DOCSLIB.ORG

3. Neocortex Expansion in Mammalian Lineages Explains Gene Family Size Variations Associated with Larger Brain Size

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
3. Neocortex Expansion in Mammalian Lineages Explains Gene Family Size Variations Associated with Larger Brain Size University of Bath PHD Genomic signatures of neurodegeneration and the evolution of mammalian brain. Castillo Morales, Atahualpa Award date: 2015 Awarding institution: University of Bath Link to publication Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 09. Oct. 2021 Genomic signatures of neurodegeneration and the evolution of mammalian brain. Atahualpa Castillo Morales A thesis submitted for the degree of Doctor of Philosophy University of Bath Department of Biology June 2015 COPYRIGHT Attention is drawn to the fact that copyright of this thesis rests with the author. A copy of this thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with the author and that they must not copy it or use material from it except as permitted by law or with the consent of the author. This thesis may be made available for consultation within the University Library and may be photocopied or lent to other libraries for the purposes of consultation. I II Table of Contents Acknowledgments .......................................................................................................... VI Contributions ............................................................................................................... VIII Abstract .......................................................................................................................... IX List of Figures ................................................................................................................. X List of Tables ................................................................................................................. XI List of Supplementary Tables ....................................................................................... XII Abbreviations .............................................................................................................. XIII 1 Introduction ................................................................................................................... 1 1.1 The genomic basis of complex phenotypes ....................................................... 1 1.2 Trade-offs in the evolution of large brains ............................................................. 3 1.4 Genetic signatures of brain evolution ..................................................................... 8 1.5 Neocorticalization, differential scaling of large brains ........................................ 12 1.6 Neurodegeneration and cellular longevity ........................................................... 14 1.7 Objectives & approach of this thesis .................................................................... 15 2. Increased brain size in mammals is associated with size variations in gene families with cell signalling, chemotaxis and immune-related functions .................................... 21 2.1 Abstract ................................................................................................................ 22 2.2 Introduction .......................................................................................................... 23 2.3 Methods ................................................................................................................ 24 2.3.1 Gene family annotations ................................................................................ 24 2.3.2 Encephalization index .................................................................................... 25 2.3.3 Correlation coefficients of gene family size and encephalization index ....... 25 2.3.4 Gene ontology terms analysis ........................................................................ 25 2.3.5 Maximum lifespan and partial correlation coefficients ................................. 26 2.3.6 Phylogenetic relatedness test ......................................................................... 26 2.3.7 Gene expression in human brain.................................................................... 27 2.3.8 Co-expression network analysis .................................................................... 27 III 2.4 Results .................................................................................................................. 28 2.4.1 Gene family size variations in line with encephalization are over-represented in mammals ............................................................................................................. 28 2.4.2 Association between gene family size and encephalization is not explained by lifespan variations ................................................................................................... 31 2.4.3 Phylogenetic relatedness does not explain the observed bias in the distribution of gene families associated with encephalization ............................... 33 2.4.4 Gene families with size increases in line with encephalization show expression signatures consistent with brain functions ............................................ 33 2.5 Discussion ............................................................................................................ 39 2.6 Conclusion ............................................................................................................ 41 3. Neocortex expansion in mammalian lineages explains gene family size variations associated with larger brain size .................................................................................... 44 3.1 Abstract ................................................................................................................ 45 3.2 Introduction .......................................................................................................... 46 3.3 Methods ................................................................................................................ 49 3.3.1 Gene Family annotations ............................................................................... 