Mutations on Protein Function
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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. -
C. Elegans Whole Genome Sequencing Reveals Mutational Signatures Related to Carcinogens and DNA Repair Deficiency
Downloaded from genome.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press C. elegans whole genome sequencing reveals mutational signatures related to carcinogens and DNA repair deficiency Authors: Bettina Meier * (1); Susanna L Cooke * (2); Joerg Weiss (1); Aymeric P Bailly (1,3); Ludmil B Alexandrov (2); John Marshall (2); Keiran Raine (2); Mark Maddison (2); Elizabeth Anderson (2); Michael R Stratton (2); Anton Gartner * (1); Peter J Campbell * (2,4,5). * These authors contributed equally to this project. Institutions: (1) Centre for Gene Regulation and Expression, University of Dundee, Dundee, UK. (2) Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK. (3) CRBM/CNRS UMR5237, University of Montpellier, Montpellier, France. (4) Department of Haematology, University of Cambridge, Cambridge, UK. (5) Department of Haematology, Addenbrooke’s Hospital, Cambridge, UK. Address for correspondence: Dr Peter J Campbell, Dr Anton Gartner, Cancer Genome Project, Centre for Gene Regulation and Expression, Wellcome Trust Sanger Institute, The University of Dundee, Hinxton CB10 1SA, Dow Street, Cambridgeshire, Dundee DD1 5EH UK. UK. Tel: +44 (0) 1223 494745 Phone: +44 (0) 1382 385809 Fax: +44 (0) 1223 494809 E-mail: [email protected] E-mail: [email protected] Running title: mutation profiling in C. elegans Keywords: mutation pattern, genetic and environmental factors, C. elegans, cisplatin, aflatoxin B1, whole-genome sequencing. Downloaded from genome.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press ABSTRACT Mutation is associated with developmental and hereditary disorders, ageing and cancer. While we understand some mutational processes operative in human disease, most remain mysterious. -
Abstracts In
ECCB 2014 Accepted Posters with Abstracts G: Bioinformatics of health and disease G01: Emile Rugamika Chimusa, Jacquiline Wangui Mugo and Nicola Mulder. Leveraging ancestry along the genome of admixed individuals to resolve missing heritability in disease scoring statistics Abstract: Human genetics has been haunted by the mystery of “missing heritability” of common traits. Although studies have discovered several variants associated with common diseases and traits, these variants typically appear to explain only a minority of the heritability. Resolving missing heritability, the difference between phenotypic variance explained by associated SNPs and estimates of narrow-sense heritability (h2), will inform strategies for disease mapping and prediction of complex traits. Among biased estimates of h2 due to epistatic interactions and rare variants not captured by genotyping arrays have been cited to be the most can be the most explanations for missing heritability. Here, we present an approach for estimating heritability of traits based on sharing local ancestry segments between pairs of unrelated individuals in an admixed population. From simulation data and real data, we demonstrated that our approach outperformed current approaches for estimating heritability of traits and holds values in admixture mapping for deconvoluting genes underlying ethnic differences in complex diseases risk. G02: Sylvain Mareschal, Pierre-Julien Viailly, Philippe Bertrand, Fabienne Desmots-Loyer, Elodie Bohers, Catherine Maingonnat, Karen Leroy, Thierry Fest and Fabrice Jardin. Next- Generation Sequencing applied to tailor targeted therapies in lymphoma: the RELYSE project Abstract: Non-Hodgkin Lymphomas (NHL) are lymphoid cell malignancies accounting for about 4% of all cancers, with an incidence rate of 12 cases per 100,000 and per year in Europe. -
Supplementary Table 1: Adhesion Genes Data Set
Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like, -
Human Genetics: International Projects and Personalized Medicine
