DOCSLIB.ORG

Downloaded from the NHGRI Website

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Downloaded from the NHGRI Website Development and Evaluation of Software for Applied Clinical Genomics by Casper Shyr BSc (Computer Science and Biology), The University of British Columbia, 2010 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Doctor of Philosophy in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Bioinformatics) The University of British Columbia (Vancouver) April 2016 © Casper Shyr, 2016 Abstract High-throughput next-generation DNA sequencing has evolved rapidly over the past 20 years. The Human Genome Project published its first draft of the human genome in 2000 at an enormous cost of 3 billion dollars, and was an international collaborative effort that spanned more than a decade. Subsequent technological innovations have decreased that cost by six orders of magnitude down to a thousand dollars, while throughput has increased by over 100 times to a current delivery of gigabase of data per run. In bioinformatics, significant efforts to capitalize on the new capacities have produced software for the identification of deviations from the reference sequence, including single nucleotide variants, short insertions/deletions, and more complex chromosomal characteristics such as copy number variations and translocations. Clinically, hospitals are starting to incorporate sequencing technology as part of exploratory projects to discover underlying causes of diseases with suspected genetic etiology, and to provide personalized clinical decision support based on patients’ genetic predispositions. As with any new large-scale data, a need has emerged for mechanisms to translate knowledge from computationally oriented informatics specialists to the clinically oriented users who interact with it. In the genomics field, the complexity of the data, combined with the gap in perspectives and skills between computational biologists and clinicians, present an unsolved grand challenge for bioinformaticians to translate patient genomic information to facilitate clinical decision-making. This doctoral thesis focuses on a comparative design analysis of clinical decision support systems and prototypes interacting with patient genomes under various sectors of healthcare to ultimately improve the treatment and well-being of patients. Through a combination of usability methodologies across multiple distinct clinical user groups, the thesis highlights reoccurring domain-specific challenges and introduces ways to overcome the roadblocks for translation of next-generation sequencing from research laboratory to a multidisciplinary hospital environment. To improve the interpretation efficiency of patient genomes and informed by the design analysis findings, a novel computational approach to prioritize exome variants ii based on automated appraisal of patient phenotypes is introduced. Finally, the thesis research incorporates applied genome analysis via clinical collaborations to inform interface design and enable mastery of genome analysis. iii Preface The work described in this thesis is based upon research done by Casper Shyr in Dr. Wyeth W. Wasserman’s group at the Centre for Molecular medicine and Therapeutics (CMMT), Child and Family Research Institute (CFRI) at the BC Children’s Hospital. Part of the research is done as collaborations with OMICS2TREATID team, led by Dr. Clara van Karnebeek, for which Casper Shyr was granted co- authorship on the publications that came out. Works that have been published in peer-reviewed scientific journals are listed below. Contributions from Casper Shyr and acknowledgements to other members are discussed below. Work in chapter 2 and 3 were done by Casper Shyr, with support and guidance from Dr. Andre Kushniruk, Dr. Jehannine Austin, Dr. Sohrab Shah, and Dr. Clara van Karnebeek. Dr. Kushniruk and Dr. Wasserman were particularly involved in designing the study. Dr. Kushniruk further assisted with the data analysis. Dr. van Karnebeek facilitated the recruitment process. Cynthia Ye, Alice Chou, and Dr. Ekaterina Nosova helped with the design of tutorial videos. Patrick Tan, Calvin Lefebvre, and David Arenillas supported the usability evaluations by being initial participants. Jonathan Chang and Michael Hockertz provided the equipment necessary to conduct