........................................................................................................ 126 APPENDIX ..................................................................................................................... 136 APPENDIX 1 .............................................................................................................. 137 APPENDIX 2 .............................................................................................................. 138 APPENDIX 3 .............................................................................................................. 139 APPENDIX 4 .............................................................................................................. 139 APPENDIX 5 .............................................................................................................. 139 APPENDIX 6 .............................................................................................................. 139 APPENDIX 7 .............................................................................................................. 140 APPENDIX 8 .............................................................................................................. 143 BIBLIOGRAPHY ........................................................................................................... 144 2 LIST OF TABLES CHAPTER 1 Table 1.1 Mouse NTD responses to different nutritional supplementations or treatments ....................................................................................................................... 28 Table 1.2 NTD mutants chosen for study ...................................................................... 34 CHAPTER 2 Table 2.1 Apob: effect of maternal FA supplementation on occurrence of resorptions 51 Table 2.2 Effect of maternal FA supplementation on incidence of exencephaly in Apob-/- embryos .............................................................................................. 51 Table 2.3 Lp: effect of maternal FA supplementation on occurrence of resorptions .... 53 Table 2.4 Effect of maternal FA supplementation on incidence of craniorachischisis in Lp-/- embryos ................................................................................................. 53 Table 2.5 Effect of maternal FA supplementation on incidence of looped tail in Lp+/- embryos ......................................................................................................... 53 Table 2.6 Genotype distribution of observed Apob embryos ........................................ 55 Table 2.7 Genotype distribution of observed Lp embryos ............................................. 55 Table 2.8 Gender specific distribution of exencephaly frequency and embryonic loss in Apob............................................................................................................... 56 Table 2.9 Gender specific distribution of craniorachischisis and looped tail frequency and embryonic loss in Lp............................................................................... 57 CHAPTER 3 Table 3.1 Test and control mice used for experiments .................................................. 71 Table 3.2 Comparison of metabolite levels in each mutant to its corresponding control (unpaired t-tests with Welch’s correction) .................................................... 82 3 CHAPTER 4 Table 4.1 Early lethality of FA-supplemented Lrp6-/- embryos ................................... 104 Table 4.2 Effect of maternal FA supplementation on incidence of NTDs in Lrp6-/- embryos ....................................................................................................... 105 Table 4.3 Genotype distribution of observed embryos from Lrp6+/- x
Load more

Recommended publications
  • Related Malignant Phenotypes in the Nf1-Deficient MPNST
    Published OnlineFirst February 19, 2013; DOI: 10.1158/1541-7786.MCR-12-0593 Molecular Cancer Genomics Research RAS/MEK–Independent Gene Expression Reveals BMP2- Related Malignant Phenotypes in the Nf1-Deficient MPNST Daochun Sun1, Ramsi Haddad2,3, Janice M. Kraniak2, Steven D. Horne1, and Michael A. Tainsky1,2 Abstract Malignant peripheral nerve sheath tumor (MPNST) is a type of soft tissue sarcoma that occurs in carriers of germline mutations in Nf1 gene as well as sporadically. Neurofibromin, encoded by the Nf1 gene, functions as a GTPase-activating protein (GAP) whose mutation leads to activation of wt-RAS and mitogen-activated protein kinase (MAPK) signaling in neurofibromatosis type I (NF1) patients' tumors. However, therapeutic targeting of RAS and MAPK have had limited success in this disease. In this study, we modulated NRAS, mitogen-activated protein/extracellular signal–regulated kinase (MEK)1/2, and neurofibromin levels in MPNST cells and determined gene expression changes to evaluate the regulation of signaling pathways in MPNST cells. Gene expression changes due to neurofibromin modulation but independent of NRAS and MEK1/2 regulation in MPNST cells indicated bone morphogenetic protein 2 (Bmp2) signaling as a key pathway. The BMP2-SMAD1/5/8 pathway was activated in NF1-associated MPNST cells and inhibition of BMP2 signaling by LDN-193189 or short hairpin RNA (shRNA) to BMP2 decreased the motility and invasion of NF1-associated MPNST cells. The pathway-specific gene changes provide a greater understanding of the complex role of neurofibromin in MPNST pathology and novel targets for drug discovery. Mol Cancer Res; 11(6); 616–27.
