DOCSLIB.ORG

ABSTRACT MITCHELL III, ROBERT DRAKE. Global Human Health

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
ABSTRACT MITCHELL III, ROBERT DRAKE. Global Human Health ABSTRACT MITCHELL III, ROBERT DRAKE. Global Human Health Risks for Arthropod Repellents or Insecticides and Alternative Control Strategies. (Under the direction of Dr. R. Michael Roe). Protein-coding genes and environmental chemicals. New paradigms for human health risk assessment of environmental chemicals emphasize the use of molecular methods and human-derived cell lines. In this study, we examined the effects of the insect repellent DEET (N, N-diethyl-m-toluamide) and the phenylpyrazole insecticide fipronil (fluocyanobenpyrazole) on transcript levels in primary human hepatocytes. These chemicals were tested individually and as a mixture. RNA-Seq showed that 100 µM DEET significantly increased transcript levels for 108 genes and lowered transcript levels for 64 genes and fipronil at 10 µM increased the levels of 2,246 transcripts and decreased the levels for 1,428 transcripts. Fipronil was 21-times more effective than DEET in eliciting changes, even though the treatment concentration was 10-fold lower for fipronil versus DEET. The mixture of DEET and fipronil produced a more than additive effect (levels increased for 3,017 transcripts and decreased for 2,087 transcripts). The transcripts affected in our treatments influenced various biological pathways and processes important to normal cellular functions. Long non-protein coding RNAs and environmental chemicals. While the synthesis and use of new chemical compounds is at an all-time high, the study of their potential impact on human health is quickly falling behind. We chose to examine the effects of two common environmental chemicals, the insect repellent DEET and the insecticide fipronil, on transcript levels of long non-protein coding RNAs (lncRNAs) in primary human hepatocytes. While lncRNAs are believed to play a critical role in numerous important biological processes many still remain uncharacterized and their functions and modes of action remain largely unclear. RNA-Seq showed that 100 µM DEET significantly increased transcript levels for 2 lncRNAs and lowered transcript levels for 18 lncRNAs while fipronil at 10 µM increased transcript levels for 76 lncRNAs and decreased levels for 193 lncRNAs. A mixture of 100 µM DEET and 10 µM fipronil increased transcript levels for 75 lncRNAs and lowered transcript levels for 258 lncRNAs. Differentially expressed lncRNA genes were mapped to chromosomes, analyzed by proximity to neighboring protein-coding genes, and functionally characterized via gene ontology and molecular mapping algorithms. While further testing is required to assess the organismal impact of changes in transcript levels, initial analysis links several of the dysregulated lncRNAs to processes and pathways critical to proper cellular function. Tick Haller’s organ detects infrared light. The Haller’s organ (HO), unique to ticks and mites, is found only on the first tarsus of the front pair of legs. The current thinking is that the HO’s main function is chemosensation analogous to the insect antennae, but the functionality of its atypical structure (exclusive to the Acari) is unexplained. We provide the first evidence that the HO allows the American dog tick, Dermacentor variabilis, to respond to infrared (IR) light. Unfed D. variabilis adults with their HOs present were positively phototactic to IR. However, when the HOs were removed by amputation of the tarsi bearing the HOs, no IR response was detected. Ticks in these experiments were also attracted to white light with and without the HOs, but were only positively phototactic to white light when the ocelli (primitive eyes) were present. Covering the eyes did not prevent IR attraction. A TRPA1 receptor was characterized from a D. variabilis-specific HO transcriptome we constructed. This receptor was homologous to the transient receptor potential cation channel, subfamily A, member 1 (TRPA1) from the pit organ of the pit viper, python, and boa families of snakes, the only receptor identified so far for IR detection. The ability of ticks to use IR for host finding is consistent with its obligatory hematophagy and has practical applications in tick trapping and the development of new repellents. © Copyright 2017 Robert Drake Mitchell III All Rights Reserved Global Human Health Risks for Arthropod Repellents or Insecticides and Alternative Control Strategies by Robert Drake Mitchell III A dissertation submitted to the Graduate Faculty of North Carolina State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Entomology Raleigh, North Carolina 2017 APPROVED BY: _______________________________ _______________________________ Dr. R. Michael Roe Dr. Daniel Sonenshine Committee Chair _______________________________ _______________________________ Dr. Ernest Hodgson Dr. Marcé Lorenzen _______________________________ Dr. Dominic Reisig DEDICATION I dedicate this dissertation to my mother and father, Bob and Beulah Mitchell. Without your love and support I wouldn’t be the man I am today or had the opportunities you provided. Thank you from the bottom of my heart. Also, to my fiancé Tiffany and my sisters Marie and Chris for their love and support. ii BIOGRAPHY Robert Drake Mitchell III was born to Bob and Beulah Mitchell on January 8, 1980 during a blizzard in Norfolk, VA. He was the third child in the family and the only boy. He attended Norfolk Collegiate School in Norfolk, VA through the entirety of high school and continued his education at American University in Washington, DC. Soon after receiving a bachelor’s degree in Biology he attended Old Dominion University in Norfolk, VA in pursuit of a Master’s degree. Under the tutelage of Dr. Daniel E. Sonenshine