Genome-Wide Characterization of Genetic Variants and Putative
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Identifying Novel Disease-Associated Variants and Understanding The
Identifying Novel Disease-variants and Understanding the Role of the STAT1-STAT4 Locus in SLE A dissertation submitted to the Graduate School of University of Cincinnati In partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Immunology Graduate Program of the College of Medicine by Zubin H. Patel B.S., Worcester Polytechnic Institute, 2009 John B. Harley, M.D., Ph.D. Committee Chair Gurjit Khurana Hershey, M.D., Ph.D Leah C. Kottyan, Ph.D. Harinder Singh, Ph.D. Matthew T. Weirauch, Ph.D. Abstract Systemic Lupus Erythematosus (SLE) or lupus is an autoimmune disorder caused by an overactive immune system with dysregulation of both innate and adaptive immune pathways. It can affect all major organ systems and may lead to inflammation of the serosal and mucosal surfaces. The pathogenesis of lupus is driven by genetic factors, environmental factors, and gene-environment interactions. Heredity accounts for a substantial proportion of SLE risk, and the role of specific genetic risk loci has been well established. Identifying the specific causal genetic variants and the underlying molecular mechanisms has been a major area of investigation. This thesis describes efforts to develop an analytical approach to identify candidate rare variants from trio analyses and a fine-mapping analysis at the STAT1-STAT4 locus, a well-replicated SLE-risk locus. For the STAT1-STAT4 locus, subsequent functional biological studies demonstrated genotype dependent gene expression, transcription factor binding, and DNA regulatory activity. Rare variants are classified as variants across the genome with an allele-frequency less than 1% in ancestral populations. -
Hearing Aging Is 14.1±0.4% GWAS-Heritable
medRxiv preprint doi: https://doi.org/10.1101/2021.07.05.21260048; this version posted July 7, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license . Predicting age from hearing test results with machine learning reveals the genetic and environmental factors underlying accelerated auditory aging Alan Le Goallec1,2+, Samuel Diai1+, Théo Vincent1, Chirag J. Patel1* 1Department of Biomedical Informatics, Harvard Medical School, Boston, MA, 02115, USA 2Department of Systems, Synthetic and Quantitative Biology, Harvard University, Cambridge, MA, 02118, USA +Co-first authors *Corresponding author Contact information: Chirag J Patel [email protected] Abstract With the aging of the world population, age-related hearing loss (presbycusis) and other hearing disorders such as tinnitus become more prevalent, leading to reduced quality of life and social isolation. Unveiling the genetic and environmental factors leading to age-related auditory disorders could suggest lifestyle and therapeutic interventions to slow auditory aging. In the following, we built the first machine learning-based hearing age predictor by training models to predict chronological age from hearing test results (root mean squared error=7.10±0.07 years; R-Squared=31.4±0.8%). We defined hearing age as the prediction outputted by the model on unseen samples, and accelerated auditory aging as the difference between a participant’s hearing age and age. We then performed a genome wide association study [GWAS] and found that accelerated hearing aging is 14.1±0.4% GWAS-heritable. -
Supplementary Information