    [Show full text]
  • Investigation of Candidate Genes and Mechanisms Underlying Obesity
    Prashanth et al. BMC Endocrine Disorders (2021) 21:80 https://doi.org/10.1186/s12902-021-00718-5 RESEARCH ARTICLE Open Access Investigation of candidate genes and mechanisms underlying obesity associated type 2 diabetes mellitus using bioinformatics analysis and screening of small drug molecules G. Prashanth1 , Basavaraj Vastrad2 , Anandkumar Tengli3 , Chanabasayya Vastrad4* and Iranna Kotturshetti5 Abstract Background: Obesity associated type 2 diabetes mellitus is a metabolic disorder ; however, the etiology of obesity associated type 2 diabetes mellitus remains largely unknown. There is an urgent need to further broaden the understanding of the molecular mechanism associated in obesity associated type 2 diabetes mellitus. Methods: To screen the differentially expressed genes (DEGs) that might play essential roles in obesity associated type 2 diabetes mellitus, the publicly available expression profiling by high throughput sequencing data (GSE143319) was downloaded and screened for DEGs. Then, Gene Ontology (GO) and REACTOME pathway enrichment analysis were performed. The protein - protein interaction network, miRNA - target genes regulatory network and TF-target gene regulatory network were constructed and analyzed for identification of hub and target genes. The hub genes were validated by receiver operating characteristic (ROC) curve analysis and RT- PCR analysis. Finally, a molecular docking study was performed on over expressed proteins to predict the target small drug molecules. Results: A total of 820 DEGs were identified between
    [Show full text]
  • Pleiotrophin Regulates the Ductular Reaction by Controlling the Migration
    Gut Online First, published on March 10, 2015 as 10.1136/gutjnl-2014-308176 Hepatology ORIGINAL ARTICLE Gut: first published as 10.1136/gutjnl-2014-308176 on 16 January 2015. Downloaded from Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches Gregory A Michelotti,1 Anikia Tucker,1 Marzena Swiderska-Syn,1 Mariana Verdelho Machado,1 Steve S Choi,1,2 Leandi Kruger,1 Erik Soderblom,3 J Will Thompson,3 Meredith Mayer-Salman,3 Heather A Himburg,4 Cynthia A Moylan,1,2 Cynthia D Guy,5 Katherine S Garman,1,2 Richard T Premont,1 John P Chute,4 Anna Mae Diehl1 ▸ Additional material is ABSTRACT published online only. To view Objective The ductular reaction (DR) involves Significance of this study please visit the journal online (http://dx.doi.org/10.1136/ mobilisation of reactive-appearing duct-like cells (RDC) gutjnl-2014-308176). along canals of Hering, and myofibroblastic (MF) differentiation of hepatic stellate cells (HSC) in the space 1Division of Gastroenterology, What is already known about this subject? Duke University, Durham, of Disse. Perivascular cells in stem cell niches produce ▸ Various types of liver injury promote a ductular North Carolina, USA pleiotrophin (PTN) to inactivate the PTN receptor, protein reaction (DR) characterised by the periportal 2Section of Gastroenterology, tyrosine phosphatase receptor zeta-1 (PTPRZ1), thereby accumulation of small ductules, myofibroblasts Durham Veterans Affairs augmenting phosphoprotein-dependent signalling. We and collagen matrix. Medical Center, Durham, ▸ Pleiotrophin (PTN) is a heparin-binding growth North Carolina, USA hypothesised that the DR is regulated by PTN/PTPRZ1 3Proteomics Center, signalling.
