DOCSLIB.ORG

Annotation Landscape Analysis with Genecards Arye Harel*1, Aron Inger, Gil Stelzer1, Liora Strichman-Almashanu1, Irina Dalah1, Marilyn Safran1,2 and Doron Lancet1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Annotation Landscape Analysis with Genecards Arye Harel*1, Aron Inger, Gil Stelzer1, Liora Strichman-Almashanu1, Irina Dalah1, Marilyn Safran1,2 and Doron Lancet1 BMC Bioinformatics BioMed Central Research article Open Access GIFtS: annotation landscape analysis with GeneCards Arye Harel*1, Aron Inger, Gil Stelzer1, Liora Strichman-Almashanu1, Irina Dalah1, Marilyn Safran1,2 and Doron Lancet1 Address: 1Department of Molecular Genetics, Weizmann Institute of Science Rehovot 76100, Israel and 2Department of Biological Services (Bioinformatics Unit), Weizmann Institute of Science, Rehovot 76100, Israel Email: Arye Harel* - [email protected]; Aron Inger - [email protected]; Gil Stelzer - [email protected]; Liora Strichman-Almashanu - [email protected]; Irina Dalah - [email protected]; Marilyn Safran - [email protected]; Doron Lancet - [email protected] * Corresponding author Published: 23 October 2009 Received: 22 February 2009 Accepted: 23 October 2009 BMC Bioinformatics 2009, 10:348 doi:10.1186/1471-2105-10-348 This article is available from: http://www.biomedcentral.com/1471-2105/10/348 © 2009 Harel et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Gene annotation is a pivotal component in computational genomics, encompassing prediction of gene function, expression analysis, and sequence scrutiny. Hence, quantitative measures of the annotation landscape constitute a pertinent bioinformatics tool. GeneCards® is a gene-centric compendium of rich annotative information for over 50,000 human gene entries, building upon 68 data sources, including Gene Ontology (GO), pathways, interactions, phenotypes, publications and many more. Results: We present the GeneCards Inferred Functionality Score (GIFtS) which allows a quantitative assessment of a gene's annotation status, by exploiting the unique wealth and diversity of GeneCards information. The GIFtS tool, linked from the GeneCards home page, facilitates browsing the human genome by searching for the annotation level of a specified gene, retrieving a list of genes within a specified range of GIFtS value, obtaining random genes with a specific GIFtS value, and experimenting with the GIFtS weighting algorithm for a variety of annotation categories. The bimodal shape of the GIFtS distribution suggests a division of the human gene repertoire into two main groups: the high-GIFtS peak consists almost entirely of protein-coding genes; the low- GIFtS peak consists of genes from all of the categories. Cluster analysis of GIFtS annotation vectors provides the classification of gene groups by detailed positioning in the annotation arena. GIFtS also provide measures which enable the evaluation of the databases that serve as GeneCards sources. An inverse correlation is found (for GIFtS>25) between the number of genes annotated by each source, and the average GIFtS value of genes associated with that source. Three typical source prototypes are revealed by their GIFtS distribution: genome-wide sources, sources comprising mainly highly annotated genes, and sources comprising mainly poorly annotated genes. The degree of accumulated knowledge for a given gene measured by GIFtS was correlated (for GIFtS>30) with the number of publications for a gene, and with the seniority of this entry in the HGNC database. Conclusion: GIFtS can be a valuable tool for computational procedures which analyze lists of large set of genes resulting from wet-lab or computational research. GIFtS may also assist the scientific community with identification of groups of uncharacterized genes for diverse applications, such as delineation of novel functions and charting unexplored areas of the human genome. Page 1 of 11 (page number not for citation purposes) BMC Bioinformatics 2009, 10:348 http://www.biomedcentral.com/1471-2105/10/348 Background In the quest for revealing the function of DNA sequences, 100000 scientists have used a variety of approaches, from molecu- lar techniques targeting specific genes, to systematic anal- yses of thousands of functional units encompassed by the transcriptome, proteome, and metabolome. This hetero- 10000 geneous mass of knowledge is time-dependent, with new information constantly arising from a variety of