DOCSLIB.ORG

Reassessment of the Type I Diabetes Association of the OAS1 Locus

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Reassessment of the Type I Diabetes Association of the OAS1 Locus Genes and Immunity (2009) 10, S69–S73 & 2009 Macmillan Publishers Limited All rights reserved 1466-4879/09 $32.00 www.nature.com/gene ORIGINAL ARTICLE Reassessment of the type I diabetes association of the OAS1 locus H-Q Qu1,2, C Polychronakos1,2 and the Type I Diabetes Genetics Consortium 1Department of Pediatrics, McGill University, Montreal, Que´bec, Canada; 2Department of Human Genetics, McGill University, Montreal, Que´bec, Canada To reassess the type I diabetes (T1D) association of the OAS1 locus, the Type I Diabetes Genetics Consortium (T1DGC) genotyped 11 tag single-nucleotide polymorphisms spanning B41 kb from the 50 to 30 flanking region. For each sample obtained from over 2000 affected sib-pair families from nine cohorts, the genotyping was performed on both the Illumina Golden Gate and Sequenom iPlex platforms. The data suggest that there may be a weak association with T1D for two OAS1 polymorphisms, rs3741981 and rs10774671, in populations of European descent. The OAS1 locus is close to a recently identified T1D-associated linkage disequilibrium (LD) block in human chromosome 12q24. Extended LD in populations earlier examined may account for the prior observation of an association of T1D with OAS1 variants. This possibility needs to be addressed further by fine mapping of the T1D association represented in 12q24. Genes and Immunity (2009) 10, S69–S73; doi:10.1038/gene.2009.95 Keywords: autoimmune disease; OAS1; genetic susceptibility; linkage disequilibrium; single-nucleotide polymorphism; type I diabetes Introduction org) SNPs within and around OAS1 with minor allele frequency 41% at r2X0.80 (Supplementary Figure 1). The 20,50-oligoadenylate synthetase genes (OAS1, OAS2, Both the splicing site SNP (rs10774671) and the non- OAS3) that are located in human chromosome 12q24 synonymous SNP (nsSNP rs3741981) were included. encode a family of enzymes pivotal in innate anti-viral defense.1–4 OAS1 has a major function in the total constitutive activity of OAS enzymes.5 The first reported Results association of type I diabetes (T1D) with the OAS1 locus was with the single-nucleotide polymorphism (SNP) All 11 SNPs selected for the OAS1 locus were genotyped rs10774671.6 This SNP occurred in a region that involved by both the Illumina GoldenGate and the Sequenom a splicing site. The minor (G) allele of rs10774671 iPlex platforms. Of the 11159 individuals from 2298 introduces a splicing site and is associated with families (5003 affected), a total of 1477 individuals had no increased OAS enzyme activity; further, this SNP was genotypes from either platform because of unavailability associated with T1D susceptibility.6 of samples at the time of genotyping. In addition, 322 Although methodological limitations of that study individuals had only the Illumina genotypes and 401 were later identified,7 in our independent study on individuals had only Sequenom genotypes. As this rate candidate polymorphisms, the highly correlated of genotype availability is similar to that of other (r2 ¼ 0.69) non-synonymous (Ser162Gly) SNP rs3741981 candidate genes in the T1DGC experiment, these missing of the OAS1 gene was significantly associated with T1D genotypes seem to be unrelated to assay quality. risk.8 In two large cohorts of European descent, however, The genotyping quality assessment of each SNP no statistically significant association of OAS1 SNPs with (Table 1) eliminated rs7135579 because of low call rate T1D was observed.7 and significant deviation of the rs7135579 genotype To reassess the T1D association of the OAS1 locus, the distribution from Hardy–Weinberg Equilibrium expecta- Type I Diabetes Genetics Consortium (T1DGC) geno- tion. Both of the earlier associated OAS1 candidate SNPs, typed 11 tag SNPs. The 11 SNPs