    [Show full text]
  • 140503 IPF Signatures Supplement Withfigs Thorax
    Supplementary material for Heterogeneous gene expression signatures correspond to distinct lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis Daryle J. DePianto1*, Sanjay Chandriani1⌘*, Alexander R. Abbas1, Guiquan Jia1, Elsa N. N’Diaye1, Patrick Caplazi1, Steven E. Kauder1, Sabyasachi Biswas1, Satyajit K. Karnik1#, Connie Ha1, Zora Modrusan1, Michael A. Matthay2, Jasleen Kukreja3, Harold R. Collard2, Jackson G. Egen1, Paul J. Wolters2§, and Joseph R. Arron1§ 1Genentech Research and Early Development, South San Francisco, CA 2Department of Medicine, University of California, San Francisco, CA 3Department of Surgery, University of California, San Francisco, CA ⌘Current address: Novartis Institutes for Biomedical Research, Emeryville, CA. #Current address: Gilead Sciences, Foster City, CA. *DJD and SC contributed equally to this manuscript §PJW and JRA co-directed this project Address correspondence to Paul J. Wolters, MD University of California, San Francisco Department of Medicine Box 0111 San Francisco, CA 94143-0111 [email protected] or Joseph R. Arron, MD, PhD Genentech, Inc. MS 231C 1 DNA Way South San Francisco, CA 94080 [email protected] 1 METHODS Human lung tissue samples Tissues were obtained at UCSF from clinical samples from IPF patients at the time of biopsy or lung transplantation. All patients were seen at UCSF and the diagnosis of IPF was established through multidisciplinary review of clinical, radiological, and pathological data according to criteria established by the consensus classification of the American Thoracic Society (ATS) and European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and the Latin American Thoracic Association (ALAT) (ref. 5 in main text). Non-diseased normal lung tissues were procured from lungs not used by the Northern California Transplant Donor Network.
    [Show full text]
  • Macrophages/Microglia in the Glioblastoma Tumor Microenvironment
    International Journal of Molecular Sciences Review Macrophages/Microglia in the Glioblastoma Tumor Microenvironment Jun Ma, Clark C. Chen * and Ming Li * Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA; [email protected] * Correspondence: [email protected] (C.C.C.); [email protected] (M.L.) Abstract: The complex interaction between glioblastoma and its microenvironment has been rec- ognized for decades. Among various immune profiles, the major population is tumor-associated macrophage, with microglia as its localized homolog. The present definition of such myeloid cells is based on a series of cell markers. These good sentinel cells experience significant changes, facilitat- ing glioblastoma development and protecting it from therapeutic treatments. Huge, complicated mechanisms are involved during the overall processes. A lot of effort has been dedicated to crack the mysterious codes in macrophage/microglia recruiting, activating, reprogramming, and functioning. We have made our path. With more and more key factors identified, a lot of new therapeutic methods could be explored to break the ominous loop, to enhance tumor sensitivity to treatments, and to improve the prognosis of glioblastoma patients. However, it might be a synergistic system rather than a series of clear, stepwise events. There are still significant challenges before the light of truth can shine onto the field. Here, we summarize recent advances in this field, reviewing the path we have been on and where we are now. Keywords: glioblastoma; tumor microenvironment; glioblastoma-associated macrophages/microglia; macrophage; microglia Citation: Ma, J.; Chen, C.C.; Li, M. Macrophages/Microglia in the Glioblastoma Tumor Int. J. Mol. Sci. Microenvironment. 1. Glioblastoma Associated Macrophages/Microglia 2021, 22, 5775.
    [Show full text]
  • 1 No. Affymetrix ID Gene Symbol Genedescription Gotermsbp Q Value 1. 209351 at KRT14 Keratin 14 Structural Constituent of Cyto
    1 Affymetrix Gene Q No. GeneDescription GOTermsBP ID Symbol value structural constituent of cytoskeleton, intermediate 1. 209351_at KRT14 keratin 14 filament, epidermis development <0.01 biological process unknown, S100 calcium binding calcium ion binding, cellular 2. 204268_at S100A2 protein A2 component unknown <0.01 regulation of progression through cell cycle, extracellular space, cytoplasm, cell proliferation, protein kinase C inhibitor activity, protein domain specific 3. 33323_r_at SFN stratifin/14-3-3σ binding <0.01 regulation of progression through cell cycle, extracellular space, cytoplasm, cell proliferation, protein kinase C inhibitor activity, protein domain specific 4. 33322_i_at SFN stratifin/14-3-3σ binding <0.01 structural constituent of cytoskeleton, intermediate 5. 201820_at KRT5 keratin 5 filament, epidermis development <0.01 structural constituent of cytoskeleton, intermediate 6. 209125_at KRT6A keratin 6A filament, ectoderm development <0.01 regulation of progression through cell cycle, extracellular space, cytoplasm, cell proliferation, protein kinase C inhibitor activity, protein domain specific 7. 209260_at SFN stratifin/14-3-3σ binding <0.01 structural constituent of cytoskeleton, intermediate 8. 213680_at KRT6B keratin 6B filament, ectoderm development <0.01 receptor activity, cytosol, integral to plasma membrane, cell surface receptor linked signal transduction, sensory perception, tumor-associated calcium visual perception, cell 9. 202286_s_at TACSTD2 signal transducer 2 proliferation, membrane <0.01 structural constituent of cytoskeleton, cytoskeleton, intermediate filament, cell-cell adherens junction, epidermis 10. 200606_at DSP desmoplakin development <0.01 lectin, galactoside- sugar binding, extracellular binding, soluble, 7 space, nucleus, apoptosis, 11. 206400_at LGALS7 (galectin 7) heterophilic cell adhesion <0.01 2 S100 calcium binding calcium ion binding, epidermis 12. 205916_at S100A7 protein A7 (psoriasin 1) development <0.01 S100 calcium binding protein A8 (calgranulin calcium ion binding, extracellular 13.