Drug Metabol Pers Ther 2016; 31(1): 3–8 Mini Review Maria Apellaniz-Ruiza, Cristina Gallegoa, Sara Ruiz-Pintoa, Angel Carracedo and Cristina Rodríguez-Antona* Human genetics: international projects and personalized medicine DOI 10.1515/dmpt-2015-0032 Received August 31, 2015; accepted October 19, 2015; previously Introduction published online November 18, 2015 Genetic variation databases describe naturally occur- Abstract: In this article, we present the progress driven ring genetic differences among individuals of the same by the recent technological advances and new revolu- species. This variation, accounting for 0.1% of our DNA tionary massive sequencing technologies in the field of [1], permits the flexibility and survival of a population human genetics. We discuss this knowledge in relation in the face of changing environmental circumstances, with drug response prediction, from the germline genetic but it also influences how people differ in their risk of variation compiled in the 1000 Genomes Project or in the disease or their response to drugs. It is well known that Genotype-Tissue Expression project, to the phenome- variability in response to drug therapy is the rule rather genome archives, the international cancer projects, such than the exception for most drugs, and these differences as The Cancer Genome Atlas or the International Cancer are among the major challenges in current clinical prac- Genome Consortium, and the epigenetic variation and its tice, drug development, and drug regulation [2, 3]. Thus, influence in gene expression, including the regulation of rather than accepting the “one drug fits all” approach, drug metabolism. This review is based on the lectures pre- researchers envision that drugs need to be tailored to fit sented by the speakers of the Symposium “Human Genet- the profile of each individual patient. -
Metastatic Adrenocortical Carcinoma Displays Higher Mutation Rate and Tumor Heterogeneity Than Primary Tumors
ARTICLE DOI: 10.1038/s41467-018-06366-z OPEN Metastatic adrenocortical carcinoma displays higher mutation rate and tumor heterogeneity than primary tumors Sudheer Kumar Gara1, Justin Lack2, Lisa Zhang1, Emerson Harris1, Margaret Cam2 & Electron Kebebew1,3 Adrenocortical cancer (ACC) is a rare cancer with poor prognosis and high mortality due to metastatic disease. All reported genetic alterations have been in primary ACC, and it is 1234567890():,; unknown if there is molecular heterogeneity in ACC. Here, we report the genetic changes associated with metastatic ACC compared to primary ACCs and tumor heterogeneity. We performed whole-exome sequencing of 33 metastatic tumors. The overall mutation rate (per megabase) in metastatic tumors was 2.8-fold higher than primary ACC tumor samples. We found tumor heterogeneity among different metastatic sites in ACC and discovered recurrent mutations in several novel genes. We observed 37–57% overlap in genes that are mutated among different metastatic sites within the same patient. We also identified new therapeutic targets in recurrent and metastatic ACC not previously described in primary ACCs. 1 Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. 2 Center for Cancer Research, Collaborative Bioinformatics Resource, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. 3 Department of Surgery and Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA. Correspondence and requests for materials should be addressed to E.K. (email: [email protected]) NATURE COMMUNICATIONS | (2018) 9:4172 | DOI: 10.1038/s41467-018-06366-z | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-06366-z drenocortical carcinoma (ACC) is a rare malignancy with types including primary ACC from the TCGA to understand our A0.7–2 cases per million per year1,2. -
Strategic Plan 2011-2016
Strategic Plan 2011-2016 Wellcome Trust Sanger Institute Strategic Plan 2011-2016 Mission The Wellcome Trust Sanger Institute uses genome sequences to advance understanding of the biology of humans and pathogens in order to improve human health. -i- Wellcome Trust Sanger Institute Strategic Plan 2011-2016 - ii - Wellcome Trust Sanger Institute Strategic Plan 2011-2016 CONTENTS Foreword ....................................................................................................................................1 Overview .....................................................................................................................................2 1. History and philosophy ............................................................................................................ 5 2. Organisation of the science ..................................................................................................... 5 3. Developments in the scientific portfolio ................................................................................... 7 4. Summary of the Scientific Programmes 2011 – 2016 .............................................................. 8 4.1 Cancer Genetics and Genomics ................................................................................ 8 4.2 Human Genetics ...................................................................................................... 10 4.3 Pathogen Variation .................................................................................................. 13 4.4 Malaria -
