DOCSLIB.ORG

Genetics of Familial Intrahepatic Cholestasis Syndromes S W C Van Mil, R H J Houwen, L W J Klomp

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Genetics of Familial Intrahepatic Cholestasis Syndromes S W C Van Mil, R H J Houwen, L W J Klomp 449 REVIEW J Med Genet: first published as 10.1136/jmg.2004.026187 on 3 June 2005. Downloaded from Genetics of familial intrahepatic cholestasis syndromes S W C van Mil, R H J Houwen, L W J Klomp ............................................................................................................................... J Med Genet 2005;42:449–463. doi: 10.1136/jmg.2004.026187 Bile acids and bile salts have essential functions in the liver During the last decade, many loci underlying intrahepatic cholestasis have been mapped, the and in the small intestine. Their synthesis in the liver genes have been identified, and protein functions provides a metabolic pathway for the catabolism of have been studied. Taken together with the cholesterol and their detergent properties promote the recent exciting discovery of nuclear hormone receptors that act as bile acid sensors by solubilisation of essential nutrients and vitamins in the small transcriptional regulation of key enzymes and intestine. Inherited conditions that prevent the synthesis of transporters in bile acid metabolism, these bile acids or their excretion cause cholestasis, or impaired studies have allowed a detailed understanding of the molecular mechanisms and regulation of bile flow. These disorders generally lead to severe human bile formation. This review summarises recent liver disease, underscoring the essential role of bile acids in insights into the genetics of familial intrahepatic metabolism. Recent advances in the elucidation of gene cholestasis syndromes and the functions and defects underlying familial cholestasis syndromes has regulation of the affected proteins. We have divided most familial cholestasis syndromes in greatly increased knowledge about the process of bile flow. classes comprising bile acid synthesis defects and The expression of key proteins involved in bile flow is tightly bile salt transport defects because the genetic regulated by transcription factors of the nuclear hormone disorders in these different classes have common aspects in disease outcome and possible treat- receptor family, which function as sensors of bile acids and ment, which will be discussed below. We have cholesterol. Here we review the genetics of familial classified a defect in bile acid conjugation as a cholestasis disorders, the functions of the affected genes in synthesis defect and we tentatively consider familial intrahepatic cholestasis type 1 (FIC1) bile flow, and their regulation by bile acids and cholesterol. disease as a bile salt transport defect, although ........................................................................... the exact mode by which FIC1 disease causes intrahepatic cholestasis is unknown. ach day, approximately 500 mg of bile acids are synthesised from cholesterol in the adult PHYSIOLOGY AND CELL BIOLOGY OF Ehuman liver. Newly synthesised bile acids BILE FORMATION http://jmg.bmj.com/ are conjugated with either glycine or taurine and Biliary excretion of different compounds is an subsequently secreted into bile and stored in the important function of the liver. Synthesis and gallbladder. Biliary secretion of bile salts against a concentration gradient requires the hydrolysis of adenosine triphosphate (ATP) and this process Abbreviations: ABC, ATP-binding cassette; AKR1D1, D4-3-oxosteroid-5b reductase; AMACR, 2-methylacyl- provides the driving force for bile flow. Because CoA racemase; ASBT, apical sodium-dependent bile salt of their detergent properties, bile acids are transporter; ATP, adenosine triphosphate; BAAT, bile acid on October 2, 2021 by guest. Protected copyright. inherently cytotoxic, and hence it is important CoA:amino acid N-acyltransferase; BRIC, benign that intracellular levels of bile acids are tightly recurrent intrahepatic cholestasis; BSEP, bile salt export regulated. This is largely accomplished by tran- pump; C27 3b-HSD, 3b-D5-C27-hydroxysteroid oxidoreductase; CA, cholic acid; CDCA, scriptional regulation of genes encoding proteins chenodeoxycholic acid; CEA, carcinoembryonic antigen; involved in bile acid synthesis and transport. CTX, cerebrotendinous xanthomatosis; DCA, deoxycholic Cholestasis, or impaired bile flow, is one of the acid; DHCA, dihydroxycholestanoic acid; FHCA, familial most common and devastating manifestations