    [Show full text]
  • Genetic Alterations of Protein Tyrosine Phosphatases in Human Cancers
    Oncogene (2015) 34, 3885–3894 © 2015 Macmillan Publishers Limited All rights reserved 0950-9232/15 www.nature.com/onc REVIEW Genetic alterations of protein tyrosine phosphatases in human cancers S Zhao1,2,3, D Sedwick3,4 and Z Wang2,3 Protein tyrosine phosphatases (PTPs) are enzymes that remove phosphate from tyrosine residues in proteins. Recent whole-exome sequencing of human cancer genomes reveals that many PTPs are frequently mutated in a variety of cancers. Among these mutated PTPs, PTP receptor T (PTPRT) appears to be the most frequently mutated PTP in human cancers. Beside PTPN11, which functions as an oncogene in leukemia, genetic and functional studies indicate that most of mutant PTPs are tumor suppressor genes. Identification of the substrates and corresponding kinases of the mutant PTPs may provide novel therapeutic targets for cancers harboring these mutant PTPs. Oncogene (2015) 34, 3885–3894; doi:10.1038/onc.2014.326; published online 29 September 2014 INTRODUCTION tyrosine/threonine-specific phosphatases. (4) Class IV PTPs include Protein tyrosine phosphorylation has a critical role in virtually all four Drosophila Eya homologs (Eya1, Eya2, Eya3 and Eya4), which human cellular processes that are involved in oncogenesis.1 can dephosphorylate both tyrosine and serine residues. Protein tyrosine phosphorylation is coordinately regulated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases 1 THE THREE-DIMENSIONAL STRUCTURE AND CATALYTIC (PTPs). Although PTKs add phosphate to tyrosine residues in MECHANISM OF PTPS proteins, PTPs remove it. Many PTKs are well-documented oncogenes.1 Recent cancer genomic studies provided compelling The three-dimensional structures of the catalytic domains of evidence that many PTPs function as tumor suppressor genes, classical PTPs (RPTPs and non-RPTPs) are extremely well because a majority of PTP mutations that have been identified in conserved.5 Even the catalytic domain structures of the dual- human cancers are loss-of-function mutations.
    [Show full text]
  • Comprehensive Protein Tyrosine Phosphatase Mrna Profiling Identifies New Regulators in the Progression of Glioma Annika M
    Bourgonje et al. Acta Neuropathologica Communications (2016) 4:96 DOI 10.1186/s40478-016-0372-x RESEARCH Open Access Comprehensive protein tyrosine phosphatase mRNA profiling identifies new regulators in the progression of glioma Annika M. Bourgonje1, Kiek Verrijp2, Jan T. G. Schepens1, Anna C. Navis2, Jolanda A. F. Piepers1, Chantal B. C. Palmen1, Monique van den Eijnden4, Rob Hooft van Huijsduijnen4, Pieter Wesseling2,3, William P. J. Leenders2 and Wiljan J. A. J. Hendriks1* Abstract The infiltrative behavior of diffuse gliomas severely reduces therapeutic potential of surgical resection and radiotherapy, and urges for the identification of new drug-targets affecting glioma growth and migration. To address the potential role of protein tyrosine phosphatases (PTPs), we performed mRNA expression profiling for 91 of the 109 known human PTP genes on a series of clinical diffuse glioma samples of different grades and compared our findings with in silico knowledge from REMBRANDT and TCGA databases. Overall PTP family expression levels appeared independent of characteristic genetic aberrations associated with lower grade or high grade gliomas. Notably, seven PTP genes (DUSP26, MTMR4, PTEN, PTPRM, PTPRN2, PTPRT and PTPRZ1) were differentially expressed between grade II-III gliomas and (grade IV) glioblastomas. For DUSP26, PTEN, PTPRM and PTPRT, lower expression levels correlated with poor prognosis, and overexpression of DUSP26 or PTPRT in E98 glioblastoma cells reduced tumorigenicity. Our study represents the first in-depth analysis of PTP family expression in diffuse glioma subtypes and warrants further investigations into PTP-dependent signaling events as new entry points for improved therapy. Keywords: Glioblastoma, Astrocytoma, EGFR, Oligodendroglioma, IDH1, DUSP26, MTMR4, PTEN, PTP, PTPRM, PTPRN2, PTPRT, PTPRZ1, Malignancy Introduction has slightly improved over the past decades, the prospect Gliomas arise from glial (precursor) cells and represent with current treatment is only a median 15 months fol- the most frequent type of primary brain tumor.