he developed a love for his work as well as a respect for its importance. He attended Eastern Virginia Medical School for three years as a graduate student before moving to Raleigh, NC to pursue a Ph.D. in Entomology at North Carolina State University under the guidance of Dr. R. Michael Roe. iii ACKNOWLEDGEMENTS To my family and friends. I’d like to thank everyone that has supported me along the way, including my fiancé Tiffany Benzine, my mother Beulah Mitchell, my sisters Marie Davis and Christine Mitchell, and my father Bob Mitchell who passed away six years ago. I regret that he is not here to see me succeed, but I know that he always had faith in me and will cherish that feeling for the rest of my life. Also, my nieces and nephews, who I hope have success in their own lives. I’d also like to personally thank two mentors that I hope to emulate throughout my career, Dr. Daniel Sonenshine and Dr. R. Michael Roe. Without either of them I’d not be where I am today or have the dedication and appreciation for my work that I’ve developed over the years and learned from them. Their tireless efforts have provided so much for the scientific community and for myself as well. My committee members have also been instrumental in my growth and understanding so I’d like to thank them as well: Dr. Marcé Lorenzen, Dr. Ernest Hodgson, Dr. Dominic Reisig, Dr. R. Michael Roe, and Dr. Daniel Sonenshine. Each has helped me at critical steps along the way and also helped me to stay focused through good times and more difficult times. Finally, I’d like to thank those that I’ve worked with throughout the years and gotten to know very well. I have such an eclectic group of friend that have supported and challenged me throughout my education, including Anirudh Dhammi, Jiwei Zhu, Jaap van Kretschmar, Nick, Travanty, Ann Carr, Loganathan Ponnusamy, Grayson Cave, John Strider, Haley Thornton Sutton, Marcel Deguenon, Charles Apperson, Clyde Sorenson, Shane Ceraul, Sayed Khalil, Kevin Donohue, Xin Guo and so many others. iv TABLE OF CONTENTS List of Tables .......................................................................................................................... vii List of Figures .......................................................................................................................... ix Chapter 1: Impact of Environmental Chemicals on the Transcriptome of Primary Human Hepatocytes: Potential for Health Effects ..................................................................................1 Abstract ..........................................................................................................................2 Introduction ....................................................................................................................3 Materials and Methods ...................................................................................................5 Cell Culture and Treatments ..........................................................................................5 RNA Isolation, Quality Assessment, and Sequencing ...................................................7 Data Analysis .................................................................................................................8 Quantitative PCR (qPCR) Analysis .............................................................................10 Results ..........................................................................................................................12 DEET and Fipronil Exposure Alter Gene Expression in Primary Human Hepatocytes ..................................................................................................................12 DEET-Fipronil Mixture ...............................................................................................15 Impact of DEET, Fipronil and DEET plus Fipronil
Load more

Recommended publications
  • Regulation and Dysregulation of Chromosome Structure in Cancer
    Regulation and Dysregulation of Chromosome Structure in Cancer The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Hnisz, Denes et al. “Regulation and Dysregulation of Chromosome Structure in Cancer.” Annual Review of Cancer Biology 2, 1 (March 2018): 21–40 © 2018 Annual Reviews As Published https://doi.org/10.1146/annurev-cancerbio-030617-050134 Version Author's final manuscript Citable link http://hdl.handle.net/1721.1/117286 Terms of Use Creative Commons Attribution-Noncommercial-Share Alike Detailed Terms http://creativecommons.org/licenses/by-nc-sa/4.0/ Regulation and dysregulation of chromosome structure in cancer Denes Hnisz1*, Jurian Schuijers1, Charles H. Li1,2, Richard A. Young1,2* 1 Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA 2 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA * Corresponding authors Corresponding Authors: Denes Hnisz Whitehead Institute for Biomedical Research 455 Main Street Cambridge, MA 02142 Tel: (617) 258-7181 Fax: (617) 258-0376 [email protected] Richard A. Young Whitehead Institute for Biomedical Research 455 Main Street Cambridge, MA 02142 Tel: (617) 258-5218 Fax: (617) 258-0376 [email protected] 1 Summary Cancer arises from genetic alterations that produce dysregulated gene expression programs. Normal gene regulation occurs in the context of chromosome loop structures called insulated neighborhoods, and recent studies have shown that these structures are altered and can contribute to oncogene dysregulation in various cancer cells. We review here the types of genetic and epigenetic alterations that influence neighborhood structures and contribute to gene dysregulation in cancer, present models for insulated neighborhoods associated with the most prominent human oncogenes, and discuss how such models may lead to further advances in cancer diagnosis and therapy.