of hypercholanaemia; FIC1, familial intrahepatic cholestasis liver disease. Cholestasis is clinically charac- type 1; FXR, farnesoid X receptor; GFC, Greenland terised by elevated plasma concentrations of familial cholestasis; GGT, gamma-glutamyl See end of article for transpeptidase; GPI, glycosyl phosphatidyl inositol; authors’ affiliations biliary constituents, resulting in jaundice, malab- HSD3B7, 3b-D5-C27-hydroxysteroid oxidoreductase; ....................... sorption of fats and fat-soluble vitamins and, in IBABP, ileal bile acid binding protein; ICP, intrahepatic Correspondence to: many cases, progressive liver damage. Both cholestasis of pregnancy; LCA, lithocholic acid; LCS, Leo W J Klomp, University acquired and hereditary forms of cholestasis lymphoedema-cholestasis syndrome; LXRa, liver X Medical Center Utrecht, have been described. Familial intrahepatic cho- receptor a; mEH, microsomal epoxide hydrolase; NAICC, North American Indian childhood cirrhosis; NTCP, Room KC02.069.1, lestasis syndromes can be caused by a deficiency Lundlaan 6, 3584 EA sodium-dependent taurocholate protein; OATP, organic Utrecht, The Netherlands; either in bile acid synthesis or in the transport of anion transporter; PBAM, primary bile acid [email protected] bile salts into bile. Elucidation of the gene defects malabsorption; PC, phosphatidyl choline; PFIC, underlying these hereditary cholestasis syn- progressive familial intrahepatic cholestasis; PXR, Revised version received dromes is of critical importance for our under- pregnane X receptor; SHP, short heterodimeric partner; 5 August 2004 tASBT, truncated form of ASBT; THCA, Accepted for publication standing of hereditary cholestasis and, trihydroxycholestanoic acid; TJP2, tight junction protein 2; 24 August 2004 consequently, for our knowledge of the process UDCA, ursodeoxycholic acid; VDR, vitamin D nuclear ....................... of bile acid synthesis and transport. receptor www.jmedgenet.com 450 van Mil, Houwen, Klomp transport of bile acids are essential for efficient bile flow. Bile bile acids enter the colon, the hydroxyl group at C-7 is acids are synthesised in the liver and stored in the removed by anaerobic bacteria, and 7-deoxy bile acids are J Med Genet: first published as 10.1136/jmg.2004.026187 on 3 June 2005. Downloaded from gallbladder. Upon digestion of a meal, bile salts are delivered formed. By this process, CA is converted to deoxycholic acid to the lumen of the small intestine where they act as (DCA) and CDCA is converted to lithocholic acid (LCA). DCA emulsifiers of dietary lipids, cholesterol, and fat-soluble and LCA are called secondary bile acids because they are vitamins. Bile salts are converted by intestinal bacteria, formed from primary bile acids in the intestine. Both are transported from the intestine to the liver via the portal reabsorbed in the colon by an unknown mechanism and circulation, and subsequently resecreted into bile. returned to the liver. In the liver, DCA is conjugated with Approximately 95% of bile salts are recovered in the gut glycine or taurine and circulates with the primary bile acids. during each cycle of this enterohepatic circulation, and the In contrast, LCA is conjugated with glycine or taurine and 5% that are lost via the faeces are replaced by de novo additionally sulfated at the C-3 position. These sulfated bile synthesis in the liver (fig 1A). salts are secreted into bile but are not efficiently absorbed In fig 1B, some important transport proteins involved in from the intestine and are therefore eliminated from the body the enterohepatic circulation of bile salts are depicted via the faeces.45 schematically. As can be seen from this figure, the Bile acids are cytotoxic when their concentrations increase enterohepatic circulation of bile salts requires regulated to abnormally high levels intracellularly or extracellularly and vectorial transport of bile salts in polarised epithelial cells, this cytotoxicity is strongly dependent on their physicochem- such as the hepatocyte and the enterocyte. The bile salt ical properties. CA is the most hydrophilic bile acid with three export pump (BSEP) mediates secretion of bile salts from the hydroxy groups and is therefore less cytotoxic, whereas DCA apical domains of hepatocytes into bile. In the intestine, the and CDCA are more harmful because they only have two apical sodium-dependent bile salt transporter (ASBT) is hydroxyl groups. LCA is the most cytotoxic naturally responsible for reabsorption of bile acids at the brush border, occurring bile acid