49 3.3.2 Encephalization index, Neocortex ratio and Maximum Lifespan ................. 49 3.3.3 Correlation coefficients of gene family size and phenotypes ........................ 50 3.3.4 Gene Ontology terms enrichment .................................................................. 50 3.3.5 Phylogenetically controlled regression .......................................................... 51 3.3.6 Gene expression prior and after peak in neocortex thickness. ....................... 51 3.4 Results .................................................................................................................. 52 3.5 Discussion ............................................................................................................ 58 4. Post-mitotic cell longevity-associated genes: a transcriptional signature of post- mitotic maintenance in neural and non-neural tissues ................................................... 62 4.1 Abstract ................................................................................................................ 63 4.2 Background .......................................................................................................... 64 4.3 Results .................................................................................................................. 66 4.4 Discussion ............................................................................................................ 81 4.5 Conclusions .......................................................................................................... 88 4.6 Materials and Methods ......................................................................................... 89 4.6.1 Cellular longevity estimates. ......................................................................... 89 4.6.2 Human tissues gene expression data.............................................................. 89 IV 4.6.3 Co-expression analyses. ................................................................................. 91 4.6.4 Enrichment of disease down regulated genes. ............................................... 91 4.6.5 Functional enrichment analysis. .................................................................... 91 4.6.7 Statistical analysis. ......................................................................................... 92 5. General Discussion .................................................................................................... 96 5.1 Variations in gene family size and encephalization ............................................. 97 5.2 Changes in gene family size and neocorticalization. ........................................... 98 5.3. Molecular basis
Load more

Recommended publications
  • Supplemental Table S1
    Entrez Gene Symbol Gene Name Affymetrix EST Glomchip SAGE Stanford Literature HPA confirmed Gene ID Profiling profiling Profiling Profiling array profiling confirmed 1 2 A2M alpha-2-macroglobulin 0 0 0 1 0 2 10347 ABCA7 ATP-binding cassette, sub-family A (ABC1), member 7 1 0 0 0 0 3 10350 ABCA9 ATP-binding cassette, sub-family A (ABC1), member 9 1 0 0 0 0 4 10057 ABCC5 ATP-binding cassette, sub-family C (CFTR/MRP), member 5 1 0 0 0 0 5 10060 ABCC9 ATP-binding cassette, sub-family C (CFTR/MRP), member 9 1 0 0 0 0 6 79575 ABHD8 abhydrolase domain containing 8 1 0 0 0 0 7 51225 ABI3 ABI gene family, member 3 1 0 1 0 0 8 29 ABR active BCR-related gene 1 0 0 0 0 9 25841 ABTB2 ankyrin repeat and BTB (POZ) domain containing 2 1 0 1 0 0 10 30 ACAA1 acetyl-Coenzyme A acyltransferase 1 (peroxisomal 3-oxoacyl-Coenzyme A thiol 0 1 0 0 0 11 43 ACHE acetylcholinesterase (Yt blood group) 1 0 0 0 0 12 58 ACTA1 actin, alpha 1, skeletal muscle 0 1 0 0 0 13 60 ACTB actin, beta 01000 1 14 71 ACTG1 actin, gamma 1 0 1 0 0 0 15 81 ACTN4 actinin, alpha 4 0 0 1 1 1 10700177 16 10096 ACTR3 ARP3 actin-related protein 3 homolog (yeast) 0 1 0 0 0 17 94 ACVRL1 activin A receptor type II-like 1 1 0 1 0 0 18 8038 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 1 0 0 0 0 19 8751 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 1 0 0 0 0 20 8728 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 1 0 0 0 0 21 81792 ADAMTS12 ADAM metallopeptidase with thrombospondin type 1 motif, 12 1 0 0 0 0 22 9507 ADAMTS4 ADAM metallopeptidase with thrombospondin type 1
    [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]
  • The Inactive X Chromosome Is Epigenetically Unstable and Transcriptionally Labile in Breast Cancer
    Supplemental Information The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer Ronan Chaligné1,2,3,8, Tatiana Popova1,4, Marco-Antonio Mendoza-Parra5, Mohamed-Ashick M. Saleem5 , David Gentien1,6, Kristen Ban1,2,3,8, Tristan Piolot1,7, Olivier Leroy1,7, Odette Mariani6, Hinrich Gronemeyer*5, Anne Vincent-Salomon*1,4,6,8, Marc-Henri Stern*1,4,6 and Edith Heard*1,2,3,8 Extended Experimental Procedures Cell Culture Human Mammary Epithelial Cells (HMEC, Invitrogen) were grown in serum-free medium (HuMEC, Invitrogen). WI- 38, ZR-75-1, SK-BR-3 and MDA-MB-436 cells were grown in Dulbecco’s modified Eagle’s medium (DMEM; Invitrogen) containing 10% fetal bovine serum (FBS). DNA Methylation analysis. We bisulfite-treated 2 µg of genomic DNA using Epitect bisulfite kit (Qiagen). Bisulfite converted DNA was amplified with bisulfite primers listed in Table S3. All primers incorporated a T7 promoter tag, and PCR conditions are available upon request. We analyzed PCR products by MALDI-TOF mass spectrometry after in vitro transcription and specific cleavage (EpiTYPER by Sequenom®). For each amplicon, we analyzed two independent DNA samples and several CG sites in the CpG Island. Design of primers and selection of best promoter region to assess (approx. 500 bp) were done by a combination of UCSC Genome Browser (http://genome.ucsc.edu) and MethPrimer (http://www.urogene.org). All the primers used are listed (Table S3). NB: MAGEC2 CpG analysis have been done with a combination of two CpG island identified in the gene core. Analysis of RNA allelic expression profiles (based on Human SNP Array 6.0) DNA and RNA hybridizations were normalized by Genotyping console.