sources. Thus, a quantitative tool for assessing annotation depth is important for directing ongoing research and for analyz- 1000 ing the emerging results. Efforts in this field have included the Genome Annotation Scores (GAS) algorithm [1], which demonstrates a quantitative methodology of Source size Source size (number of genes) assigning annotations scores at the whole genome level, 100 the GO Annotation Quality (GAQ) score, which gives a quantitative measure of GO annotations [2], and the Gene Characterization Index (GCI), which scores the extent to which a gene's functionality is described, based 10 largely on the quantification of human perception, and 0204060 applied only to protein-encoding genes [3]. We now Source rank introduce the GeneCards Inferred Functionality Scores (GIFtS) tool [4], which utilizes the wealth of gene annota- SourceFigure size1 tion within GeneCards [5] to quantify the degree of func- Source size. The number of human gene entries in each tional knowledge about >50,000 GeneCards entries. one of the sources contributing to the GIFtS score. Sources GeneCards is a comprehensive gene-centric compendium are shown by their rank according to their size (see addi- of annotative information about human genes, automati- tional file 1: Table S1). A source's size is defined to be the cally mined from nearly 70 data sources [6-12]. Thus, number of GeneCards entries containing annotations from GIFtS can provide quantitative annotation estimates for a this source. very large number of genes, and at a significant depth, made possible by the exploitation of dozens of annota- tion resources. To study the effect of overlap between sources, we gener- ated a pairwise overlap matrix for all 68 data sources (see Results additional file 2, 3, 4: Tables S2, S3 and Fig. S1-A). For this GIFtS definition and applications we utilized a parameter (see Methods) which assesses the We devised the GeneCards Inferred Functionality Score overlap by gene set sharing. The rational is that if, for (GIFtS) which allows a quantitative assessment of a gene's example, all information about a set of genes, such as annotation status, with potential relevance to the degree microRNAs, is imported from one source to another, it of relevant functional knowledge. A GIFtS value for a gene will result in an overlap in gene sets. Based on the overlap is defined as the number of GeneCards sources, out of a matrix, we proceeded to select the 20 source pairs with the total of 68 (see additional file 1: Table S1), that include highest overlap (≥0.8), and eliminated (typically) one information about this gene (see Methods). Data sources source of each pair. Fig. 1S-B (see additional file 3: Fig.S1) have heterogeneous sizes, as estimated by the number of shows that the exclusion of overlapping sources has only human gene entries for which the source contains infor- a minor effect on the overall shape of the distribution, mation (Fig. 1), having an average of 11,404 ± 10,970 hence, by inference, on the relative positions of the major- entries per source. One of GeneCards' main aims is to ity of genes on the GIFtS scale. This may suggest that hav- incorporate overlapping sources, and perform integration ing an overlap among sources does not impose an adverse of data for different annotation fields. Considerable atten- effect on proposed functionality scale. While such a find- tion is also directed to conflicts among sources, one clear ing could be interpreted as suggesting over-representation example being the GeneLoc [8] member of the GeneCards of information items, we believe that source redundancy suite, which handles conflicts in genomic coordinates also has its advantages, as pointed out below. from Ensembl [13] and NCBI [14]. The overlap problem is particularly applicable for data extracted from genome- We also asked whether overlap might exert an advanta- wide sources such as Entrez Gene, Ensembl, GO [15], Uni- geous effect. For this, we comparatively analysed the GCI Prot [16] and InterPro [17] which are all closely linked scale with 6 data sources, i.e. having a lower (but not neg- and share some of the information presented, which may ligible) degree of source overlap, and GIFtS, which has 68 introduce a degree of redundancy. sources and a considerably higher extent of source over- Page 2 of 11 (page number not for citation purposes) BMC Bioinformatics 2009, 10:348 http://www.biomedcentral.com/1471-2105/10/348 