the usability analysis. This work was supported by Canadian Institutes of Health Research (CIHR) grant number MOP-82875, Natural Sciences and Engineering Research Council of Canada (NSERC) grant number RGPIN355532-10, Omics2TreatID, and Genome Canada/Genome BC 174DE (ABC4DE project). Icons and graphic arts incorporated into the figures and tables are modified from open repositories freely available for academic use. These two chapters have received ethical approval from UBC Children’s and Women’s Research Ethics Board (H12-02738, H13-02034). The work for chapter 2 is in part published as a first-author research article in C. Shyr, A. Kushniruk, W.W. Wasserman, 2014, “Usability study of clinical exome analysis software: Top lessons learned and recommendations”, Journal of Biomedical Informatics, 51, 129- 136. iv The work for chapter 3 was in part published as a first-author research article in C.Shyr, C.D.M. van Karnebeek, A. Kushniruk, W.W. Wasserman, 2015, “Dynamic software design for clinical exome and genome analyses: insights from bioinformaticians, clinical geneticists and genetic counselors”, JAMIA, Jun 27. pii: ocv053. doi: 10.1093/jamia/ocv053. [Epub ahead of print] The work in chapter 4 was done by Casper Shyr, with data generation and analysis contributions from Jessica Lee and Mike Gottlieb. Jessica was specifically involved with extracting publication records from NCBI, and Mike was involved with the calculations of dN/dS and related gene-level measurements. Dr. Maja Tarailo-Graovac formulated the experiment and oversaw the project collectively with Dr. Wyeth wasserman. Dr. Clara van Karnebeek facilitated the clinical coordination to include a relevant patient case into the manuscript as proof-of-concept. Written informed consent was obtained from the patient’s guardian/parent/next of kin for the publication of this report. Additional acknowledgements go towards Drs. J. Wu, J. Rozmus, S. Vercauteren, K. Hildebrand, T. Dewan and A. Garcera for clinical evaluation and management of the patient; Mrs. X. Han for Sanger sequencing; Mr. B. Sayson for data management; Mrs. M. Higginson for DNA extraction, sample handling and technical data; Dr. C. Vilarino-Guell for timely whole exome sequencing; Dr. W. Cheung for MeSHOP support; Mr. D. Arenillas and Mr. M. Hatas for systems support, and Dora Pak for research management support. The work was published as joint-first-authorship with Dr. Tarailo-Graovac in: C. Shyr, M. Tarailo-Graovac, M. Gottlieb, J.J.Y. Lee, C. van Karnebeek and W.W. Wasserman, 2014, “FLAGS, Frequently Mutated Genes in Public Exomes”, BMC Medical Genomics, 7, 64. The work in chapter 5 was done by Casper Shyr, with guidance from Dr. Maja Tarailo-Graovac, Dr. Anthony Mathelier and Dr. Sohrab Shah. Jessica Lee, Wenqiang Shi, Yifeng Li, and David Arenillas provided bioinformatics advice. Mike Gottlieb supplied codes that he wrote from GeneYenta project that were adapted for my own project. I am also grateful to the clinicians involved, including Dr. S. Stockler, v Dr. G. Horvath, Dr. S. Sirrs, Dr. K. Boycott, Dr. A. Lehman, Dr. G. Sinclair, Dr. H. Vallance, Dr. R. Salvarinova, and Dr. B. Gibson. Additional contributors include Ms. C. Ye for data analysis; Dr. A. Bhavsar and Dr. Linhua for wetlab experimentation; Ms. X. Han and Dr. B. Drogemoller for Sanger sequencing; Mr. B. Sayson and Ms. K. Townsend for data management; Ms. M. Higginson for DNA extraction, sample handling and technical data; Dr. C. Vilarino-Guell providing data on Ion-torrent based whole exome sequencing; Dr. W. Cheung for MeSHOP support; Mr. M. Hatas for systems support, and Ms. Dora Pak for research management support. The work has not been published at the time of writing. Chapter 6 and Chapter 7 highlight the collaborative works done with OMICS2TREATID. Casper Shyr provided bioinformatics processing and interpretive analysis on exomes and whole-genomes. Casper also contributed to the methodologies and results write-up in the manuscripts. The work was supported by David Arenillas for software development, Miroslav Hastas for server management, Dr. Virginie Bernard, Dr. Maja Tarailo-Graovac and Jessica Lee for bioinformatics analysis. Wet lab validations were carried out by Dr. Linhua Zhang and Xiaohua Han from Dr. Colin Ross laboratory. For chapter 6, Xiahua Han performed CA5A molecular