Supplementary Information PathwayMatcher: multi-omics pathway mapping and proteoform network generation Luis Francisco Hernández Sánchez1,2,3, Bram Burger4,5, Carlos Horro4,5, Antonio Fabregat3, Stefan Johansson1,2, Pål Rasmus Njølstad1,6, Harald Barsnes4,5, Henning Hermjakob3,7, and Marc Vaudel1,2,* 1 K.G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Norway 2 Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway 3 European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom 4 Proteomics Unit, Department of Biomedicine, University of Bergen, Bergen, Norway 5 Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway 6 Department of Pediatrics, Haukeland University Hospital, Bergen, Norway 7 Beijing Proteome Research Center, National Center for Protein Sciences Beijing, Beijing, China * To whom correspondence should be addressed Abstract Mapping biomedical data to functional knowledge is an essential task in biomedicine and can be achieved by querying gene or protein identifiers in pathway knowledgebases. Here, we demonstrate that including fine-granularity information such as post-translational modifications greatly increases the specificity of the analysis. We present PathwayMatcher (github.com/PathwayAnalysisPlatform/PathwayMatcher), a bioinformatic application for mapping multi-omics data to pathways and show how this enables the -
Seq2pathway Vignette
seq2pathway Vignette Bin Wang, Xinan Holly Yang, Arjun Kinstlick May 19, 2021 Contents 1 Abstract 1 2 Package Installation 2 3 runseq2pathway 2 4 Two main functions 3 4.1 seq2gene . .3 4.1.1 seq2gene flowchart . .3 4.1.2 runseq2gene inputs/parameters . .5 4.1.3 runseq2gene outputs . .8 4.2 gene2pathway . 10 4.2.1 gene2pathway flowchart . 11 4.2.2 gene2pathway test inputs/parameters . 11 4.2.3 gene2pathway test outputs . 12 5 Examples 13 5.1 ChIP-seq data analysis . 13 5.1.1 Map ChIP-seq enriched peaks to genes using runseq2gene .................... 13 5.1.2 Discover enriched GO terms using gene2pathway_test with gene scores . 15 5.1.3 Discover enriched GO terms using Fisher's Exact test without gene scores . 17 5.1.4 Add description for genes . 20 5.2 RNA-seq data analysis . 20 6 R environment session 23 1 Abstract Seq2pathway is a novel computational tool to analyze functional gene-sets (including signaling pathways) using variable next-generation sequencing data[1]. Integral to this tool are the \seq2gene" and \gene2pathway" components in series that infer a quantitative pathway-level profile for each sample. The seq2gene function assigns phenotype-associated significance of genomic regions to gene-level scores, where the significance could be p-values of SNPs or point mutations, protein-binding affinity, or transcriptional expression level. The seq2gene function has the feasibility to assign non-exon regions to a range of neighboring genes besides the nearest one, thus facilitating the study of functional non-coding elements[2]. Then the gene2pathway summarizes gene-level measurements to pathway-level scores, comparing the quantity of significance for gene members within a pathway with those outside a pathway. -
1 Supporting Information for a Microrna Network Regulates
Supporting Information for A microRNA Network Regulates Expression and Biosynthesis of CFTR and CFTR-ΔF508 Shyam Ramachandrana,b, Philip H. Karpc, Peng Jiangc, Lynda S. Ostedgaardc, Amy E. Walza, John T. Fishere, Shaf Keshavjeeh, Kim A. Lennoxi, Ashley M. Jacobii, Scott D. Rosei, Mark A. Behlkei, Michael J. Welshb,c,d,g, Yi Xingb,c,f, Paul B. McCray Jr.a,b,c Author Affiliations: Department of Pediatricsa, Interdisciplinary Program in Geneticsb, Departments of Internal Medicinec, Molecular Physiology and Biophysicsd, Anatomy and Cell Biologye, Biomedical Engineeringf, Howard Hughes Medical Instituteg, Carver College of Medicine, University of Iowa, Iowa City, IA-52242 Division of Thoracic Surgeryh, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada-M5G 2C4 Integrated DNA Technologiesi, Coralville, IA-52241 To whom correspondence should be addressed: Email: [email protected] (M.J.W.); yi- [email protected] (Y.X.); Email: [email protected] (P.B.M.) This PDF file includes: Materials and Methods References Fig. S1. miR-138 regulates SIN3A in a dose-dependent and site-specific manner. Fig. S2. miR-138 regulates endogenous SIN3A protein expression. Fig. S3. miR-138 regulates endogenous CFTR protein expression in Calu-3 cells. Fig. S4. miR-138 regulates endogenous CFTR protein expression in primary human airway epithelia. Fig. S5. miR-138 regulates CFTR expression in HeLa cells. Fig. S6. miR-138 regulates CFTR expression in HEK293T cells. Fig. S7. HeLa cells exhibit CFTR channel activity. Fig. S8. miR-138 improves CFTR processing. Fig. S9. miR-138 improves CFTR-ΔF508 processing. Fig. S10. SIN3A inhibition yields partial rescue of Cl- transport in CF epithelia. -