lap. Focusing on the 489 genes with highest functionality sequence similarity), but also many genes that are not eas- scores in GCI, all having the same score of 10.0, we note ily defined by their symbols, such as non protein-coding that the same genes span a rather broad range of GIFtS val- genes. ues, from 51 to 84 (see additional file 5: Fig. S2-A). Thus, for the most well-annotated genes, the GIFtS scale dis- We asked what might distinguish genes with extremely plays a fine resolution not seen in GCI. We suspect that high GIFtS score (>75, right tail of the high-GIFtS peak) as this may actually arise from the diversity of overlapping compared to those at the top of the same peak (genes with sources in GIFtS. That this
Load more

Recommended publications
  • BIOINFORMATICS DOI: 10.1093/Bioinformatics/Btg1030
    Vol. 19 Suppl. 1 2003, pages i222–i224 BIOINFORMATICS DOI: 10.1093/bioinformatics/btg1030 GeneLoc: exon-based integration of human genome maps Naomi Rosen, Vered Chalifa-Caspi, Orit Shmueli, Avital Adato, Michal Lapidot, Julie Stampnitzky, Marilyn Safran ∗ and Doron Lancet Weizmann Institute of Science, Rehovot, Israel Received on January 6, 2003; accepted on February 20, 2003 ABSTRACT to provide a comprehensive gene list, NCBI’s LocusLink Motivation: Despite the numerous available whole- contains thousands of model genes, categorized by level genome mapping resources, no comprehensive, inte- and type of support. Even known genes appearing in every grated map of the human genome yet exists. database may have different names in each database. The Results: GeneLoc, software adjunct to GeneCards and biologist must move among databases to figure out which UDB, integrates gene lists by comparing genomic coordi- genes are the same, and which could be a novel gene nates at the exon level and assigns unique and meaningful sought. UCSC’s Genome Browser website maps genes identifiers to each gene. from several sources on the same scale, but the maps are Availability: http://bioinfo.weizmann.ac.il/genecards and not integrated, making it difficult to relate genes from http://genecards.weizmann.ac.il/udb different sources. As stated (Jongeneel, 2000),‘there is an Supplementary information: http://bioinfo.weizmann.ac. urgent need for a human gene index that can be used to il/cards-bin/AboutGCids.cgi, http://genecards.weizmann. identify transcripts unambiguously.’ The author contends ac.il/GeneLocAlg.html that this index should have, among others, the following Contact: [email protected] qualities: comprehensiveness, uniqueness, and stability.
    [Show full text]
  • Evolution of Multiple Cell Clones Over a 29-Year Period of a CLL Patient
    ARTICLE Received 11 May 2016 | Accepted 1 Nov 2016 | Published 16 Dec 2016 DOI: 10.1038/ncomms13765 OPEN Evolution of multiple cell clones over a 29-year period of a CLL patient Zhikun Zhao1,2,3,*, Lynn Goldin4,*, Shiping Liu1,5,*, Liang Wu1,*, Weiyin Zhou6,*, Hong Lou6,*, Qichao Yu1,7, Shirley X. Tsang8, Miaomiao Jiang1,3, Fuqiang Li1, MaryLou McMaster4, Yang Li1, Xinxin Lin1, Zhifeng Wang1, Liqin Xu1, Gerald Marti9, Guibo Li1,10,KuiWu1,10, Meredith Yeager6, Huanming Yang1,11, Xun Xu1,**, Stephen J. Chanock4,**, Bo Li1,**, Yong Hou1,10,**, Neil Caporaso4,** & Michael Dean1,4,** Chronic lymphocytic leukaemia (CLL) is a frequent B-cell malignancy, characterized by recurrent somatic chromosome alterations and a low level of point mutations. Here we present single-nucleotide polymorphism microarray analyses of a single CLL patient over 29 years of observation and treatment, and transcriptome and whole-genome sequencing at selected time points. We identify chromosome alterations 13q14 À ,6qÀ and 12q þ in early cell clones, elimination of clonal populations following therapy, and subsequent appearance of a clone containing trisomy 12 and chromosome 10 copy-neutral loss of heterogeneity that marks a major population dominant at death. Serial single-cell RNA sequencing reveals an expression pattern with high FOS, JUN and KLF4 at disease acceleration, which resolves following therapy, but reoccurs following relapse and death. Transcriptome evolution indicates complex changes in expression occur over time. In conclusion, CLL can evolve gradually during indolent phases, and undergo rapid changes following therapy. 1 BGI-Shenzhen, Shenzhen 518083, China. 2 State Key Laboratory of Bioelectronics, Southeast University, Nanjing 210096, China.