with only one hydroxyl group. UDCA, a while the ileal bile acid binding protein (IBABP) is thought to naturally occurring bile acid in black bears but detected in transport bile acids through the cytoplasm of the enterocytes humans only in trace amounts, is devoid of cytotoxic to the basolateral membrane. A truncated form of ASBT properties; this bile acid is relatively hydrophilic, although (tASBT) transports bile acids from the enterocytes into the it is a di-hydroxy bile acid, but the hydroxyl group at C-7 is in blood. At the basolateral membrane of the hepatocytes, the the b rather than the a configuration as in CDCA.6 UDCA is sodium-dependent taurocholate protein (NTCP) and to a used as a
Load more

Recommended publications
  • Location Analysis of Estrogen Receptor Target Promoters Reveals That
    Location analysis of estrogen receptor ␣ target promoters reveals that FOXA1 defines a domain of the estrogen response Jose´ e Laganie` re*†, Genevie` ve Deblois*, Ce´ line Lefebvre*, Alain R. Bataille‡, Franc¸ois Robert‡, and Vincent Gigue` re*†§ *Molecular Oncology Group, Departments of Medicine and Oncology, McGill University Health Centre, Montreal, QC, Canada H3A 1A1; †Department of Biochemistry, McGill University, Montreal, QC, Canada H3G 1Y6; and ‡Laboratory of Chromatin and Genomic Expression, Institut de Recherches Cliniques de Montre´al, Montreal, QC, Canada H2W 1R7 Communicated by Ronald M. Evans, The Salk Institute for Biological Studies, La Jolla, CA, July 1, 2005 (received for review June 3, 2005) Nuclear receptors can activate diverse biological pathways within general absence of large scale functional data linking these putative a target cell in response to their cognate ligands, but how this binding sites with gene expression in specific cell types. compartmentalization is achieved at the level of gene regulation is Recently, chromatin immunoprecipitation (ChIP) has been used poorly understood. We used a genome-wide analysis of promoter in combination with promoter or genomic DNA microarrays to occupancy by the estrogen receptor ␣ (ER␣) in MCF-7 cells to identify loci recognized by transcription factors in a genome-wide investigate the molecular mechanisms underlying the action of manner in mammalian cells (20–24). This technology, termed 17␤-estradiol (E2) in controlling the growth of breast cancer cells. ChIP-on-chip or location analysis, can therefore be used to deter- We identified 153 promoters bound by ER␣ in the presence of E2. mine the global gene expression program that characterize the Motif-finding algorithms demonstrated that the estrogen re- action of a nuclear receptor in response to its natural ligand.
    [Show full text]
  • Activation of the Bile Acid Pathway and No Observed Antimicrobial Peptide Sequences in the Skin of a Poison Frog
    INVESTIGATION Activation of the Bile Acid Pathway and No Observed Antimicrobial Peptide Sequences in the Skin of a Poison Frog Megan L. Civitello,* Robert Denton,* Michael A. Zasloff,† and John H. Malone*,1 *Institute of Systems Genomics, Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut 06269 and †Georgetown University School of Medicine, MedStar Georgetown Transplant Institute, Washington D.C. 20057 ORCID IDs: 0000-0002-8629-1376 (R.D.); 0000-0003-1369-3769 (J.H.M.) ABSTRACT The skin secretions of many frogs have genetically-encoded, endogenous antimicrobial KEYWORDS peptides (AMPs). Other species, especially aposematic poison frogs, secrete exogenously derived alkaloids Anti-microbial that serve as potent defense molecules. The origins of these defense systems are not clear, but a novel bile- peptides acid derived metabolite, tauromantellic acid, was recently discovered and shown to be endogenous in defensive poison frogs (Mantella, Dendrobates, and Epipedobates). These observations raise questions about the secretions evolutionary history of AMP genetic elements, the mechanism and function of tauromatellic acid produc- phylogenetic tion, and links between these systems. To understand the diversity and expression of AMPs among frogs, history we assembled skin transcriptomes of 13 species across the anuran phylogeny. Our analyses revealed a bile acid pathway diversity of AMPs and AMP expression levels across the phylogenetic history of frogs, but no observations of AMPs in Mantella. We examined genes expressed in the bile-acid metabolic pathway and found that CYP7A1 (Cytochrome P450), BAAT (bile acid-CoA: amino acid N-acyltransferase), and AMACR (alpha- methylacyl-CoA racemase) were highly expressed in the skin of M.