analyses, M. Higginson and M. Zhou conducted DNA extraction, sample handling, and technical data, and M. Thomas and M. Lafek oversaw consent procedure and data management. K. MacKenzie conducted psychological testing of the siblings, and J. Rilstone helped with text editing. Additional acknowledgements extend towards colleagues in the Departments of Pediatrics and Medical Genetics, University of British Columbia (Canada) for clinical management of patients; Dr. D. Wishart and Dr. Rupa Mandal for NMR analyses (University of Alberta, Canada); Dr. M. Baumgärtner and Dr. P. Burda (Zürich University, Switzerland), Dr. J. Cameron (University of Toronto, Canada), Dr. M. Evans (University of Edinburgh, United Kingdom), Dr. M. Kaczocha and Dr. R. Haltiwänger (Stony Brook University, USA), Dr. G. Lavery (University of Birmingham, United Kingdom), Dr. A. Waheed and Dr. W. Sly (St. Louis University, USA), Dr. S. Corvera (University of Massachusetts Medical School, USA) for in vitro studies
Load more

Recommended publications
  • Identification of the Binding Partners for Hspb2 and Cryab Reveals
    Brigham Young University BYU ScholarsArchive Theses and Dissertations 2013-12-12 Identification of the Binding arP tners for HspB2 and CryAB Reveals Myofibril and Mitochondrial Protein Interactions and Non- Redundant Roles for Small Heat Shock Proteins Kelsey Murphey Langston Brigham Young University - Provo Follow this and additional works at: https://scholarsarchive.byu.edu/etd Part of the Microbiology Commons BYU ScholarsArchive Citation Langston, Kelsey Murphey, "Identification of the Binding Partners for HspB2 and CryAB Reveals Myofibril and Mitochondrial Protein Interactions and Non-Redundant Roles for Small Heat Shock Proteins" (2013). Theses and Dissertations. 3822. https://scholarsarchive.byu.edu/etd/3822 This Thesis is brought to you for free and open access by BYU ScholarsArchive. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of BYU ScholarsArchive. For more information, please contact [email protected], [email protected]. Identification of the Binding Partners for HspB2 and CryAB Reveals Myofibril and Mitochondrial Protein Interactions and Non-Redundant Roles for Small Heat Shock Proteins Kelsey Langston A thesis submitted to the faculty of Brigham Young University in partial fulfillment of the requirements for the degree of Master of Science Julianne H. Grose, Chair William R. McCleary Brian Poole Department of Microbiology and Molecular Biology Brigham Young University December 2013 Copyright © 2013 Kelsey Langston All Rights Reserved ABSTRACT Identification of the Binding Partners for HspB2 and CryAB Reveals Myofibril and Mitochondrial Protein Interactors and Non-Redundant Roles for Small Heat Shock Proteins Kelsey Langston Department of Microbiology and Molecular Biology, BYU Master of Science Small Heat Shock Proteins (sHSP) are molecular chaperones that play protective roles in cell survival and have been shown to possess chaperone activity.
    [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]
  • Análise Integrativa De Perfis Transcricionais De Pacientes Com
    UNIVERSIDADE DE SÃO PAULO FACULDADE DE MEDICINA DE RIBEIRÃO PRETO PROGRAMA DE PÓS-GRADUAÇÃO EM GENÉTICA ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas Ribeirão Preto – 2012 ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas Tese apresentada à Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo para obtenção do título de Doutor em Ciências. Área de Concentração: Genética Orientador: Prof. Dr. Eduardo Antonio Donadi Co-orientador: Prof. Dr. Geraldo A. S. Passos Ribeirão Preto – 2012 AUTORIZO A REPRODUÇÃO E DIVULGAÇÃO TOTAL OU PARCIAL DESTE TRABALHO, POR QUALQUER MEIO CONVENCIONAL OU ELETRÔNICO, PARA FINS DE ESTUDO E PESQUISA, DESDE QUE CITADA A FONTE. FICHA CATALOGRÁFICA Evangelista, Adriane Feijó Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas. Ribeirão Preto, 2012 192p. Tese de Doutorado apresentada à Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo. Área de Concentração: Genética. Orientador: Donadi, Eduardo Antonio Co-orientador: Passos, Geraldo A. 1. Expressão gênica – microarrays 2. Análise bioinformática por module maps 3. Diabetes mellitus tipo 1 4. Diabetes mellitus tipo 2 5. Diabetes mellitus gestacional FOLHA DE APROVAÇÃO ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas.