Biological and Prognostic Significance of Chromosome 5Q Deletions in Myeloid Malignancies Aristoteles A.N
Review Biological and Prognostic Significance of Chromosome 5q Deletions in Myeloid Malignancies Aristoteles A.N. Giagounidis,1Ulrich Germing,2 and Carlo Aul1 Abstract The presence of del(5q), either as the sole karyotypic abnormality or as part of a more complex karyotype, has distinct clinical implications for myelodysplastic syndromes (MDS) and acute myeloid leukemia. The 5qÀ syndrome, a subtype of low-riskMDS, is characterized by an isolated 5q deletion and <5% blasts in the bone marrow and can serve as a useful model for studying the role of 5q deletions in the pathogenesis and prognosis of myeloid malignancies. Recent clinical results with lenalidomide, an oral immunomodulatory drug, have shown durable erythroid responses, including transfusion independence and complete cytogenetic remissions in patients with del(5q) MDS with or without additional chromosomal abnormalities. These results indicate that lenalidomide can overcome the pathogenic effect of 5q deletion in MDS and restore bone marrow balance. The data provide important new insights into the pathobiology of 5q chromo- somal deletions in myeloid malignancies. Cytogenetic abnormalities are detected in the bone marrow of preponderance, refractory macrocytic anemia, normal or high over 50% of patients diagnosed with primary myelodysplastic platelet counts, hypolobulated megakaryocytes, and modest syndromes (MDS) or myeloid leukemias, and up to 80% of leukopenia (11, 14, 17). The prognosis is favorable in 5qÀ patients with secondary or therapy-related MDS (1, 2). These syndrome with relatively low risk of transformation to AML abnormalities can be characterized as being balanced or (11, 18). Although the limits of 5q deletions vary among unbalanced (3, 4). Balanced cytogenetic abnormalities include patients with 5qÀ syndrome, the most frequent deletion is reciprocal translocations, inversions, and insertions (3, 5, 6). -
Aneuploidy: Using Genetic Instability to Preserve a Haploid Genome?
Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Science (Cancer Biology) Aneuploidy: Using genetic instability to preserve a haploid genome? Submitted by: Ramona Ramdath In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Science Examination Committee Signature/Date Major Advisor: David Allison, M.D., Ph.D. Academic James Trempe, Ph.D. Advisory Committee: David Giovanucci, Ph.D. Randall Ruch, Ph.D. Ronald Mellgren, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: April 10, 2009 Aneuploidy: Using genetic instability to preserve a haploid genome? Ramona Ramdath University of Toledo, Health Science Campus 2009 Dedication I dedicate this dissertation to my grandfather who died of lung cancer two years ago, but who always instilled in us the value and importance of education. And to my mom and sister, both of whom have been pillars of support and stimulating conversations. To my sister, Rehanna, especially- I hope this inspires you to achieve all that you want to in life, academically and otherwise. ii Acknowledgements As we go through these academic journeys, there are so many along the way that make an impact not only on our work, but on our lives as well, and I would like to say a heartfelt thank you to all of those people: My Committee members- Dr. James Trempe, Dr. David Giovanucchi, Dr. Ronald Mellgren and Dr. Randall Ruch for their guidance, suggestions, support and confidence in me. My major advisor- Dr. David Allison, for his constructive criticism and positive reinforcement. -
Download Thesis