    [Show full text]
  • Molecular Analysis of the Genetic Heterogeneity Between Primary and Recurrent Glioblastoma
    Syracuse University SURFACE Syracuse University Honors Program Capstone Syracuse University Honors Program Capstone Projects Projects Spring 5-1-2009 Molecular Analysis of the Genetic Heterogeneity Between Primary and Recurrent Glioblastoma Anushi Shah Follow this and additional works at: https://surface.syr.edu/honors_capstone Part of the Biology Commons, and the Genetics and Genomics Commons Recommended Citation Shah, Anushi, "Molecular Analysis of the Genetic Heterogeneity Between Primary and Recurrent Glioblastoma" (2009). Syracuse University Honors Program Capstone Projects. 449. https://surface.syr.edu/honors_capstone/449 This Honors Capstone Project is brought to you for free and open access by the Syracuse University Honors Program Capstone Projects at SURFACE. It has been accepted for inclusion in Syracuse University Honors Program Capstone Projects by an authorized administrator of SURFACE. For more information, please contact [email protected]. Molecular Analysis of the Genetic Heterogeneity Between Primary and Recurrent Glioblastoma A Capstone Project Submitted in Partial Fulfillment of the Requirements of the Renée Crown University Honors Program at Syracuse University Anushi Shah Candidate for B.S. Biology & Psychology and B.A. Anthropology Degree and Renée Crown University Honors May 2009 Honors Capstone Project in: __________Biology__________ Capstone Project Advisor: ____________________________ (Dr. Frank Middleton) Honors Reader: ____________________________ (Dr. Shannon Novak) Honors Director: __ __________________________ Samuel Gorovitz Date: _____________ April 21 st , 2009 Abstract Introduction: Glioblastoma multiforme (GBM) is one of the deadliest forms of brain cancer, and affects more than 18,000 new cases each year in the United States alone. The current standard of treatment for GBM includes surgical removal of the tumor, along with radiation and chemotherapy.