    [Show full text]
  • ABSTRACT MITCHELL III, ROBERT DRAKE. Global Human Health
    ABSTRACT MITCHELL III, ROBERT DRAKE. Global Human Health Risks for Arthropod Repellents or Insecticides and Alternative Control Strategies. (Under the direction of Dr. R. Michael Roe). Protein-coding genes and environmental chemicals. New paradigms for human health risk assessment of environmental chemicals emphasize the use of molecular methods and human-derived cell lines. In this study, we examined the effects of the insect repellent DEET (N, N-diethyl-m-toluamide) and the phenylpyrazole insecticide fipronil (fluocyanobenpyrazole) on transcript levels in primary human hepatocytes. These chemicals were tested individually and as a mixture. RNA-Seq showed that 100 µM DEET significantly increased transcript levels for 108 genes and lowered transcript levels for 64 genes and fipronil at 10 µM increased the levels of 2,246 transcripts and decreased the levels for 1,428 transcripts. Fipronil was 21-times more effective than DEET in eliciting changes, even though the treatment concentration was 10-fold lower for fipronil versus DEET. The mixture of DEET and fipronil produced a more than additive effect (levels increased for 3,017 transcripts and decreased for 2,087 transcripts). The transcripts affected in our treatments influenced various biological pathways and processes important to normal cellular functions. Long non-protein coding RNAs and environmental chemicals. While the synthesis and use of new chemical compounds is at an all-time high, the study of their potential impact on human health is quickly falling behind. We chose to examine the effects of two common environmental chemicals, the insect repellent DEET and the insecticide fipronil, on transcript levels of long non-protein coding RNAs (lncRNAs) in primary human hepatocytes.
    [Show full text]
  • Browsing Genes and Genomes with Ensembl
    The Bioinformatics Roadshow Tórshavn, The Faroe Islands 28-29 November 2012 BROWSING GENES AND GENOMES WITH ENSEMBL EXERCISES AND ANSWERS 1 BROWSER 3 BIOMART 8 VARIATION 13 COMPARATIVE GENOMICS 18 2 Note: These exercises are based on Ensembl version 69 (October 2012). After in future a new version has gone live, version 69 will still be available at http://e69.ensembl.org/. If your answer doesn’t correspond with the given answer, please consult the instructor. ______________________________________________________________ BROWSER ______________________________________________________________ Exercise 1 – Exploring a gene (a) Find the human F9 (coagulation factor IX) gene. On which chromosome and which strand of the genome is this gene located? How many transcripts (splice variants) have been annotated for it? (b) What is the longest transcript? How long is the protein it encodes? Has this transcript been annotated automatically (by Ensembl) or manually (by Havana)? How many exons does it have? Are any of the exons completely or partially untranslated? (c) Have a look at the external references for ENST00000218099. What is the function of F9? (d) Is it possible to monitor expression of ENST00000218099 with the ILLUMINA HumanWG_6_V2 microarray? If so, can it also be used to monitor expression of the other two transcripts? (e) In which part (i.e. the N-terminal or C-terminal half) of the protein encoded by ENST00000218099 does its peptidase activity reside? (f) Have any missense variants been discovered for the protein encoded by ENST00000218099? (g) Is there a mouse orthologue predicted for the human F9 gene? (h) If you have yourself a gene of interest, explore what information Ensembl displays about it! ______________________________________________________________ Answer (a) 8 Go to the Ensembl homepage (http://www.ensembl.org/).