    [Show full text]
  • Supplemental Figure and Table Legends
    Supplemental figure and table legends Supplementary Figure 1: KIAA1841 is well conserved among vertebrates. NCBI HomoloGene pairwise alignment scores of human KIAA1841 sequence compared to other vertebrate orthologs. Supplementary Figure 2: µ-germline transcripts (GLT) and AID mRNA expression are not affected by overexpression of KIAA1841. Splenic B cells were isolated from wild-type mice, and transduced with retroviral vector control (pMIG) or a vector expressing KIAA1841. Levels of µ-GLT and AID mRNA were determined at 72h post-infection by RT-qPCR, and normalized to -actin mRNA and the pMIG control. The mean of three independent experiments +/- SD is shown. NS, p = not significant, p 0.05, two-tailed paired student’s t-test. Supplementary Figure 3: Overexpression of untagged and Xpress-tagged KIAA1841 does not affect cell proliferation. Splenic B cells were isolated from wild-type mice, stimulated with LPS+IL4, and transduced with retroviral vector control (pMIG) or a vector expressing KIAA1841 or Xpress (Xp)-tagged KIAA1841. Cells are labeled with seminaphthorhodafluor (SNARF) cell tracking dye and SNARF intensity was measured at 0h, 24h, and 48h after retroviral infection. Histograms of transduced cells (GFP+) for pMIG control, KIAA1841 and Xp-KIAA1841 were superimposed at each time point. Three independent retroviral infection experiments are shown. Supplementary Figure 4: Sequence alignment of the putative SANT domain of KIAA1841 with the SANT domain of SWI3. Alignment was performed using ClustalOmega; *, conserved residue, :, strongly similar residues, ., weakly similar residues. Numbers indicate amino acid residues in each sequence. Helix 3, which has been reported to be important for the chromatin remodeling function of SWI3 (Boyer et.
    [Show full text]
  • Molecular Dissection of Inbreeding Depression for Semen Quality Traits in Cattle
    FACULTY OF AGRICULTURE Maja Ferenčaković Molecular dissection of inbreeding depression for semen quality traits in cattle DOCTORAL THESIS Zagreb, 2015 AGRONOMSKI FAKULTET Maja Ferenčaković Molekularna disekcija inbriding depresije za svojstva kvalitete sperme kod goveda DOKTORSKI RAD Zagreb, 2015. FACULTY OF AGRICULTURE Maja Ferenčaković Molecular dissection of inbreeding depression for semen quality traits in cattle DOCTORAL THESIS Supervisors: Professor Ino Čurik, PhD Professor Johann Sölkner, PhD Zagreb, 2015 AGRONOMSKI FAKULTET Maja Ferenčaković Molekularna disekcija inbriding depresije za svojstva kvalitete sperme kod goveda DOKTORSKI RAD Mentori: prof. dr. sc. Ino Čurik Univ. Prof. DI. Dr. Johann Sölkner Zagreb, 2015. Supervisors: prof. dr. sc. Ino Čurik Department of Animal Science Faculty of Agriculture, University of Zagreb Svetošimunska cesta 25, 10000 Zagreb, Croatia [email protected] Univ. Prof. DI. Dr. Johann Sölkner University of Natural Resources and Life Sciences, Vienna, Austria [email protected] This doctoral thesis was evaluated by the Dissertation Evaluation Committee members: 1. Miroslav Kapš, PhD Full professor, Faculty of Agriculture, University of Zagreb, Croatia 2. Johannes Arjen Lenstra, PhD Associate professor, Utrecht University, Institute for Risk Assessment Sciences, The Netherlands 3. Vlatka Čubrić Čurik, PhD Assistant professor, Faculty of Agriculture, University of Zagreb, Croatia Doctoral thesis was defended at Faculty of Agriculture, University of Zagreb on ____________ 2015 in front of the Dissertation Defense Committee members: 1. Miroslav Kapš, PhD, _______________ Full professor, Faculty of Agriculture, University of Zagreb, Croatia, 2. Johannes Arjen Lenstra, PhD, _______________ Associate professor, Utrecht University, Institute for Risk Assessment Sciences, The Netherlands, 3. Vlatka Čubrić Čurik, PhD, _______________ Assistant professor, Faculty of Agriculture, University of Zagreb, Croatia.