    [Show full text]
  • Concept of an Active Amplification Mechanism in the Infrared
    HYPOTHESIS AND THEORY published: 21 December 2015 doi: 10.3389/fphys.2015.00391 Concept of an Active Amplification Mechanism in the Infrared Organ of Pyrophilous Melanophila Beetles Erik S. Schneider 1 †, Anke Schmitz 2 † and Helmut Schmitz 2*† 1 Institute of Zoology, University of Graz, Graz, Austria, 2 Institute of Zoology, University of Bonn, Bonn, Germany Jewel beetles of the genus Melanophila possess a pair of metathoracic infrared (IR) organs. These organs are used for forest fire detection because Melanophila larvae can only develop in fire killed trees. Several reports in the literature and a modeling of a historic oil tank fire suggest that beetles may be able to detect large fires by means of their IR organs from distances of more than 100 km. In contrast, the highest sensitivity of the IR organs, so far determined by behavioral and physiological experiments, allows a detection of large fires from distances up to 12 km only. Sensitivity thresholds, however, have always been determined in non-flying beetles. Therefore, the complete micromechanical environment of the IR organs in flying beetles has not been taken into Edited by: Sylvia Anton, consideration. Because the so-called photomechanic sensilla housed in the IR organs Institut National de la Recherche respond bimodally to mechanical as well as to IR stimuli, it is proposed that flying Agronomique, France beetles make use of muscular energy coupled out of the flight motor to considerably Reviewed by: Maria Hellwig, increase the sensitivity of their IR sensilla during intermittent search flight sequences. University of Vienna, Austria In a search flight the beetle performs signal scanning with wing beat frequency while Daniel Robert, the inputs of the IR organs on both body sides are compared.
    [Show full text]
  • Universidade Estadual De Campinas Instituto De Biologia
    UNIVERSIDADE ESTADUAL DE CAMPINAS INSTITUTO DE BIOLOGIA VERÔNICA APARECIDA MONTEIRO SAIA CEREDA O PROTEOMA DO CORPO CALOSO DA ESQUIZOFRENIA THE PROTEOME OF THE CORPUS CALLOSUM IN SCHIZOPHRENIA CAMPINAS 2016 1 VERÔNICA APARECIDA MONTEIRO SAIA CEREDA O PROTEOMA DO CORPO CALOSO DA ESQUIZOFRENIA THE PROTEOME OF THE CORPUS CALLOSUM IN SCHIZOPHRENIA Dissertação apresentada ao Instituto de Biologia da Universidade Estadual de Campinas como parte dos requisitos exigidos para a obtenção do Título de Mestra em Biologia Funcional e Molecular na área de concentração de Bioquímica. Dissertation presented to the Institute of Biology of the University of Campinas in partial fulfillment of the requirements for the degree of Master in Functional and Molecular Biology, in the area of Biochemistry. ESTE ARQUIVO DIGITAL CORRESPONDE À VERSÃO FINAL DA DISSERTAÇÃO DEFENDIDA PELA ALUNA VERÔNICA APARECIDA MONTEIRO SAIA CEREDA E ORIENTADA PELO DANIEL MARTINS-DE-SOUZA. Orientador: Daniel Martins-de-Souza CAMPINAS 2016 2 Agência(s) de fomento e nº(s) de processo(s): CNPq, 151787/2F2014-0 Ficha catalográfica Universidade Estadual de Campinas Biblioteca do Instituto de Biologia Mara Janaina de Oliveira - CRB 8/6972 Saia-Cereda, Verônica Aparecida Monteiro, 1988- Sa21p O proteoma do corpo caloso da esquizofrenia / Verônica Aparecida Monteiro Saia Cereda. – Campinas, SP : [s.n.], 2016. Orientador: Daniel Martins de Souza. Dissertação (mestrado) – Universidade Estadual de Campinas, Instituto de Biologia. 1. Esquizofrenia. 2. Espectrometria de massas. 3. Corpo caloso.