    [Show full text]
  • Non-Coding Rnas As Cancer Hallmarks in Chronic Lymphocytic Leukemia
    International Journal of Molecular Sciences Review Non-Coding RNAs as Cancer Hallmarks in Chronic Lymphocytic Leukemia Linda Fabris 1, Jaroslav Juracek 2 and George Calin 1,* 1 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; [email protected] 2 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; [email protected] * Correspondence: [email protected] Received: 24 July 2020; Accepted: 10 September 2020; Published: 14 September 2020 Abstract: The discovery of non-coding RNAs (ncRNAs) and their role in tumor onset and progression has revolutionized the way scientists and clinicians study cancers. This discovery opened new layers of complexity in understanding the fine-tuned regulation of cellular processes leading to cancer. NcRNAs represent a heterogeneous group of transcripts, ranging from a few base pairs to several kilobases, that are able to regulate gene networks and intracellular pathways by interacting with DNA, transcripts or proteins. Deregulation of ncRNAs impinge on several cellular responses and can play a major role in each single hallmark of cancer. This review will focus on the most important short and long non-coding RNAs in chronic lymphocytic leukemia (CLL), highlighting their implications as potential biomarkers and therapeutic targets as they relate to the well-established hallmarks of cancer. The key molecular events in the onset of CLL will be contextualized, taking into account the role of the “dark matter” of the genome. Keywords: chronic lymphocytic leukemia; lncRNA; miRNA; hallmarks 1. Introduction: Current Status of Chronic Lymphocytic Leukemia Research Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the Western world, representing more than 30% of all leukemia cases [1].
    [Show full text]
  • Genome Analysis and Knowledge
    Dahary et al. BMC Medical Genomics (2019) 12:200 https://doi.org/10.1186/s12920-019-0647-8 SOFTWARE Open Access Genome analysis and knowledge-driven variant interpretation with TGex Dvir Dahary1*, Yaron Golan1, Yaron Mazor1, Ofer Zelig1, Ruth Barshir2, Michal Twik2, Tsippi Iny Stein2, Guy Rosner3,4, Revital Kariv3,4, Fei Chen5, Qiang Zhang5, Yiping Shen5,6,7, Marilyn Safran2, Doron Lancet2* and Simon Fishilevich2* Abstract Background: The clinical genetics revolution ushers in great opportunities, accompanied by significant challenges. The fundamental mission in clinical genetics is to analyze genomes, and to identify the most relevant genetic variations underlying a patient’s phenotypes and symptoms. The adoption of Whole Genome Sequencing requires novel capacities for interpretation of non-coding variants. Results: We present TGex, the Translational Genomics expert, a novel genome variation analysis and interpretation platform, with remarkable exome analysis capacities and a pioneering approach of non-coding variants interpretation. TGex’s main strength is combining state-of-the-art variant filtering with knowledge-driven analysis made possible by VarElect, our highly effective gene-phenotype interpretation tool. VarElect leverages the widely used GeneCards knowledgebase, which integrates information from > 150 automatically-mined data sources. Access to such a comprehensive data compendium also facilitates TGex’s broad variant annotation, supporting evidence exploration, and decision making. TGex has an interactive, user-friendly, and easy adaptive interface, ACMG compliance, and an automated reporting system. Beyond comprehensive whole exome sequence capabilities, TGex encompasses innovative non-coding variants interpretation, towards the goal of maximal exploitation of whole genome sequence analyses in the clinical genetics practice. This is enabled by GeneCards’ recently developed GeneHancer, a novel integrative and fully annotated database of human enhancers and promoters.