    [Show full text]
  • Supporting Evidence from the Primates Keith R Oliver1* and Wayne K Greene2
    Oliver and Greene Mobile DNA 2011, 2:8 http://www.mobilednajournal.com/content/2/1/8 REVIEW Open Access Mobile DNA and the TE-Thrust hypothesis: supporting evidence from the primates Keith R Oliver1* and Wayne K Greene2 Abstract Transposable elements (TEs) are increasingly being recognized as powerful facilitators of evolution. We propose the TE-Thrust hypothesis to encompass TE-facilitated processes by which genomes self-engineer coding, regulatory, karyotypic or other genetic changes. Although TEs are occasionally harmful to some individuals, genomic dynamism caused by TEs can be very beneficial to lineages. This can result in differential survival and differential fecundity of lineages. Lineages with an abundant and suitable repertoire of TEs have enhanced evolutionary potential and, if all else is equal, tend to be fecund, resulting in species-rich adaptive radiations, and/or they tend to undergo major evolutionary transitions. Many other mechanisms of genomic change are also important in evolution, and whether the evolutionary potential of TE-Thrust is realized is heavily dependent on environmental and ecological factors. The large contribution of TEs to evolutionary innovation is particularly well documented in the primate lineage. In this paper, we review numerous cases of beneficial TE-caused modifications to the genomes of higher primates, which strongly support our TE-Thrust hypothesis. Introduction extent of evolution on the different clades within that Building on the groundbreaking work of McClintock [1] lineage. and numerous others [2-14], we further advanced the proposition of transposable elements (TEs) as powerful The TE-Thrust Hypothesis facilitators of evolution [15] and now formalise this into The ubiquitous, very diverse, and mostly extremely ‘The TE-Thrust hypothesis’.Inthispaper,wepresent ancient TEs are powerful facilitators of genome evolu- much specific evidence in support of this hypothesis, tion, and therefore of phenotypic diversity.
    [Show full text]
  • Molecular Characterization of the T(4;9)12Gso Mutation and Analysis of the Associated Fitness, Skeletal, and Lymphoproliferative Phenotypes
    University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 8-2002 Molecular Characterization of the T(4;9)12Gso Mutation and Analysis of the Associated Fitness, Skeletal, and Lymphoproliferative Phenotypes Laura Ray Chittenden University of Tennessee - Knoxville Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Biomedical Engineering and Bioengineering Commons Recommended Citation Chittenden, Laura Ray, "Molecular Characterization of the T(4;9)12Gso Mutation and Analysis of the Associated Fitness, Skeletal, and Lymphoproliferative Phenotypes. " PhD diss., University of Tennessee, 2002. https://trace.tennessee.edu/utk_graddiss/2105 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Laura Ray Chittenden entitled "Molecular Characterization of the T(4;9)12Gso Mutation and Analysis of the Associated Fitness, Skeletal, and Lymphoproliferative Phenotypes." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the requirements for the degree of Doctor of Philosophy, with a major in Biomedical Engineering.
    [Show full text]
  • Mouse Baat Knockout Project (CRISPR/Cas9)
    https://www.alphaknockout.com Mouse Baat Knockout Project (CRISPR/Cas9) Objective: To create a Baat knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Baat gene (NCBI Reference Sequence: NM_007519 ; Ensembl: ENSMUSG00000039653 ) is located on Mouse chromosome 4. 4 exons are identified, with the ATG start codon in exon 2 and the TGA stop codon in exon 4 (Transcript: ENSMUST00000043056). Exon 2 will be selected as target site. Cas9 and gRNA will be co-injected into fertilized eggs for KO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Exon 2 starts from the coding region. Exon 2 covers 36.98% of the coding region. The size of effective KO region: ~517 bp. The KO region does not have any other known gene. Page 1 of 8 https://www.alphaknockout.com Overview of the Targeting Strategy Wildtype allele 5' gRNA region gRNA region 3' 1 2 4 Legends Exon of mouse Baat Knockout region Page 2 of 8 https://www.alphaknockout.com Overview of the Dot Plot (up) Window size: 15 bp Forward Reverse Complement Sequence 12 Note: The 2000 bp section upstream of Exon 2 is aligned with itself to determine if there are tandem repeats. Tandem repeats are found in the dot plot matrix. The gRNA site is selected outside of these tandem repeats. Overview of the Dot Plot (down) Window size: 15 bp Forward Reverse Complement Sequence 12 Note: The 2000 bp section downstream of Exon 2 is aligned with itself to determine if there are tandem repeats.