    [Show full text]
  • Sequencing-Based Computational Methods for Identifying Impactful Genomic Alterations in Cancers
    Sequencing-based computational methods for identifying impactful genomic alterations in cancers by Isaac Charles Joseph A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Computational Biology in the Graduate Division of the University of California, Berkeley Committee in charge: Professor Lior Pachter, Chair Professor Joseph Costello Associate Professor Haiyan Huang Professor Anthony Joseph Fall 2016 Sequencing-based computational methods for identifying impactful genomic alterations in cancers Copyright 2016 by Isaac Charles Joseph 1 Abstract Sequencing-based computational methods for identifying impactful genomic alterations in cancers by Isaac Charles Joseph Doctor of Philosophy in Computational Biology University of California, Berkeley Professor Lior Pachter, Chair Recent advances in collecting sequencing data from tumors is promising for both immediate individual patient treatment and investigation of cancer mechanisms. A resultant central goal is identifying changes in tumors that are impactful towards these ends. Here, we develop two tools to identify impactful changes at different levels. We develop both methods in the context of gliomas, a common form of brain cancer. Firstly, we develop and assess a tool for assessing the impact of fusion genes, a type of common mutation using RNA-sequencing data. We validate the tool by working with collaborators in The Cancer Genome Atlas. Secondly, we develop a tool for an overall assessment of patient outcome by integrating data from diverse sequencing platforms. We validate this tool using simulation, data from consortiums, and collaborators at UCSF. i To those that suffer It is you that have convinced me that there is something still worth fighting for in this world.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Browsing Genes and Genomes with Ensembl
    The Bioinformatics Roadshow Tórshavn, The Faroe Islands 28-29 November 2012 BROWSING GENES AND GENOMES WITH ENSEMBL EXERCISES AND ANSWERS 1 BROWSER 3 BIOMART 8 VARIATION 13 COMPARATIVE GENOMICS 18 2 Note: These exercises are based on Ensembl version 69 (October 2012). After in future a new version has gone live, version 69 will still be available at http://e69.ensembl.org/. If your answer doesn’t correspond with the given answer, please consult the instructor. ______________________________________________________________ BROWSER ______________________________________________________________ Exercise 1 – Exploring a gene (a) Find the human F9 (coagulation factor IX) gene. On which chromosome and which strand of the genome is this gene located? How many transcripts (splice variants) have been annotated for it? (b) What is the longest transcript? How long is the protein it encodes? Has this transcript been annotated automatically (by Ensembl) or manually (by Havana)? How many exons does it have? Are any of the exons completely or partially untranslated? (c) Have a look at the external references for ENST00000218099. What is the function of F9? (d) Is it possible to monitor expression of ENST00000218099 with the ILLUMINA HumanWG_6_V2 microarray? If so, can it also be used to monitor expression of the other two transcripts? (e) In which part (i.e. the N-terminal or C-terminal half) of the protein encoded by ENST00000218099 does its peptidase activity reside? (f) Have any missense variants been discovered for the protein encoded by ENST00000218099? (g) Is there a mouse orthologue predicted for the human F9 gene? (h) If you have yourself a gene of interest, explore what information Ensembl displays about it! ______________________________________________________________ Answer (a) 8 Go to the Ensembl homepage (http://www.ensembl.org/).