span B41 kb from the rs3741981 and rs10774671, have genotype distribution in 50 to 30 flanking region of the OAS1 gene and capture Hardy–Weinberg Equilibrium and exhibit highly consis- 95.9% of the available HapMap (http://www.hapmap. tent results between the genotyping platforms. The results of association analysis between the OAS1 SNPs and T1D are shown in Table 2. The discrepancies in results between the two technologies are largely because Correspondence: Dr C Polychronakos, Departments of Pediatrics of incomplete overlap of the DNA sets tested (7% of the and Human Genetics, Pediatric Endocrinology McGill University Health Center (Children’s Hospital), 2300 Tupper, Montre´al, Que´bec samples were genotyped in only one of the two Canada H3H 1P3. platforms), rather than technical differences between E-mail: [email protected] platforms as shown by the high concordance rates in Reassessment of the T1D association of the OAS1 locus Hi-Q Qu et al S70 Table 1 The 11 SNPs in the OAS1 locus studied by the T1DGC Marker Physical position ILMN call rate ILMN HWE p SQNM call rate SQNM HWE p Concordance rate of ILMN vs SQNM rs3741982 111791701 0.998 0.070 0.984 0.138 0.958 rs12177 111798145 0.999 0.514 0.982 0.443 0.957 rs2240193 111798381 0.999 0.179 0.985 0.393 0.993 rs2240191 111798451 0.997 0.743 0.970 0.006 0.989 rs12309946 111798975 0.998 0.869 0.992 0.857 1.000 rs4766662 111808419 0.984 0.457 0.981 0.214 0.978 rs3741981a 111811590 0.999 0.166 0.988 0.137 0.999 rs10774671a 111819913 1.000 0.188 0.994 0.162 0.999 rs7135579 111829602 0.930 5.58 Â 10À18 0.989 0.016 0.970 rs3803057 111831454 1.000 0.398 0.990 0.793 0.999 rs7967461 111832479 1.000 0.133 0.993 0.184 0.999 Abbreviations: HWE, Hardy–Weinberg equilibrium; ILMN, Illumina GoldenGate; SQNM, Sequenom iPlex; SNP, single-nucleotide polymorphism; T1D, type I diabetes; T1DGC, Type I Diabetes Genetics Consortium. aEarlier reported to be associated with T1D.6,8 Table 2 The T1D association test of the 11 OAS1 SNPs Table 3 The genotypic association test of rs3741981 and rs10774671 Marker Minor MAF ILMN Z ILMN P SQNM Z SQNM P allele Marker Genotype Frequency ILMN ILMN SQNM SQNM Z P Z P rs3741982 A 0.383 0.192 0.848 À0.510 0.610 rs12177 A 0.491 À0.294 0.768 0.699 0.484 rs3741981 A/A 0.327 0.599 0.549 0.441 0.659 rs2240193 T 0.066 À1.138 0.255 À1.734 0.083 A/G 0.481 À1.541 0.123 À1.858 0.063 rs2240191 A 0.170 À1.157 0.247 À1.134 0.257 G/G 0.192 1.507 0.132 2.133 0.033a rs12309946 A 0.040 0.508 0.611 0.408 0.683 rs4766662 A 0.222 À0.091 0.927 0.797 0.426 rs10774671 C/C 0.137 1.634 0.102 2.013 0.044a rs3741981 G 0.433 0.484 0.628 0.987 0.324 C/T 0.455 À1.087 0.277 À0.363 0.717 rs10774671a C 0.365 0.842 0.400 1.925 0.054 T/T 0.408 0.075 0.940 À1.051 0.293 rs7135579 A 0.103 À2.058b 0.040b À0.154 0.877 rs3803057 A 0.049 À0.871 0.384 À1.980 0.048 Abbreviations: ILMN, Illumina GoldenGate; SQNM, Sequenom rs7967461 G 0.370 0.859 0.390 1.784 0.074 iPlex. The genotypic type I diabetes (T1D) association was tested by the Abbreviations: ILMN, Illumina GoldenGate; MAF, minor allele family based association test (FBAT) (http://www.biostat.harvard. frequency; SQNM, Sequenom iPlex; SNP, single-nucleotide poly- edu/Bfbat/fbat.htm). morphism; T1D, type I diabetes. aPo0.05. aThe Type I Diabetes Genetics Consortium (T1DGC) genotyped the DNA antisense strand. The C allele of rs10774671 corresponds to the G allele in the sense strand, which produces a splicing site. T1D families and 4287 T1D cases vs 4735 controls from bPoor genotyping assay. the same population.7 Thus, the possible genotypic association still lacks statistical validation. The observed borderline significance may be due to the multiple Table 1. In these affected sib-pair families from the hypotheses implicitly tested. T1DGC, there was no evidence of a statistically sig- nificant allelic association of OAS1 SNPs with T1D risk. In our earlier study, the genotypic association with T1D was under a recessive model.8 In this