    [Show full text]
  • Emerging Genetic Alterations Linked to Male Infertility: X-Chromosome Copy Number Variation and Spermatogenesis Regulatory Genes’ Expression
    Central Annals of Reproductive Medicine and Treatment Bringing Excellence in Open Access Research Article *Corresponding author Susana Fernandes, Department of Genetics, Faculty of Medicine of University of Porto, Al. Prof. Hernâni Emerging Genetic Alterations Monteiro, 4200 - 319 Porto, Portugal; Tel: 351 22 551 36 47; Email: Submitted: 12 October 2016 Linked to Male Infertility: Accepted: 10 February 2017 Published: 14 February 2017 X-Chromosome Copy Number Copyright © 2017 Fernandes et al. Variation and Spermatogenesis OPEN ACCESS Keywords Regulatory Genes’ Expression • Male infertility • Spermatogenesis Catarina Costa1, Maria João Pinho1,2, Alberto Barros1,2,3, and • DNA copy number variations • Gene expression Susana Fernandes1,2* 1Department of Genetics, Faculty of Medicine of University of Porto, Portugal 2i3S – Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal 3Centre for Reproductive Genetics A Barros, Portugal Abstract The etiopathogenesis of primary testicular failure remains undefined in 50% of cases. Most of these idiopathic cases probably result from genetic mutations/anomalies. Novel causes, like Copy Number Variation and gene expression profile, are being explored thanks to recent advances in the field of genetics. Our aim was to study Copy Number Variation (CNV) 67, a patient-specific CNV related to spermatogenic anomaly and evaluate the expression of regulatory genes AKAP4, responsible for sperm fibrous sheet assembly, and STAG3, essential for sister chromatid cohesion during meiosis. One hundred infertile men were tested for CNV67 with quantitative PCR (qPCR). Quantitative real-time PCR was performed to evaluate gene expression patterns of the two mentioned genes in testicular biopsies from 22 idiopathic infertile patients. CNV67 deletion was found in 2% of patients, with the same semen phenotype described in previous studies.
    [Show full text]
  • Downloaded from [266]
    Patterns of DNA methylation on the human X chromosome and use in analyzing X-chromosome inactivation by Allison Marie Cotton B.Sc., The University of Guelph, 2005 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in The Faculty of Graduate Studies (Medical Genetics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) January 2012 © Allison Marie Cotton, 2012 Abstract The process of X-chromosome inactivation achieves dosage compensation between mammalian males and females. In females one X chromosome is transcriptionally silenced through a variety of epigenetic modifications including DNA methylation. Most X-linked genes are subject to X-chromosome inactivation and only expressed from the active X chromosome. On the inactive X chromosome, the CpG island promoters of genes subject to X-chromosome inactivation are methylated in their promoter regions, while genes which escape from X- chromosome inactivation have unmethylated CpG island promoters on both the active and inactive X chromosomes. The first objective of this thesis was to determine if the DNA methylation of CpG island promoters could be used to accurately predict X chromosome inactivation status. The second objective was to use DNA methylation to predict X-chromosome inactivation status in a variety of tissues. A comparison of blood, muscle, kidney and neural tissues revealed tissue-specific X-chromosome inactivation, in which 12% of genes escaped from X-chromosome inactivation in some, but not all, tissues. X-linked DNA methylation analysis of placental tissues predicted four times higher escape from X-chromosome inactivation than in any other tissue. Despite the hypomethylation of repetitive elements on both the X chromosome and the autosomes, no changes were detected in the frequency or intensity of placental Cot-1 holes.
    [Show full text]
  • Reduced Transfer Coefficient of Carbon Monoxide in Pulmonary Arterial Hypertension Implicates Rare Protein-Truncating Variants I
    bioRxiv preprint doi: https://doi.org/10.1101/2019.12.11.871210; this version posted December 12, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Reduced transfer coefficient of carbon monoxide in pulmonary arterial hypertension implicates rare protein- truncating variants in KDR Genotype-phenotype inference reveals novel PAH risk genes Emilia M. Swietlik, M.D.[1], Daniel Greene, PhD[2,3], Na Zhu, PhD[4,5], Karyn Megy, PhD[2,3], Marcella Cogliano, M.Sc.[6], Smitha Rajaram, M.D.[7], Divya Pandya, M.Sc.[1], Tobias Tilly, M.Sc.[1], Katie A. Lutz, BS[8], Carrie C. L. Welch, PhD[4], Michael W. Pauciulo, BS, MBA[8,9], Laura Southgate, PhD[10], Jennifer M. Martin, M.St.[3], Carmen M. Treacy, B.Sc.[1], Harm J. Bogaard, M.D., PhD[11], Colin Church, PhD[12], Gerry Coghlan, M.D.[13], Anna W. Coleman, MS[8], Robin Condliffe, M.D.[14], Mélanie Eyries, PhD[15], Henning Gall, M.D., PhD[16], Stefano Ghio, M.D.[17], Simon Holden, PhD[18], Luke Howard, M.D., PhD.[19], David G. Kiely, M.D.[14], Gabor Kovacs, M.D.[20,21], Jim Lordan, PhD[22], Rajiv D. Machado, PhD[10], Robert V. MacKenzie Ross, M.B, B.Chir[23], Shahin Moledina, M.B.Ch.B.[24], David Montani, M.D., PhD[25], Horst Olschewski, M.D.[20,21], Joanna Pepke-Zaba, PhD[26], Christopher J.