    [Show full text]
  • Full Review Molecular Disease Presentation in Diabetic Nephropathy
    Nephrol Dial Transplant (2015) 30: iv17–iv25 doi: 10.1093/ndt/gfv267 Full Review Molecular disease presentation in diabetic nephropathy Downloaded from https://academic.oup.com/ndt/article/30/suppl_4/iv17/2324968 by guest on 25 September 2021 Andreas Heinzel1, Irmgard Mühlberger1, Gil Stelzer2, Doron Lancet2, Rainer Oberbauer3, Maria Martin4 and Paul Perco1 1emergentec biodevelopment GmbH, Vienna, Austria, 2Weizmann Institute of Science, Rehovot, Israel, 3Medical University of Vienna, Vienna, Austria and 4EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, UK Correspondence and offprint requests to: Paul Perco; E-mail: [email protected] ABSTRACT INTRODUCTION Diabetic nephropathy, as the most prevalent chronic disease of Kidney disease is a common problem in patients with diabetes. the kidney, has also become the primary cause of end-stage Depending on the degree of GFR impairment and/or albumin- renal disease with the incidence of kidney disease in type 2 dia- uria, roughly 30% of subjects are affected. As with most betics continuously rising. As with most chronic diseases, the diabetes-associated comorbidities, the pathophysiology is pathophysiology is multifactorial with a number of deregulated multifactorial and the molecular pathways involved in the ini- molecular processes contributing to disease manifestation and tiation and progression constitute a wide and complex as well as progression. Current therapy mainly involves interfering in the redundant network of regulators. Considerable success has renin–angiotensin–aldosterone
    [Show full text]
  • Causal Varian Discovery in Familial Congenital Heart Disease - an Integrative -Omic Approach Wendy Demos Marquette University
    Marquette University e-Publications@Marquette Master's Theses (2009 -) Dissertations, Theses, and Professional Projects Causal Varian discovery in Familial Congenital Heart Disease - An Integrative -Omic Approach Wendy Demos Marquette University Recommended Citation Demos, Wendy, "Causal Varian discovery in Familial Congenital Heart Disease - An Integrative -Omic Approach" (2012). Master's Theses (2009 -). 140. https://epublications.marquette.edu/theses_open/140 CAUSAL VARIANT DISCOVERY IN FAMILIAL CONGENITAL HEART DISEASE – AN INTEGRATIVE –OMIC APPROACH by Wendy M. Demos A Thesis submitted to the Faculty of the Graduate School, Marquette University, in Partial Fulfillment of the Requirements for the Degree of Master of Science Milwaukee, Wisconsin May 2012 ABSTRACT CAUSAL VARIANT DISCOVERY IN FAMILIAL CONGENITAL HEART DISEASE – AN INTEGRATIVE –OMIC APPROACH Wendy M. Demos Marquette University, 2012 Background : Hypoplastic left heart syndrome (HLHS) is a congenital heart defect that leads to neonatal death or compromised quality of life for those affected and their families. This syndrome requires extensive medical intervention for the affected to survive. It is characterized by significant underdevelopment or non-existence of the components of the left heart and the aorta, including the left ventricular cavity and mass. There are many factors ranging from genetics to environmental relationships hypothesized to lead to the development of the syndrome, including recent studies suggesting a link between hearing impairment and congenital heart defects (CHD). Although broadly characterized those factors remain poorly understood. The goal of this project is to systematically utilize bioinformatics tools to determine the relationships of novel mutations found in exome sequencing to a familial congenital heart defect. Methods A systematic genomic and proteomic approach involving exome sequencing, pathway analysis, and protein modeling was implemented to examine exome sequencing data of a patient with HLHS.