This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ The Genetics and Spread of Amyotrophic Lateral Sclerosis Jones, Ashley Richard Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 07. Oct. 2021 THE GENETICS AND SPREAD OF AMYOTROPHIC LATERAL SCLEROSIS Ashley Richard Jones PhD in Clinical Neuroscience - 1 - Abstract Our knowledge of the genetic contribution to Amyotrophic Lateral Sclerosis (ALS) is rapidly growing, and there is increasing research into how ALS spreads through the motor system and beyond. -
Mutation Analysis of Genes Within the Dynactin Complex in a Cohort of Hereditary Peripheral Neuropathies
Clin Genet 2016: 90: 127–133 © 2015 John Wiley & Sons A/S. Printed in Singapore. All rights reserved Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12712 Original Article Mutation analysis of genes within the dynactin complex in a cohort of hereditary peripheral neuropathies a a Tey S., Ahmad-Annuar A., Drew A.P., Shahrizaila N., Nicholson G.A., S. Tey , A. Ahmad-Annuar , Kennerson M.L. Mutation analysis of genes within the dynactin complex in A.P. Drewb, N. Shahrizailac, , a cohort of hereditary peripheral neuropathies. G.A. Nicholsonb d and Clin Genet 2016: 90: 127–133. © John Wiley & Sons A/S. Published by M.L. Kennersonb,d John Wiley & Sons Ltd, 2015 aDepartment of Biomedical Science, The cytoplasmic dynein–dynactin genes are attractive candidates for Faculty of Medicine, University of Malaya, b neurodegenerative disorders given their functional role in retrograde Kuala Lumpur, Malaysia, Northcott transport along neurons. The cytoplasmic dynein heavy chain (DYNC1H1) Neuroscience Laboratory, ANZAC Research Institute, and Sydney Medical gene has been implicated in various neurodegenerative disorders, and School, University of Sydney, Sydney, dynactin 1 (DCTN1) genes have been implicated in a wide spectrum of Australia, cDepartment of Medicine, disorders including motor neuron disease, Parkinson’s disease, spinobulbar Faculty of Medicine, University of Malaya, muscular atrophy and hereditary spastic paraplegia. However, the Kuala Lumpur, Malaysia, and dMolecular involvement of other dynactin genes with inherited peripheral neuropathies Medicine Laboratory, Concord Hospital, (IPN) namely, hereditary sensory neuropathy, hereditary motor neuropathy Sydney, Australia and Charcot–Marie–Tooth disease is under reported. We screened eight genes; DCTN1-6 and ACTR1A and ACTR1B in 136 IPN patients using Key words: Charcot–Marie–Tooth – whole-exome sequencing and high-resolution melt (HRM) analysis. -
Physiological and Pathophysiological Regulation of the Ryanodine Receptor in Skeletal Muscle
Physiological and pathophysiological regulation of the ryanodine receptor in skeletal muscle Alisa Umanskaya Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2015 © 2015 Alisa Umanskaya All rights reserved Abstract Physiological and pathophysiological regulation of ryanodine receptor in skeletal muscle Alisa Umanskaya Ryanodine receptor calcium release channels are essential for skeletal muscle contraction, as they mediate the release of calcium ions from intracellular stores into the cytosol. The data presented in this dissertation demonstrate the evolutionarily conserved mechanisms of skeletal muscle ryanodine receptor regulation in the physiological and pathophysiological states. Adrenergic stimulation causes increased skeletal muscle force, however, despite the well- established role of this physiological response, the molecular mechanism is not known. Here we present a mechanism whereby phosphorylation of a single amino acid on the ryanodine receptor is a key signal in the physiological stress-induced inotropic response in mouse skeletal muscle. Therefore acute post-translational modifications of ryanodine receptor channels are important for healthy muscle contraction. Conversely, chronic stress-induced post-translational modifications result in poorly functioning murine ryanodine receptor channels that contribute to skeletal muscle dysfunction in age- dependent skeletal muscle weakness and Muscular Dystrophies. Finally, we present data that demonstrates striking evolutionary conservation in ryanodine receptor regulation in the physiological and pathophysiological states between mice and C. elegans. This work has broad implications for understanding the underlying mechanisms of skeletal muscle contraction and important disorders that affect human health. Furthermore, this works presents ryanodine receptor channels as a viable therapeutic target for age-related skeletal muscle weakness, Muscular Dystrophies, and also implicates C. -