    [Show full text]
  • Emerging Genetic Alterations Linked to Male Infertility: X-Chromosome Copy Number Variation and Spermatogenesis Regulatory Genes’ Expression
    Central Annals of Reproductive Medicine and Treatment Bringing Excellence in Open Access Research Article *Corresponding author Susana Fernandes, Department of Genetics, Faculty of Medicine of University of Porto, Al. Prof. Hernâni Emerging Genetic Alterations Monteiro, 4200 - 319 Porto, Portugal; Tel: 351 22 551 36 47; Email: Submitted: 12 October 2016 Linked to Male Infertility: Accepted: 10 February 2017 Published: 14 February 2017 X-Chromosome Copy Number Copyright © 2017 Fernandes et al. Variation and Spermatogenesis OPEN ACCESS Keywords Regulatory Genes’ Expression • Male infertility • Spermatogenesis Catarina Costa1, Maria João Pinho1,2, Alberto Barros1,2,3, and • DNA copy number variations • Gene expression Susana Fernandes1,2* 1Department of Genetics, Faculty of Medicine of University of Porto, Portugal 2i3S – Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal 3Centre for Reproductive Genetics A Barros, Portugal Abstract The etiopathogenesis of primary testicular failure remains undefined in 50% of cases. Most of these idiopathic cases probably result from genetic mutations/anomalies. Novel causes, like Copy Number Variation and gene expression profile, are being explored thanks to recent advances in the field of genetics. Our aim was to study Copy Number Variation (CNV) 67, a patient-specific CNV related to spermatogenic anomaly and evaluate the expression of regulatory genes AKAP4, responsible for sperm fibrous sheet assembly, and STAG3, essential for sister chromatid cohesion during meiosis. One hundred infertile men were tested for CNV67 with quantitative PCR (qPCR). Quantitative real-time PCR was performed to evaluate gene expression patterns of the two mentioned genes in testicular biopsies from 22 idiopathic infertile patients. CNV67 deletion was found in 2% of patients, with the same semen phenotype described in previous studies.
    [Show full text]
  • Downloaded from [266]
    Patterns of DNA methylation on the human X chromosome and use in analyzing X-chromosome inactivation by Allison Marie Cotton B.Sc., The University of Guelph, 2005 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in The Faculty of Graduate Studies (Medical Genetics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) January 2012 © Allison Marie Cotton, 2012 Abstract The process of X-chromosome inactivation achieves dosage compensation between mammalian males and females. In females one X chromosome is transcriptionally silenced through a variety of epigenetic modifications including DNA methylation. Most X-linked genes are subject to X-chromosome inactivation and only expressed from the active X chromosome. On the inactive X chromosome, the CpG island promoters of genes subject to X-chromosome inactivation are methylated in their promoter regions, while genes which escape from X- chromosome inactivation have unmethylated CpG island promoters on both the active and inactive X chromosomes. The first objective of this thesis was to determine if the DNA methylation of CpG island promoters could be used to accurately predict X chromosome inactivation status. The second objective was to use DNA methylation to predict X-chromosome inactivation status in a variety of tissues. A comparison of blood, muscle, kidney and neural tissues revealed tissue-specific X-chromosome inactivation, in which 12% of genes escaped from X-chromosome inactivation in some, but not all, tissues. X-linked DNA methylation analysis of placental tissues predicted four times higher escape from X-chromosome inactivation than in any other tissue. Despite the hypomethylation of repetitive elements on both the X chromosome and the autosomes, no changes were detected in the frequency or intensity of placental Cot-1 holes.
    [Show full text]
  • Genetic and Genomic Analysis of Hyperlipidemia, Obesity and Diabetes Using (C57BL/6J × TALLYHO/Jngj) F2 Mice
    University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Nutrition Publications and Other Works Nutrition 12-19-2010 Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice Taryn P. Stewart Marshall University Hyoung Y. Kim University of Tennessee - Knoxville, [email protected] Arnold M. Saxton University of Tennessee - Knoxville, [email protected] Jung H. Kim Marshall University Follow this and additional works at: https://trace.tennessee.edu/utk_nutrpubs Part of the Animal Sciences Commons, and the Nutrition Commons Recommended Citation BMC Genomics 2010, 11:713 doi:10.1186/1471-2164-11-713 This Article is brought to you for free and open access by the Nutrition at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Nutrition Publications and Other Works by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. Stewart et al. BMC Genomics 2010, 11:713 http://www.biomedcentral.com/1471-2164/11/713 RESEARCH ARTICLE Open Access Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice Taryn P Stewart1, Hyoung Yon Kim2, Arnold M Saxton3, Jung Han Kim1* Abstract Background: Type 2 diabetes (T2D) is the most common form of diabetes in humans and is closely associated with dyslipidemia and obesity that magnifies the mortality and morbidity related to T2D. The genetic contribution to human T2D and related metabolic disorders is evident, and mostly follows polygenic inheritance. The TALLYHO/ JngJ (TH) mice are a polygenic model for T2D characterized by obesity, hyperinsulinemia, impaired glucose uptake and tolerance, hyperlipidemia, and hyperglycemia.