    [Show full text]
  • Genetics of Hypertrophic Cardiomyopathy: Advances and Pitfalls in Molecular Diagnosis and Therapy
    The Application of Clinical Genetics Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Genetics of hypertrophic cardiomyopathy: advances and pitfalls in molecular diagnosis and therapy Catarina Roma-Rodrigues1 Abstract: Hypertrophic cardiomyopathy (HCM) is a primary disease of the cardiac muscle that Alexandra R Fernandes1,2 occurs mainly due to mutations (.1,400 variants) in genes encoding for the cardiac sarcomere. HCM, the most common familial form of cardiomyopathy, affecting one in every 500 people 1UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e in the general population, is typically inherited in an autosomal dominant pattern, and presents Tecnologia da Universidade Nova de variable expressivity and age-related penetrance. Due to the morphological and pathological Lisboa, Campus de Caparica, Caparica, Portugal; 2Centro de Química heterogeneity of the disease, the appearance and progression of symptoms is not straightforward. Estrutural, Instituto Superior Técnico, Most HCM patients are asymptomatic, but up to 25% develop significant symptoms, including Universidade de Lisboa, Lisboa, chest pain and sudden cardiac death. Sudden cardiac death is a dramatic event, since it occurs Portugal without warning and mainly in younger people, including trained athletes. Molecular diagnosis of HCM is of the outmost importance, since it may allow detection of subjects carrying muta- tions on HCM-associated genes before development of clinical symptoms of HCM. However, due to the genetic heterogeneity of HCM, molecular diagnosis is difficult. Currently, there are mainly four techniques used for molecular diagnosis of HCM, including Sanger sequencing, high resolution melting, mutation detection using DNA arrays, and next-generation sequencing techniques.
    [Show full text]
  • Inferring Biological Networks from Genome-Wide Transcriptional And
    INFERRING BIOLOGICAL NETWORKS FROM GENOME-WIDE TRANSCRIPTIONAL AND FITNESS DATA By WAZEER MOHAMMAD VARSALLY A thesis submitted to The University of Birmingham for the degree of Doctor of Philosophy College of Life and Environmental Sciences School of Biosciences The University of Birmingham July 2013 I University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. ABSTRACT In the last 15 years, the increased use of high throughput biology techniques such as genome-wide gene expression profiling, fitness profiling and protein interactomics has led to the generation of an extraordinary amount of data. The abundance of such diverse data has proven to be an essential foundation for understanding the complexities of molecular mechanisms and underlying pathways within a biological system. One approach of extrapolating biological information from this wealth of data has been through the use of reverse engineering methods to infer biological networks. This thesis demonstrates the capabilities and applications of such methodologies in identifying functionally enriched network modules in the yeast species Saccharomyces cerevisiae and Schizosaccharomyces pombe. This study marks the first time a mutual information based network inference approach has been applied to a set of specific genome-wide expression and fitness compendia, as well as the integration of these multi- level compendia.
    [Show full text]
  • Supplementary Data
    Supplemental figures Supplemental figure 1: Tumor sample selection. A total of 98 thymic tumor specimens were stored in Memorial Sloan-Kettering Cancer Center tumor banks during the study period. 64 cases corresponded to previously untreated tumors, which were resected upfront after diagnosis. Adjuvant treatment was delivered in 7 patients (radiotherapy in 4 cases, cyclophosphamide- doxorubicin-vincristine (CAV) chemotherapy in 3 cases). 34 tumors were resected after induction treatment, consisting of chemotherapy in 16 patients (cyclophosphamide-doxorubicin- cisplatin (CAP) in 11 cases, cisplatin-etoposide (PE) in 3 cases, cisplatin-etoposide-ifosfamide (VIP) in 1 case, and cisplatin-docetaxel in 1 case), in radiotherapy (45 Gy) in 1 patient, and in sequential chemoradiation (CAP followed by a 45 Gy-radiotherapy) in 1 patient. Among these 34 patients, 6 received adjuvant radiotherapy. 1 Supplemental Figure 2: Amino acid alignments of KIT H697 in the human protein and related orthologs, using (A) the Homologene database (exons 14 and 15), and (B) the UCSC Genome Browser database (exon 14). Residue H697 is highlighted with red boxes. Both alignments indicate that residue H697 is highly conserved. 2 Supplemental Figure 3: Direct comparison of the genomic profiles of thymic squamous cell carcinomas (n=7) and lung primary squamous cell carcinomas (n=6). (A) Unsupervised clustering analysis. Gains are indicated in red, and losses in green, by genomic position along the 22 chromosomes. (B) Genomic profiles and recurrent copy number alterations in thymic carcinomas and lung squamous cell carcinomas. Gains are indicated in red, and losses in blue. 3 Supplemental Methods Mutational profiling The exonic regions of interest (NCBI Human Genome Build 36.1) were broken into amplicons of 500 bp or less, and specific primers were designed using Primer 3 (on the World Wide Web for general users and for biologist programmers (see Supplemental Table 2) [1].