    [Show full text]
  • Semantic Prioritization of Novel Causative Genomic Variants in Mendelian and Oligogenic Diseases
    Semantic Prioritization of Novel Causative Genomic Variants in Mendelian and Oligogenic Diseases Dissertation by Imane Boudellioua In Partial Fulfillment of the Requirements For the Degree of Doctor of Philosophy King Abdullah University of Science and Technology Thuwal, Kingdom of Saudi Arabia February, 2019 2 EXAMINATION COMMITTEE PAGE The dissertation of Imane Boudellioua is approved by the examination committee Committee Chairperson: Prof. Robert Hoehndorf Committee Members: Prof. Stefan T. Arold, Prof. Xin Gao, and Prof. Dietrich Rebholz-Schuhmann 3 ©February, 2019 Imane Boudellioua All Rights Reserved 4 ABSTRACT Semantic Prioritization of Novel Causative Genomic Variants in Mendelian and Oligogenic Diseases Imane Boudellioua Recent advances in Next Generation Sequencing (NGS) technologies have facili- tated the generation of massive amounts of genomic data which in turn is bringing the promise that personalized medicine will soon become widely available. As a result, there is an increasing pressure to develop computational tools to analyze and interpret genomic data. In this dissertation, we present a systematic approach for interrogat- ing patients' genomes to identify candidate causal genomic variants of Mendelian and oligogenic diseases. To achieve that, we leverage the use of biomedical data available from extensive biological experiments along with machine learning techniques to build predictive models that rival the currently adopted approaches in the field. We inte- grate a collection of features representing molecular information about the genomic variants and information derived from biological networks. Furthermore, we incorpo- rate genotype-phenotype relations by exploiting semantic technologies and automated reasoning inferred throughout a cross-species phenotypic ontology network obtained from human, mouse, and zebra fish studies.
    [Show full text]
  • The Emerging Role of Acyl-Coa Thioesterases and Acyltransferases in Regulating Peroxisomal Lipid Metabolism☆
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1822 (2012) 1397–1410 Contents lists available at SciVerse ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbadis Review The emerging role of acyl-CoA thioesterases and acyltransferases in regulating peroxisomal lipid metabolism☆ Mary C. Hunt a,⁎, Marina I. Siponen b,1, Stefan E.H. Alexson c a Dublin Institute of Technology, School of Biological Sciences, College of Sciences & Health, Kevin Street, Dublin 8, Ireland b Department of Medical Biochemistry and Biophysics, Structural Genomics Consortium, Karolinska Institutet, SE-171 77 Stockholm, Sweden c Karolinska Institutet, Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska University Hospital at Huddinge, SE-141 86 Stockholm, Sweden article info abstract Article history: The importance of peroxisomes in lipid metabolism is now well established and peroxisomes contain approx- Received 15 November 2011 imately 60 enzymes involved in these lipid metabolic pathways. Several acyl-CoA thioesterase enzymes Received in revised form 3 March 2012 (ACOTs) have been identified in peroxisomes that catalyze the hydrolysis of acyl-CoAs (short-, medium-, Accepted 16 March 2012 long- and very long-chain), bile acid-CoAs, and methyl branched-CoAs, to the free fatty acid and coenzyme Available online 23 March 2012 A. A number of acyltransferase enzymes, which are structurally and functionally related to ACOTs, have also been identified in peroxisomes, which conjugate (or amidate) bile acid-CoAs and acyl-CoAs to amino acids, Keywords: Acyl-CoA thioesterase resulting in the production of amidated bile acids and fatty acids.