    [Show full text]
  • A New Cerkl Mouse Model Generated by CRISPR-Cas9 Shows
    Retina ANewCerkl Mouse Model Generated by CRISPR-Cas9 Shows Progressive Retinal Degeneration and Altered Morphological and Electrophysiological Phenotype Elena B. Domènech,1,2 Rosa Andrés,1,2 M. José López-Iniesta,1 Serena Mirra,1,2 Rocío García-Arroyo,1 Santiago Milla,3 Florentina Sava,1 Jordi Andilla,4 Pablo Loza-Álvarez,4 Pedro de la Villa,3,5 Roser Gonzàlez-Duarte,1,2,6 and Gemma Marfany1,2,6,7 1Department of Genetics, Microbiology and Statistics, University of Barcelona, Barcelona, Spain 2CIBERER/ISCIII, University of Barcelona, Barcelona, Spain 3Department of Systems Biology, University of Alcalá, Madrid, Spain 4ICFO–The Institute of Photonic Sciences, Barcelona Institute of Science and Technology, Barcelona, Spain 5Ramón y Cajal Institute for Health Research, Madrid, Spain 6DBGen Ocular Genomics, Barcelona, Spain 7Institute of Biomedicine, University of Barcelona, Barcelona, Spain Correspondence: Gemma Marfany, PURPOSE. Close to 100 genes cause retinitis pigmentosa, a Mendelian rare disease that Avinguda Diagonal, 643, edifici affects 1 out of 4000 people worldwide. Mutations in the ceramide kinase-like gene Prevosti, planta 1, 08028 Barcelona, (CERKL) are a prevalent cause of autosomal recessive cause retinitis pigmentosa and Spain; cone–rod dystrophy, but the functional role of this gene in the retina has yet to be fully [email protected]. determined. We aimed to generate a mouse model that resembles the phenotypic traits of Received: January 20, 2020 patients carrying CERKL mutations to undertake functional studies and assay therapeutic Accepted: June 14, 2020 approaches. Published: July 13, 2020 METHODS. The Cerkl locus has been deleted (around 97 kb of genomic DNA) by gene Citation: Domènech EB, Andrés R, editing using the CRISPR-Cas9 D10A nickase.
    [Show full text]
  • S41467-020-18249-3.Pdf
    ARTICLE https://doi.org/10.1038/s41467-020-18249-3 OPEN Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain Lei Zhao1,2,17, Zhongqi Li 1,2,17, Joaquim S. L. Vong2,3,17, Xinyi Chen1,2, Hei-Ming Lai1,2,4,5,6, Leo Y. C. Yan1,2, Junzhe Huang1,2, Samuel K. H. Sy1,2,7, Xiaoyu Tian 8, Yu Huang 8, Ho Yin Edwin Chan5,9, Hon-Cheong So6,8, ✉ ✉ Wai-Lung Ng 10, Yamei Tang11, Wei-Jye Lin12,13, Vincent C. T. Mok1,5,6,14,15 &HoKo 1,2,4,5,6,8,14,16 1234567890():,; The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovas- cular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation- dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which pro- minently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood–brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed tran- scriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible.
    [Show full text]
  • Tumor Suppressors in Chronic Lymphocytic Leukemia: from Lost Partners to Active Targets
    cancers Review Tumor Suppressors in Chronic Lymphocytic Leukemia: From Lost Partners to Active Targets 1, 1, 2 1 Giacomo Andreani y , Giovanna Carrà y , Marcello Francesco Lingua , Beatrice Maffeo , 3 2, 1, , Mara Brancaccio , Riccardo Taulli y and Alessandro Morotti * y 1 Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Italy; [email protected] (G.A.); [email protected] (G.C.); beatrice.maff[email protected] (B.M.) 2 Department of Oncology, University of Torino, 10043 Orbassano, Italy; [email protected] (M.F.L.); [email protected] (R.T.) 3 Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Turin, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-011-9026305 These authors equally contributed to the work. y Received: 21 January 2020; Accepted: 4 March 2020; Published: 9 March 2020 Abstract: Tumor suppressors play an important role in cancer pathogenesis and in the modulation of resistance to treatments. Loss of function of the proteins encoded by tumor suppressors, through genomic inactivation of the gene, disable all the controls that balance growth, survival, and apoptosis, promoting cancer transformation. Parallel to genetic impairments, tumor suppressor products may also be functionally inactivated in the absence of mutations/deletions upon post-transcriptional and post-translational modifications. Because restoring tumor suppressor functions remains the most effective and selective approach to induce apoptosis in cancer, the dissection of mechanisms of tumor suppressor inactivation is advisable in order to further augment targeted strategies. This review will summarize the role of tumor suppressors in chronic lymphocytic leukemia and attempt to describe how tumor suppressors can represent new hopes in our arsenal against chronic lymphocytic leukemia (CLL).