    [Show full text]
  • Pleiotrophin Suppression of Receptor Protein Tyrosine Phosphatase-ß
    15066 • The Journal of Neuroscience, October 24, 2012 • 32(43):15066–15075 Cellular/Molecular Pleiotrophin Suppression of Receptor Protein Tyrosine Phosphatase-␤/␨ Maintains the Self-Renewal Competence of Fetal Human Oligodendrocyte Progenitor Cells Crystal R. McClain,1,3 Fraser J. Sim,1,3 and Steven A. Goldman1,2,3 Departments of 1Neurology and 2Neurosurgery and 3Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York 14642 Oligodendrocyte progenitor cells (OPCs) persist in human white matter, yet the mechanisms by which they are maintained in an undif- ferentiated state are unknown. Human OPCs differentially express protein tyrosine phosphatase receptor ␤/␨ (PTPRZ1) and its inhibi- tory ligand, pleiotrophin, suggesting the maintenance of an autocrine loop by which PTPRZ1 activity is tonically suppressed. PTPRZ1 constitutively promotes the tyrosine dephosphorylation of ␤-catenin and, thus, ␤-catenin participation in T cell factor (TCF)-mediated transcription. Using CD140a/PDGFR␣-based fluorescence-activated cell sorting to isolate fetal OPCs from the fetal brain at gestational ages16–22weeks,weaskedwhetherpleiotrophinmodulatedtheexpansionofOPCsand,ifso,whetherthiswaseffectedthroughtheserial engagementofPTPRZ1and␤-catenin-dependentsignals,suchasTCF-mediatedtranscription.LentiviralshRNAiknockdownofPTPRZ1 induced TCF-mediated transcription and substantially augmented GSK3␤ inhibition-induced TCF-reporter luciferase expression, sug- gesting dual regulation of ␤-catenin and the importance of PTPRZ1
    [Show full text]
  • The Human Gene Connectome As a Map of Short Cuts for Morbid Allele Discovery
    The human gene connectome as a map of short cuts for morbid allele discovery Yuval Itana,1, Shen-Ying Zhanga,b, Guillaume Vogta,b, Avinash Abhyankara, Melina Hermana, Patrick Nitschkec, Dror Friedd, Lluis Quintana-Murcie, Laurent Abela,b, and Jean-Laurent Casanovaa,b,f aSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; bLaboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris Descartes University, Institut National de la Santé et de la Recherche Médicale U980, Necker Medical School, 75015 Paris, France; cPlateforme Bioinformatique, Université Paris Descartes, 75116 Paris, France; dDepartment of Computer Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; eUnit of Human Evolutionary Genetics, Centre National de la Recherche Scientifique, Unité de Recherche Associée 3012, Institut Pasteur, F-75015 Paris, France; and fPediatric Immunology-Hematology Unit, Necker Hospital for Sick Children, 75015 Paris, France Edited* by Bruce Beutler, University of Texas Southwestern Medical Center, Dallas, TX, and approved February 15, 2013 (received for review October 19, 2012) High-throughput genomic data reveal thousands of gene variants to detect a single mutated gene, with the other polymorphic genes per patient, and it is often difficult to determine which of these being of less interest. This goes some way to explaining why, variants underlies disease in a given individual. However, at the despite the abundance of NGS data, the discovery of disease- population level, there may be some degree of phenotypic homo- causing alleles from such data remains somewhat limited. geneity, with alterations of specific physiological pathways under- We developed the human gene connectome (HGC) to over- come this problem.
    [Show full text]
  • Supplementary Table 2: Infection-Sensitive Genes
    Supplementary Table 2: Infection-Sensitive Genes Supplementary Table 2: Upregulated with Adenoviral Infection (pages 1 - 7)- genes that were significant by ANOVA as well as significantly increased in control compared to both 'infected control' (Ad-LacZ) and 'calcineurin infected' (Ad-aCaN). Downregulated with Adenoviral Infection (pages 7 - 13) as above except for direction of change. Columns: Probe Set- Affymetrix probe set identifier for RG-U34A microarray, Symbol and Title- annotated information for above probe set (annotation downloaded June, 2004), ANOVA- p-value for 1-way Analysis of Variance, Uninfected, Ad-LacZ and Ad- aCaN- mean ± SEM expression for uninfected control, adenovirus mediated LacZ treated control, and adenovirus mediated calcineurin treated cultures respectively. Upregulated with Adenoviral Infection Probe Set Symbol Title ANOVA Uninfected Ad-LacZ Ad-aCaN Z48444cds_at Adam10 a disintegrin and metalloprotease domain 10 0.00001 837 ± 31 1107 ± 24 1028 ± 29 L26986_at Adcy8 adenylyl cyclase 8 0.00028 146 ± 12 252 ± 21 272 ± 21 U94340_at Adprt ADP-ribosyltransferase 1 0.00695 2096 ± 100 2783 ± 177 2586 ± 118 U01914_at Akap8 A kinase anchor protein 8 0.00080 993 ± 44 1194 ± 65 1316 ± 44 AB008538_at Alcam activated leukocyte cell adhesion molecule 0.01012 2775 ± 136 3580 ± 216 3429 ± 155 M34176_s_at Ap2b1 adaptor-related protein complex 2, beta 1 subunit 0.01389 2408 ± 199 2947 ± 143 3071 ± 116 D44495_s_at Apex1 apurinic/apyrimidinic endonuclease 1 0.00089 4959 ± 185 5816 ± 202 6057 ± 158 U16245_at Aqp5 aquaporin 5 0.02710
    [Show full text]