    [Show full text]
  • Type of the Paper (Article
    Article Differential Expression Profile of lncRNAs from Primary Human Hepatocytes Following DEET and Fipronil Exposure Robert D. Mitchell III 1, Andrew D. Wallace 2, Ernest Hodgson 2,3 and R. Michael Roe 1,* 1 Department of Entomology and Plant Pathology, North Carolina Agromedicine Institute, Campus Box 7647, 3230 Ligon Street, North Carolina State University, Raleigh, NC 27695, USA; [email protected] (R.D.M.) 2 Toxicology Program, Department of Biology, North Carolina State University, Raleigh, NC 27695, USA; [email protected] (A.D.W.); [email protected] (E.H.) 3 Department of Applied Ecology, Toxicology Program, Department of Biology, North Carolina Agromedicine Institute, North Carolina State University, Raleigh, NC 27695, USA * Correspondence: [email protected]; Tel.: +1-919-515-4325 Received: 15 August 2017; Accepted: 4 October 2017; Published: 7 October 2017 Abstract: While the synthesis and use of new chemical compounds is at an all-time high, the study of their potential impact on human health is quickly falling behind, and new methods are needed to assess their impact. We chose to examine the effects of two common environmental chemicals, the insect repellent N,N-diethyl-m-toluamide (DEET) and the insecticide fluocyanobenpyrazole (fipronil), on transcript levels of long non-protein coding RNAs (lncRNAs) in primary human hepatocytes using a global RNA-Seq approach. While lncRNAs are believed to play a critical role in numerous important biological processes, many still remain uncharacterized, and their functions and modes of action remain largely unclear, especially in relation to environmental chemicals. RNA- Seq showed that 100 µM DEET significantly increased transcript levels for 2 lncRNAs and lowered transcript levels for 18 lncRNAs, while fipronil at 10 µM increased transcript levels for 76 lncRNAs and decreased levels for 193 lncRNAs.
    [Show full text]
  • Karla Alejandra Vizcarra Zevallos Análise Da Função De Genes
    Karla Alejandra Vizcarra Zevallos Análise da função de genes candidatos à manutenção da inativação do cromossomo X em humanos Dissertação apresentada ao Pro- grama de Pós‐Graduação Inter- unidades em Biotecnologia USP/ Instituto Butantan/ IPT, para obtenção do Título de Mestre em Ciências. São Paulo 2017 Karla Alejandra Vizcarra Zevallos Análise da função de genes candidatos à manutenção da inativação do cromossomo X em humanos Dissertação apresentada ao Pro- grama de Pós‐Graduação Inter- unidades em Biotecnologia do Instituto de Ciências Biomédicas USP/ Instituto Butantan/ IPT, para obtenção do Título de Mestre em Ciências. Área de concentração: Biotecnologia Orientadora: Profa. Dra. Lygia da Veiga Pereira Carramaschi Versão corrigida. A versão original eletrônica encontra-se disponível tanto na Biblioteca do ICB quanto na Biblioteca Digital de Teses e Dissertações da USP (BDTD) São Paulo 2017 UNIVERSIDADE DE SÃO PAULO Programa de Pós-Graduação Interunidades em Biotecnologia Universidade de São Paulo, Instituto Butantan, Instituto de Pesquisas Tecnológicas Candidato(a): Karla Alejandra Vizcarra Zevallos Título da Dissertação: Análise da função de genes candidatos à manutenção da inativação do cromossomo X em humanos Orientador: Profa. Dra. Lygia da Veiga Pereira Carramaschi A Comissão Julgadora dos trabalhos de Defesa da Dissertação de Mestrado, em sessão pública realizada a ........./......../.........., considerou o(a) candidato(a): ( ) Aprovado(a) ( ) Reprovado(a) Examinador(a): Assinatura: ..............................................................................