    [Show full text]
  • In Silico Haplotyping, Genotyping and Analysis of Resequencing Data Using Markov Models
    IN SILICO HAPLOTYPING, GENOTYPING AND ANALYSIS OF RESEQUENCING DATA USING MARKOV MODELS by Yun Li A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Biostatistics) in The University of Michigan 2009 Doctoral Committee: Professor Gonçalo R. Abecasis, Co-Chair Professor Michael Lee Boehnke, Co-Chair Professor Margit Burmeister Professor Roderick J.A. Little Assistant Professor Noah A. Rosenberg © Yun Li 2009 To Mom, Dad, Iory and Duan. ii Acknowledgements I am grateful to the myriad of people who have made this work possible. First of all, I would like to thank Gonçalo and Mike for teaching me about science, for letting me discover how much I can enjoy research, for being encouraging and enthusiastic both because of and despite what we found, for guiding me to grow up as an independent researcher, for being exceptional role models both career-wise and family-wise, and for being approachable anytime I need help. I owe gratitude to my committee: Rod, Margit and Noah for their help and guidance beyond their duties as committee members. I sincerely appreciate their time, advice, and encouragement. Special thanks to Rod for brining in the missing data perspectives; to Margit for always asking questions that I have an answer in the next few slides; and to Noah for access to the HGDP data. I would like also to thank the CSG members: they make everyday research joyful and keep my spirits up even during my down times. I am also fortunate to be around a group of good friends including Qixuan, Jin, Rui, Jun, and Liming, who have made my 5-year graduate studies more colorful.
    [Show full text]
  • The Regulation of Htert by Alternative Splicing
    THE REGULATION OF HTERT BY ALTERNATIVE SPLICING APPROVED BY SUPERVISORY COMMITTEE First Name Last Name, credentials Jerry Shay, Ph.D. Woodring Wright, M.D., Ph.D. Hongtao Yu, Ph.D. Melanie Cobb, Ph.D. Beatriz Fontoura, Ph.D. DEDICATION I would like to thank the members of my Graduate Committee and mentors, Jerry Shay and Woodring Wright, all of the members of the Shay/Wright lab, my collaborators, the UTSW MSTP, my friends, my family, my significant other and my two cats, Kerrigan and Tofu. THE REGULATION OF HTERT BY ALTERLATIVE SPLICING by LAURA YU YUAN DISSERTATION Presented to the Faculty of the Graduate School of Biomedical Sciences The University of Texas Southwestern Medical Center at Dallas In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY The University of Texas Southwestern Medical Center at Dallas Dallas, Texas May, 2019 Copyright by Laura Yu Yuan, 2019 All Rights Reserved THE REGULATION OF HTERT BY ALTERNATIVE SPLICING Publication No. Laura Yu Yuan, M.D., Ph.D. The University of Texas Southwestern Medical Center at Dallas, 2019 Supervising Professors: Jerry Shay, Ph.D., and Woodring Wright, M.D., Ph.D. Telomeres are non-coding DNA hexameric repeats (TTAGGG in mammals) located at the ends of linear chromosomes that, along with their associated proteins, protect against the loss of genomic material during cell division and prevent the recognition of chromosome ends as double-strand breaks. Human telomeres shorten with continued cell proliferation but are maintained by human telomerase reverse transcriptase (hTERT), an enzyme that synthesizes telomeric repeats using an RNA template.
    [Show full text]
  • Epigenetic Modifications to Cytosine and Alzheimer's Disease
    University of Kentucky UKnowledge Theses and Dissertations--Chemistry Chemistry 2017 EPIGENETIC MODIFICATIONS TO CYTOSINE AND ALZHEIMER’S DISEASE: A QUANTITATIVE ANALYSIS OF POST-MORTEM TISSUE Elizabeth M. Ellison University of Kentucky, [email protected] Digital Object Identifier: https://doi.org/10.13023/ETD.2017.398 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Ellison, Elizabeth M., "EPIGENETIC MODIFICATIONS TO CYTOSINE AND ALZHEIMER’S DISEASE: A QUANTITATIVE ANALYSIS OF POST-MORTEM TISSUE" (2017). Theses and Dissertations--Chemistry. 86. https://uknowledge.uky.edu/chemistry_etds/86 This Doctoral Dissertation is brought to you for free and open access by the Chemistry at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Chemistry by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known.
    [Show full text]