    [Show full text]
  • Animal Models to Study Bile Acid Metabolism T ⁎ Jianing Li, Paul A
    BBA - Molecular Basis of Disease 1865 (2019) 895–911 Contents lists available at ScienceDirect BBA - Molecular Basis of Disease journal homepage: www.elsevier.com/locate/bbadis ☆ Animal models to study bile acid metabolism T ⁎ Jianing Li, Paul A. Dawson Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, GA 30322, United States ARTICLE INFO ABSTRACT Keywords: The use of animal models, particularly genetically modified mice, continues to play a critical role in studying the Liver relationship between bile acid metabolism and human liver disease. Over the past 20 years, these studies have Intestine been instrumental in elucidating the major pathways responsible for bile acid biosynthesis and enterohepatic Enterohepatic circulation cycling, and the molecular mechanisms regulating those pathways. This work also revealed bile acid differences Mouse model between species, particularly in the composition, physicochemical properties, and signaling potential of the bile Enzyme acid pool. These species differences may limit the ability to translate findings regarding bile acid-related disease Transporter processes from mice to humans. In this review, we focus primarily on mouse models and also briefly discuss dietary or surgical models commonly used to study the basic mechanisms underlying bile acid metabolism. Important phenotypic species differences in bile acid metabolism between mice and humans are highlighted. 1. Introduction characteristics such as small size, short gestation period and life span, which facilitated large-scale laboratory breeding and housing, the Interest in bile acids can be traced back almost three millennia to availability of inbred and specialized strains as genome sequencing the widespread use of animal biles in traditional Chinese medicine [1].
    [Show full text]
  • Gnomad Lof Supplement
    1 gnomAD supplement gnomAD supplement 1 Data processing 4 Alignment and read processing 4 Variant Calling 4 Coverage information 5 Data processing 5 Sample QC 7 Hard filters 7 Supplementary Table 1 | Sample counts before and after hard and release filters 8 Supplementary Table 2 | Counts by data type and hard filter 9 Platform imputation for exomes 9 Supplementary Table 3 | Exome platform assignments 10 Supplementary Table 4 | Confusion matrix for exome samples with Known platform labels 11 Relatedness filters 11 Supplementary Table 5 | Pair counts by degree of relatedness 12 Supplementary Table 6 | Sample counts by relatedness status 13 Population and subpopulation inference 13 Supplementary Figure 1 | Continental ancestry principal components. 14 Supplementary Table 7 | Population and subpopulation counts 16 Population- and platform-specific filters 16 Supplementary Table 8 | Summary of outliers per population and platform grouping 17 Finalizing samples in the gnomAD v2.1 release 18 Supplementary Table 9 | Sample counts by filtering stage 18 Supplementary Table 10 | Sample counts for genomes and exomes in gnomAD subsets 19 Variant QC 20 Hard filters 20 Random Forest model 20 Features 21 Supplementary Table 11 | Features used in final random forest model 21 Training 22 Supplementary Table 12 | Random forest training examples 22 Evaluation and threshold selection 22 Final variant counts 24 Supplementary Table 13 | Variant counts by filtering status 25 Comparison of whole-exome and whole-genome coverage in coding regions 25 Variant annotation 30 Frequency and context annotation 30 2 Functional annotation 31 Supplementary Table 14 | Variants observed by category in 125,748 exomes 32 Supplementary Figure 5 | Percent observed by methylation.