    [Show full text]
  • Human Social Genomics in the Multi-Ethnic Study of Atherosclerosis
    Getting “Under the Skin”: Human Social Genomics in the Multi-Ethnic Study of Atherosclerosis by Kristen Monét Brown A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Epidemiological Science) in the University of Michigan 2017 Doctoral Committee: Professor Ana V. Diez-Roux, Co-Chair, Drexel University Professor Sharon R. Kardia, Co-Chair Professor Bhramar Mukherjee Assistant Professor Belinda Needham Assistant Professor Jennifer A. Smith © Kristen Monét Brown, 2017 [email protected] ORCID iD: 0000-0002-9955-0568 Dedication I dedicate this dissertation to my grandmother, Gertrude Delores Hampton. Nanny, no one wanted to see me become “Dr. Brown” more than you. I know that you are standing over the bannister of heaven smiling and beaming with pride. I love you more than my words could ever fully express. ii Acknowledgements First, I give honor to God, who is the head of my life. Truly, without Him, none of this would be possible. Countless times throughout this doctoral journey I have relied my favorite scripture, “And we know that all things work together for good, to them that love God, to them who are called according to His purpose (Romans 8:28).” Secondly, I acknowledge my parents, James and Marilyn Brown. From an early age, you two instilled in me the value of education and have been my biggest cheerleaders throughout my entire life. I thank you for your unconditional love, encouragement, sacrifices, and support. I would not be here today without you. I truly thank God that out of the all of the people in the world that He could have chosen to be my parents, that He chose the two of you.
    [Show full text]
  • A Seventh Locus for Otosclerosis, OTSC7, Maps to Chromosome 6Q13–16.1
    European Journal of Human Genetics (2007) 15, 362–368 & 2007 Nature Publishing Group All rights reserved 1018-4813/07 $30.00 www.nature.com/ejhg ARTICLE A seventh locus for otosclerosis, OTSC7, maps to chromosome 6q13–16.1 Melissa Thys1, Kris Van Den Bogaert1, Vassiliki Iliadou2, Kathleen Vanderstraeten1, Nele Dieltjens1, Isabelle Schrauwen1, Wenjie Chen3, Nikolaos Eleftheriades4, Maria Grigoriadou5, Robert Jan Pauw6, Cor RWJ Cremers6, Richard JH Smith3, Michael B Petersen5 and Guy Van Camp*,1 1Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, Antwerp, Belgium; 2Clinical Psychoacoustics and Neurootology Laboratory, Neuroscience Department, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece; 3Molecular Otolaryngology Research Laboratories, Department of Otolaryngology, University of Iowa, 200 Hawkins Drive, Iowa City, IA, USA; 4Otolaryngology Departement, St Lucas Clinic, Thessaloniki, Greece; 5Department of Genetics, Institute of Child Health, ‘Aghia Sophia’ Children’s Hospital, Athens, Greece; 6Department of Otorhinolaryngology, University Medical Center St Radboud, Philips van Leydenlaan 15, Nijmegen, The Netherlands Otosclerosis is a common form of hearing impairment among white adults with a prevalence of 0.3–0.4%. It is caused by abnormal bone homeostasis of the otic capsule that compromises free motion of the stapes in the oval window. Otosclerosis is in most patients a multifactorial disease, caused by both genetic and environmental factors. In some cases, the disease is inherited as a monogenic autosomal dominant trait, sometimes with reduced penetrance. However, families large enough for genetic linkage studies are extremely rare. To date, five loci (OTSC1-5) have been reported, but none of the responsible genes have been cloned yet. An additional locus, OTSC6, has been reported to the HUGO nomenclature committee but the relevant linkage study has not been published.