Structural Determinants of Adhesion by Protocadherin-19 and Implications for Its Role in Epilepsy Sharon Cooper Cedarville University, [email protected]
Cedarville University DigitalCommons@Cedarville Science and Mathematics Faculty Publications Department of Science and Mathematics 10-27-2016 Structural Determinants of Adhesion by Protocadherin-19 and Implications for Its Role in Epilepsy Sharon Cooper Cedarville University, [email protected] James D. Jontes Marcos Sotomayor Follow this and additional works at: http://digitalcommons.cedarville.edu/ science_and_mathematics_publications Part of the Biology Commons, and the Cell Biology Commons Recommended Citation Cooper, S. R., Jontes, J. D., Sotomayor, M. (2016) Structural determinants of adhesion by Protocadherin-19 and implications for its role in epilepsy. eLife. 5:e18529. http://dx.doi.org/10.7554/eLife.18529. This Article is brought to you for free and open access by DigitalCommons@Cedarville, a service of the Centennial Library. It has been accepted for inclusion in Science and Mathematics Faculty Publications by an authorized administrator of DigitalCommons@Cedarville. For more information, please contact [email protected]. RESEARCH ARTICLE Structural determinants of adhesion by Protocadherin-19 and implications for its role in epilepsy Sharon R Cooper1,2, James D Jontes2*, Marcos Sotomayor1* 1Department of Chemistry and Biochemistry, The Ohio State University, Columbus, United States; 2Department of Neuroscience, The Ohio State University, Columbus, United States Abstract Non-clustered d-protocadherins are homophilic cell adhesion molecules essential for the development of the vertebrate nervous system, as several are closely linked to neurodevelopmental disorders. Mutations in protocadherin-19 (PCDH19) result in a female-limited, infant-onset form of epilepsy (PCDH19-FE). Over 100 mutations in PCDH19 have been identified in patients with PCDH19-FE, about half of which are missense mutations in the adhesive extracellular domain. -
Germline Determinants of the Somatic Mutation Landscape in 2,642 Cancer Genomes
bioRxiv preprint doi: https://doi.org/10.1101/208330; this version posted November 1, 2017. 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. Germline determinants of the somatic mutation landscape in 2,642 cancer genomes Sebastian M Waszak1*, Grace Tiao2*, Bin Zhu3*, Tobias Rausch1*, Francesc Muyas4,5#, Bernardo Rodríguez-Martín6,7#, Raquel Rabionet4#, Sergei Yakneen1#, Georgia Escaramis4,8, Yilong Li9, Natalie Saini10, Steven A Roberts11, German M Demidov4,5, Esa Pitkänen1; Olivier Delaneau12-14, Jose Maria Heredia-Genestar15, Joachim Weischenfeldt1,16, Suyash S Shringarpure17, Jieming Chen18; Hidewaki Nakagawa19, Ludmil B Alexandrov20, Oliver Drechsel4,5, L Jonathan Dursi21, Ayellet V Segre2, Erik Garrison9, Serap Erkek1, Nina Habermann1, Lara Urban22, Ekta Khurana23, Andy Cafferkey22, Shuto Hayashi24, Seiya Imoto25, Lauri A Aaltonen26, Eva G Alvarez6,7, Adrian Baez-Ortega27, Matthew Bailey33, Mattia Bosio4,5, Alicia L Bruzos6,7, Ivo Buchhalter28, Carlos D. Bustamante29, Claudia Calabrese22, Anthony DiBiase30, Mark Gerstein31-33, Aliaksei Z Holik4,5, Xing Hua3, Kuan-lin Huang34, Ivica Letunic35, Leszek J Klimczak36, Roelof Koster3, Sushant Kumar31, Mike McLellan34, Jay Mashl34, Lisa Mirabello3, Steven Newhouse22, Aparna Prasad4,5, Gunnar Rätsch37, Matthias Schlesner28, Roland Schwarz38, Pramod Sharma30, Tal Shmaya17, Nikos Sidiropoulos16, Lei Song3, -
Executive Summary Toward a Comprehensive Genomic Analysis
National Cancer Institute and National Human Genome Research Institute National Institutes of Health U.S. Department of Health and Human Services Executive Summary Toward a Comprehensive Genomic Analysis of Cancer Convened by: Andrew von Eschenbach, M.D., Director, National Cancer Institute Francis Collins, M.D., Ph.D., Director, National Human Genome Research Institute July 20-22, 2005 The Ritz-Carlton Washington, DC Workshop Executive Summary Purpose of the Workshop “Toward a Comprehensive Genomic Analysis of Cancer” was co-organized by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) as part of their collaboration to implement the recommendation of the National Cancer Advisory Board’s Working Group on Biomedical Technology to initiate a pilot phase of the Human Cancer Genome Project (HCGP). The long-term goal of the HCGP is to develop a comprehensive catalog of the genomic changes that occur in tumors and obtain an in-depth understanding about the relation of these changes to the biological processes in cancer. Such a complete information set will potentially