    [Show full text]
  • Integrated Analysis Sheds Light on Evolutionary Trajectories of Young Transcription Start Sites in the Human Genome
    Downloaded from genome.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Research Integrated analysis sheds light on evolutionary trajectories of young transcription start sites in the human genome Cai Li,1 Boris Lenhard,2,3,4 and Nicholas M. Luscombe1,5,6 1The Francis Crick Institute, London NW1 1AT, United Kingdom; 2Computational Regulatory Genomics, MRC London Institute of Medical Sciences, London W12 0NN, United Kingdom; 3Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom; 4Sars International Centre for Marine Molecular Biology, University of Bergen, N-5008 Bergen, Norway; 5UCL Genetics Institute, University College London, London WC1E 6BT, United Kingdom; 6Okinawa Institute of Science & Technology Graduate University, Okinawa, 904-0495, Japan Understanding the molecular mechanisms and evolution of the gene regulatory system remains a major challenge in biol- ogy. Transcription start sites (TSSs) are especially interesting because they are central to initiating gene expression. Previous studies revealed widespread transcription initiation and fast turnover of TSSs in mammalian genomes. Yet, how new TSSs originate and how they evolve over time remain poorly understood. To address these questions, we analyzed ∼200,000 human TSSs by integrating evolutionary (inter- and intra-species) and functional genomic data, particularly focusing on evolutionarily young TSSs that emerged in the primate lineage. TSSs were grouped according to their evolutionary
    [Show full text]
  • The Association Between SLC25A15 Gene Polymorphisms and Hyperornithinemia‐Hyperammonemia‐Homocitrullinuria Syndrome: Using in Silico Analysis
    bioRxiv preprint doi: https://doi.org/10.1101/786301; this version posted September 30, 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. Research Article The Association between SLC25A15 Gene Polymorphisms and Hyperornithinemia‐hyperammonemia‐homocitrullinuria Syndrome: Using In Silico Analysis Nuha A. Mahmoud1*, Dina T. Ahmed2*, Zainab O. Mohammed3, Fatima A. Altyeb2, Mujahed I. Mustafa2, Mohamed A. Hassan2,4 1- Department of Biochemistry, Faculty of Medicine, National University, Khartoum, Sudan. 2- Department of Biotechnology, Africa City of Technology, Khartoum, Sudan. 3- Department of Hematology, Ribat University Hospital, Khartoum, Sudan. 4- Department of Bioinformatics, DETAGEN Genetics Diagnostic Center, Kayseri, Turkey. *Both authors contributed equally to this manuscript. Corresponding Author: Nuha A. Mahmoud: [email protected] Background: Hyperornithinemia‐hyperammonemia‐homocitrullinuria (HHH) syndrome is an autosomal recessive inborn error of the urea cycle. It is caused by mutations in the SLC25A15 gene that codes the mitochondrial ornithine transporter. The aim of this study is to detect and identify the pathogenic SNPs in SLC25A15 gene through a combination set of bioinformatics tools and their effect on the structure and function of the protein. Methods: The deleterious SNPs in SLC25A15 are detected by various bioinformatics tools, with addition to identifying their effects on the structure and function of this gene. Results: 20 deleterious SNPs out 287of were found to have their own damaging effects on the structure and function of the SLC25A15 gene.
    [Show full text]
  • Human SSAV-Related Endogenous Retroviral Element: LTR-Like Sequence and Chromosomal Localization to 18Q21
    GENOMICS 4,68-75 (1989) Human SSAV-Related Endogenous Retroviral Element: LTR-like Sequence and Chromosomal Localization to 18q21 RUTH BRACK-WERNER,* DAVID E. BARToN,t THOMAS WERNER,* BRIGITTE E. FoELLraR,t CHRISTINE LEIB-M~)scH,§ UTA Fwwx,t VOLKER ERFLE,* AND R~~DIGER HEHLMANN~ l Abt. filr Molekulare Zellpathologie and Wtstitut filr Uugetiergenetik, Gesellschaft fiir Strahlen- und Umweltforschung (GSF), D-8042 Neuherberg, Federal Republic of Germany; tDepartment of Human Genetics, Yale University School of Medicine, New Haven, Connecticut 065 10; and SMedizinische Poliklinik der Universitat Miinchen, D-8000 Munich, Federal Republic of Germany Received July 12, 1988; revised September 14, 1988 cance is not yet known. Nevertheless, they are ob- A new family of human endogenous retroviral se- viously not only silent components of the human quences was recently discovered by way of its rela- genome since some have been shown to be transcrip- tionship to the simian sarcoma-associated virus tionally active (Kato et al., 1987; Rabson et al., 1985). (SSAV). One molecular clone, termed 571, contains Expression of human endogenous retroviral sequences sequences related to the genes coding for the group- has also been associated with neoplastic disease (Gat- speciilc antigens (gag) and polymerase (pal) proteins toni-Celli et al., 1986); however, conclusive evidence of SSAV. At the 3’end of this human retroviral element for a direct role of human retroviral elements in patho- we have now found a 636-bp region which shows fea- genicity is still forthcoming. We have found human tures characteristic of a retroviral long terminal re- DNA to contain a number of sequences related to the peat, including potential signal sequences essential for simian sarcoma-associated virus/gibbon ape leukemia transcriptional control.
    [Show full text]