    [Show full text]
  • Systematic Data-Querying of Large Pediatric Biorepository Identifies Novel Ehlers-Danlos Syndrome Variant Akshatha Desai1, John J
    Desai et al. BMC Musculoskeletal Disorders (2016) 17:80 DOI 10.1186/s12891-016-0936-8 RESEARCH ARTICLE Open Access Systematic data-querying of large pediatric biorepository identifies novel Ehlers-Danlos Syndrome variant Akshatha Desai1, John J. Connolly1, Michael March1, Cuiping Hou1, Rosetta Chiavacci1, Cecilia Kim1, Gholson Lyon1, Dexter Hadley1 and Hakon Hakonarson1,2* Abstract Background: Ehlers Danlos Syndrome is a rare form of inherited connective tissue disorder, which primarily affects skin, joints, muscle, and blood cells. The current study aimed at finding the mutation that causing EDS type VII C also known as “Dermatosparaxis” in this family. Methods: Through systematic data querying of the electronic medical records (EMRs) of over 80,000 individuals, we recently identified an EDS family that indicate an autosomal dominant inheritance. The family was consented for genomic analysis of their de-identified data. After a negative screen for known mutations, we performed whole genome sequencing on the male proband, his affected father, and unaffected mother. We filtered the list of non- synonymous variants that are common between the affected individuals. Results: The analysis of non-synonymous variants lead to identifying a novel mutation in the ADAMTSL2 (p. Gly421Ser) gene in the affected individuals. Sanger sequencing confirmed the mutation. Conclusion: Our work is significant not only because it sheds new light on the pathophysiology of EDS for the affected family and the field at large, but also because it demonstrates the utility of unbiased large-scale clinical recruitment in deciphering the genetic etiology of rare mendelian diseases. With unbiased large-scale clinical recruitment we strive to sequence as many rare mendelian diseases as possible, and this work in EDS serves as a successful proof of concept to that effect.
    [Show full text]
  • Reduced Transfer Coefficient of Carbon Monoxide in Pulmonary Arterial Hypertension Implicates Rare Protein-Truncating Variants I
    bioRxiv preprint doi: https://doi.org/10.1101/2019.12.11.871210; this version posted December 12, 2019. 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. Reduced transfer coefficient of carbon monoxide in pulmonary arterial hypertension implicates rare protein- truncating variants in KDR Genotype-phenotype inference reveals novel PAH risk genes Emilia M. Swietlik, M.D.[1], Daniel Greene, PhD[2,3], Na Zhu, PhD[4,5], Karyn Megy, PhD[2,3], Marcella Cogliano, M.Sc.[6], Smitha Rajaram, M.D.[7], Divya Pandya, M.Sc.[1], Tobias Tilly, M.Sc.[1], Katie A. Lutz, BS[8], Carrie C. L. Welch, PhD[4], Michael W. Pauciulo, BS, MBA[8,9], Laura Southgate, PhD[10], Jennifer M. Martin, M.St.[3], Carmen M. Treacy, B.Sc.[1], Harm J. Bogaard, M.D., PhD[11], Colin Church, PhD[12], Gerry Coghlan, M.D.[13], Anna W. Coleman, MS[8], Robin Condliffe, M.D.[14], Mélanie Eyries, PhD[15], Henning Gall, M.D., PhD[16], Stefano Ghio, M.D.[17], Simon Holden, PhD[18], Luke Howard, M.D., PhD.[19], David G. Kiely, M.D.[14], Gabor Kovacs, M.D.[20,21], Jim Lordan, PhD[22], Rajiv D. Machado, PhD[10], Robert V. MacKenzie Ross, M.B, B.Chir[23], Shahin Moledina, M.B.Ch.B.[24], David Montani, M.D., PhD[25], Horst Olschewski, M.D.[20,21], Joanna Pepke-Zaba, PhD[26], Christopher J.
    [Show full text]
  • WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT (51) International Patent Classification: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, C12Q 1/68 (2018.01) A61P 31/18 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, C12Q 1/70 (2006.01) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/US2018/056167 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 16 October 2018 (16. 10.2018) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 62/573,025 16 October 2017 (16. 10.2017) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, ΓΕ , IS, IT, LT, LU, LV, (71) Applicant: MASSACHUSETTS INSTITUTE OF MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TECHNOLOGY [US/US]; 77 Massachusetts Avenue, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Cambridge, Massachusetts 02139 (US).
    [Show full text]