    [Show full text]
  • Network of Micrornas-Mrnas Interactions in Pancreatic Cancer
    Hindawi Publishing Corporation BioMed Research International Volume 2014, Article ID 534821, 8 pages http://dx.doi.org/10.1155/2014/534821 Research Article Network of microRNAs-mRNAs Interactions in Pancreatic Cancer Elnaz Naderi,1 Mehdi Mostafaei,2 Akram Pourshams,1 and Ashraf Mohamadkhani1 1 Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran 2 Biotechnology Engineering, Islamic Azad University,Tehran North Branch, Tehran, Iran Correspondence should be addressed to Ashraf Mohamadkhani; [email protected] Received 5 February 2014; Revised 13 April 2014; Accepted 13 April 2014; Published 7 May 2014 Academic Editor: FangXiang Wu Copyright © 2014 Elnaz Naderi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. MicroRNAs are small RNA molecules that regulate the expression of certain genes through interaction with mRNA targets and are mainly involved in human cancer. This study was conducted to make the network of miRNAs-mRNAs interactions in pancreatic cancer as the fourth leading cause of cancer death. Methods. 56 miRNAs that were exclusively expressed and 1176 genes that were downregulated or silenced in pancreas cancer were extracted from beforehand investigations. MiRNA–mRNA interactions data analysis and related networks were explored using MAGIA tool and Cytoscape 3 software. Functional annotations of candidate genes in pancreatic cancer were identified by DAVID annotation tool. Results. This network is made of 217 nodes for mRNA, 15 nodes for miRNA, and 241 edges that show 241 regulations between 15 miRNAs and 217 target genes.
    [Show full text]
  • Supplementary Table 1. Hypermethylated Loci in Estrogen-Pre-Exposed Stem/Progenitor-Derived Epithelial Cells
    Supplementary Table 1. Hypermethylated loci in estrogen-pre-exposed stem/progenitor-derived epithelial cells. Entrez Gene Probe genomic location* Control# Pre-exposed# Description Gene ID name chr5:134392762-134392807 5307 PITX1 -0.112183718 6.077605311 paired-like homeodomain transcription factor 1 chr12:006600331-006600378 171017 ZNF384 -0.450661784 6.034362758 zinc finger protein 384 57121 GPR92 G protein-coupled receptor 92 chr3:015115848-015115900 64145 ZFYVE20 -1.38491748 5.544950925 zinc finger, FYVE domain containing 20 chr7:156312210-156312270 -2.026450994 5.430611412 chr4:009794114-009794159 9948 WDR1 0.335617144 5.352264173 WD repeat domain 1 chr17:007280631-007280676 284114 TMEM102 -2.427266294 5.060047786 transmembrane protein 102 chr20:055274561-055274606 655 BMP7 0.764898513 5.023260524 bone morphogenetic protein 7 chr10:088461669-088461729 11155 LDB3 0 4.817869864 LIM domain binding 3 chr7:005314259-005314304 80028 FBXL18 0.921361233 4.779265347 F-box and leucine-rich repeat protein 18 chr9:130571259-130571313 59335 PRDM12 1.123111331 4.740306098 PR domain containing 12 chr2:054768043-054768088 6711 SPTBN1 -0.089623066 4.691756995 spectrin, beta, non-erythrocytic 1 chr10:070330822-070330882 79009 DDX50 -2.848748309 4.691491169 DEAD (Asp-Glu-Ala-Asp) box polypeptide 50 chr1:162469807-162469854 54499 TMCO1 1.495802762 4.655023656 transmembrane and coiled-coil domains 1 chr2:080442234-080442279 1496 CTNNA2 1.296310425 4.507269831 catenin (cadherin-associated protein), alpha 2 347730 LRRTM1 leucine rich repeat transmembrane
    [Show full text]