Regular Article
From www.bloodjournal.org by guest on April 6, 2015. For personal use only. Regular Article IMMUNOBIOLOGY Hemophagocytic lymphohistiocytosis caused by dominant-negative mutations in STXBP2 that inhibit SNARE-mediated membrane fusion Waldo A. Spessott,1 Maria L. Sanmillan,1 Margaret E. McCormick,1 Nishant Patel,2 Joyce Villanueva,3 Kejian Zhang,4 Kim E. Nichols,5 and Claudio G. Giraudo1 1Department of Pathology and Laboratory Medicine, and 2Division of Oncology, Department of Pediatrics, The Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA; 3Division of Bone Marrow Transplant and Immune Deficiency, and 4Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH; and 5Division of Cancer Predisposition, Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN Key Points Familial hemophagocytic lymphohistiocytosis (F-HLH) and Griscelli syndrome type 2 (GS) are life-threatening immunodeficiencies characterized by impaired cytotoxic T lymphocyte • Monoallelic STXBP2 mutations (CTL) and natural killer (NK) cell lytic activity. In the majority of cases, these disorders are affecting codon 65 impair caused by biallelic inactivating germline mutations in genes such as RAB27A (GS) and PRF1, lymphocyte cytotoxicity and UNC13D, STX11,andSTXBP2 (F-HLH). Although monoallelic (ie, heterozygous) mutations contribute to hemophagocytic have been identified in certain patients, the clinical significance and molecular mechanisms lymphohistiocytosis. by which these mutations influence CTL and NK cell function remain poorly understood. • Munc18-2R65Q/W mutant Here, we characterize 2 novel monoallelic hemophagocytic lymphohistiocytosis (HLH)- associated mutations affecting codon 65 of STXPB2, the gene encoding Munc18-2, a member proteins function in a dominant- of the SEC/MUNC18 family. -
Open Data for Differential Network Analysis in Glioma
International Journal of Molecular Sciences Article Open Data for Differential Network Analysis in Glioma , Claire Jean-Quartier * y , Fleur Jeanquartier y and Andreas Holzinger Holzinger Group HCI-KDD, Institute for Medical Informatics, Statistics and Documentation, Medical University Graz, Auenbruggerplatz 2/V, 8036 Graz, Austria; [email protected] (F.J.); [email protected] (A.H.) * Correspondence: [email protected] These authors contributed equally to this work. y Received: 27 October 2019; Accepted: 3 January 2020; Published: 15 January 2020 Abstract: The complexity of cancer diseases demands bioinformatic techniques and translational research based on big data and personalized medicine. Open data enables researchers to accelerate cancer studies, save resources and foster collaboration. Several tools and programming approaches are available for analyzing data, including annotation, clustering, comparison and extrapolation, merging, enrichment, functional association and statistics. We exploit openly available data via cancer gene expression analysis, we apply refinement as well as enrichment analysis via gene ontology and conclude with graph-based visualization of involved protein interaction networks as a basis for signaling. The different databases allowed for the construction of huge networks or specified ones consisting of high-confidence interactions only. Several genes associated to glioma were isolated via a network analysis from top hub nodes as well as from an outlier analysis. The latter approach highlights a mitogen-activated protein kinase next to a member of histondeacetylases and a protein phosphatase as genes uncommonly associated with glioma. Cluster analysis from top hub nodes lists several identified glioma-associated gene products to function within protein complexes, including epidermal growth factors as well as cell cycle proteins or RAS proto-oncogenes.