revolutionize the cancer research community’s strategies to develop and implement major new approaches to prevent, detect, diagnose, and treat cancer, through much more efficient clinical trials and accelerated introduction of more effective therapies. The workshop explored critical issues in cancer biology, genomic technologies, bioinformatics, and the bioethical, consent, and legal issues that must be factored into the design and implementation of a two- phase approach to an HCGP, starting with a focused pilot program. The aim of the pilot phase is to demonstrate that comprehensive characterization of a tumor type1, when analyzed in conjunction with carefully obtained, deep biological information about the tumor type, will facilitate the development of clinically meaningful applications in a way that has previously been unavailable to cancer researchers. -
Human Genetics 1990–2009
Portfolio Review Human Genetics 1990–2009 June 2010 Acknowledgements The Wellcome Trust would like to thank the many people who generously gave up their time to participate in this review. The project was led by Liz Allen, Michael Dunn and Claire Vaughan. Key input and support was provided by Dave Carr, Kevin Dolby, Audrey Duncanson, Katherine Littler, Suzi Morris, Annie Sanderson and Jo Scott (landscaping analysis), and Lois Reynolds and Tilli Tansey (Wellcome Trust Expert Group). We also would like to thank David Lynn for his ongoing support to the review. The views expressed in this report are those of the Wellcome Trust project team – drawing on the evidence compiled during the review. We are indebted to the independent Expert Group, who were pivotal in providing the assessments of the Wellcome Trust’s role in supporting human genetics and have informed ‘our’ speculations for the future. Finally, we would like to thank Professor Francis Collins, who provided valuable input to the development of the timelines. The Wellcome Trust is a charity registered in England and Wales, no. 210183. Contents Acknowledgements 2 Overview and key findings 4 Landmarks in human genetics 6 1. Introduction and background 8 2. Human genetics research: the global research landscape 9 2.1 Human genetics publication output: 1989–2008 10 3. Looking back: the Wellcome Trust and human genetics 14 3.1 Building research capacity and infrastructure 14 3.1.1 Wellcome Trust Sanger Institute (WTSI) 15 3.1.2 Wellcome Trust Centre for Human Genetics 15 3.1.3 Collaborations, consortia and partnerships 16 3.1.4 Research resources and data 16 3.2 Advancing knowledge and making discoveries 17 3.3 Advancing knowledge and making discoveries: within the field of human genetics 18 3.4 Advancing knowledge and making discoveries: beyond the field of human genetics – ‘ripple’ effects 19 Case studies 22 4. -
Dysregulation of Post-Transcriptional Modification by Copy Number
Yoshikawa et al. Translational Psychiatry (2021) 11:331 https://doi.org/10.1038/s41398-021-01460-1 Translational Psychiatry ARTICLE Open Access Dysregulation of post-transcriptional modification by copy number variable microRNAs in schizophrenia with enhanced glycation stress Akane Yoshikawa1,2,ItaruKushima 3,4, Mitsuhiro Miyashita 1,5,6,KazuyaToriumi 1, Kazuhiro Suzuki 1,5, Yasue Horiuchi 1, Hideya Kawaji 7, Shunya Takizawa8,NorioOzaki 3, Masanari Itokawa1 and Makoto Arai 1 Abstract Previously, we identified a subpopulation of schizophrenia (SCZ) showing increased levels of plasma pentosidine, a marker of glycation and oxidative stress. However, its causative genetic factors remain largely unknown. Recently, it has been suggested that dysregulated posttranslational modification by copy number variable microRNAs (CNV-miRNAs) may contribute to the etiology of SCZ. Here, an integrative genome-wide CNV-miRNA analysis was performed to investigate the etiology of SCZ with accumulated plasma pentosidine (PEN-SCZ). The number of CNV-miRNAs and the gene ontology (GO) in the context of miRNAs within CNVs were compared between PEN-SCZ and non-PEN-SCZ groups. Gene set enrichment analysis of miRNA target genes was further performed to evaluate the pathways affected in PEN-SCZ. We show that miRNAs were significantly enriched within CNVs in the PEN-SCZ versus non-PEN-SCZ groups (p = 0.032). Of note, as per GO analysis, the dysregulated neurodevelopmental events in the two groups may have different origins. Additionally, gene set enrichment analysis of miRNA target genes revealed that miRNAs involved in glycation/oxidative stress and synaptic neurotransmission, especially glutamate/GABA receptor signaling, fi 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; were possibly affected in PEN-SCZ.