    [Show full text]
  • Mckenna, Sim Et Al., Science, 2020
    RESEARCH ◥ zation, we combined biochemical and structural RESEARCH ARTICLE SUMMARY approaches to define the function and mecha- nism of the P5A-ATPase. STRUCTURAL BIOLOGY RESULTS: P-type ATPases form a large class of The endoplasmic reticulum P5A-ATPase is a active transporters that are present in all kingdoms of life and predominantly trans- transmembrane helix dislocase port ions or lipids across cellular membranes. The P5A-ATPase belongs to a eukaryotic- Michael J. McKenna*, Sue Im Sim*, Alban Ordureau, Lianjie Wei, J. Wade Harper, specific subfamily of P-type ATPases with un- Sichen Shao†, Eunyong Park† known substrate specificity. We reconstituted membrane protein insertion into organelles in a cell-free system and used site-specific cross- INTRODUCTION: Eukaryotic cells contain geted transmembrane proteins from the ER linking to reveal that the P5A-ATPase interacts membrane-bound organelles with distinct membrane are incompletely understood. directly with the TM of a mitochondrial tail– identities and functionalities that depend anchored protein. Human cells lacking ATP13A1 on protein composition. Correct localization RATIONALE: As a model to study membrane pro- showed mislocalization of mitochondrial tail– of proteins is thus critical for organelle func- tein localization, we focused on tail–anchored anchored proteins to the ER and secretory tion and cellular homeostasis. The endoplas- proteins, which contain a single C-terminal TM pathway. In in vitro assays, newly synthesized mic reticulum (ER) and mitochondrial outer that is necessary and largely sufficient for or- mitochondrial tail–anchored proteins aber- Downloaded from membrane are the primary destinations for ganelle localization. We reasoned that factors rantly accumulated in ER vesicles lacking newly synthesized proteins with hydrophobic that mediate mitochondrial tail–anchored pro- P5A-ATPase activity.
    [Show full text]
  • E L If D a R B U K a Ist a N B U L Ü N Ive R Sit E Si Sa Ğ . B Il. E N St
    ELIF DARBUKA İSTANBUL ÜNİVERSİTESİ SAĞ. BİL. ENST. YÜKSEK LİSANS TEZİ İSTANBUL-2018 T.C. İSTANBUL ÜNİVERSİTESİ SAĞLIK BİLİMLERİ ENSTİTÜSÜ ( YÜKSEK LİSANS TEZİ ) KOLOREKTAL KANSERLİ HASTALARDA TCEAL7 GENİNİN ARAŞTIRILMASI ELİF DARBUKA DANIŞMAN PROF. DR. ALİ NUR TURGUT ULUTİN GENETİK ANABİLİM DALI GENETİK PROGRAMI İSTANBUL-2018 ii TEZ ONAYI iii BEYAN Bu tez çalışmasının kendi çalışmam olduğunu, tezin planlanmasından yazımına kadar bütün safhalarda etik dışı davranışımın olmadığını, bu tezdeki bütün bilgileri akademik ve etik kurallar içinde elde ettiğimi, bu tez çalışmasıyla elde edilmeyen bütün bilgi ve yorumlara kaynak gösterdiğimi ve bu kaynakları da kaynaklar listesine aldığımı, yine bu tezin çalışılması ve yazımı sırasında patent ve telif haklarını ihlal edici bir davranışımın olmadığı beyan ederim. Elif DARBUKA iv İTHAF Tez çalışmamı; Aileme ithaf ediyorum… v TEŞEKKÜR Tez süresince ilgisini ve desteğini esirgemeyen tez danışmanım Prof. Dr.Turgut ULUTİN’e, Tez çalışmam ve yüksek lisans eğitimim boyunca değerli bilgilerini, katkılarını ve sabrını esirgemeyen, her konuda tecrübesine sonuna kadar güvendiğim değerli hocam Prof. Dr. Nur BUYRU’ya, Tez çalışmamın gerçekleşmesi için gerekli dokuların temin edilmesini sağlayan ve bu süreçte bana destek olan Uzm. Dr. Süleyman DEMİRYAS’a ve patolojik incelemelerde uzmanlığından faydalandığım Uzm. Dr. Nuray KEPİL’e Moleküler Genetik Laboratuvarı’na ilk adımımı attığımdan beri her konuda yardımcı olan, yol gösteren ve sabırla destek veren Doç Dr. Onur BAYKARA’ya, Dr. Seda Ekizoğlu ERATAK’a, Dr. Filiz ÖZDEMİR’e, MSc. Asuman ÇELEBİ’ye ve Dr. Didem SEVEN’e, Doç Dr. Hikmet KÖSEOĞLU’na, Laboratuvar ve yüksek lisans eğitim arkadaşlığından öte benim için dost olan, MSc. Aslı KARACAN’a, BSc. Pelin BULUT’a, BSc. Ceren ORHAN’a, MSc.
    [Show full text]