model, only Discussion homozygosity for the minor allele of each of the three The above results suggest that association of the two OAS1 SNPs (rs3741981, rs10774671, and rs3177979) OAS1 SNPs, rs3741981 and rs10774671, with T1D in conferred an increased risk for T1D. The affected sib- populations of European descent is extremely weak, if pair family collection assembled by the T1DGC suggests present at all. This weak and inconsistent association the same result for OAS1 SNPs rs3741981 and rs10774671 may be due to long-range linkage disequilibrium (LD) (Table 3) in the Sequenom assay. In the Illumina assay, the with the recently replicated association with T1D in the genotypic association under the recessive model did not region of human chromosome 12q24, involving the reach statistical significance, although a trend in the intronic SNP rs1769673610 following the Wellcome Trust same direction as that observed with the Sequenom Case–Control Consortium study.9 This association was assay was seen. The same pattern of genotypic associa- also replicated in Stage 2 of our own genome-wide tion was also shown by the Wellcome Trust Case–Control association study (Hakonarson et al., unpublished data). Consortium study (P ¼ 0.020).9 The three reported OAS1 The T1D-associated SNP rs17696736 is located in a LD SNPs were not genotyped in the Wellcome Trust Case– block of over 1 Mb in length, which is only B300 kb from Control Consortium; however, SNP rs2660 has r2 ¼ 1 with the LD block containing OAS1.
Load more

Recommended publications
  • A Genetic Variant Protective Against Severe COVID-19 Is Inherited from Neandertals
    bioRxiv preprint doi: https://doi.org/10.1101/2020.10.05.327197; this version posted October 9, 2020. 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 4.0 International license. A genetic variant protective against severe COVID-19 is inherited from Neandertals Authors Hugo Zeberg1,2* and Svante Pääbo1,3* Affiliations 1 Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, D-04103 Leipzig, Germany. 2 Department of Neuroscience, Karolinska Institutet, SE-17177 Stockholm, Sweden. 3 Okinawa Institute of Science and Technology, Onna-son, Okinawa 904-0495, Japan. *Corresponding authors: [email protected], [email protected] Abstract It was recently shown that the major genetic risk factor associated with becoming severely ill with COVID-19 when infected by SARS-CoV-2 is inherited from Neandertals. Thanks to new genetic association studies additional risk factors are now being discovered. Using data from a recent genome- wide associations from the Genetics of Mortality in Critical Care (GenOMICC) consortium, we show that a haplotype at a region associated with requiring intensive care is inherited from Neandertals. It encodes proteins that activate enzymes that are important during infections with RNA viruses. As compared to the previously described Neandertal risk haplotype, this Neandertal haplotype is protective against severe COVID-19, is of more moderate effect, and is found at substantial frequencies in all regions of the world outside Africa. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.10.05.327197; this version posted October 9, 2020.
    [Show full text]
  • 1A Multiple Sclerosis Treatment
    The Pharmacogenomics Journal (2012) 12, 134–146 & 2012 Macmillan Publishers Limited. All rights reserved 1470-269X/12 www.nature.com/tpj ORIGINAL ARTICLE Network analysis of transcriptional regulation in response to intramuscular interferon-b-1a multiple sclerosis treatment M Hecker1,2, RH Goertsches2,3, Interferon-b (IFN-b) is one of the major drugs for multiple sclerosis (MS) 3 2 treatment. The purpose of this study was to characterize the transcriptional C Fatum , D Koczan , effects induced by intramuscular IFN-b-1a therapy in patients with relapsing– 2 1 H-J Thiesen , R Guthke remitting form of MS. By using Affymetrix DNA microarrays, we obtained and UK Zettl3 genome-wide expression profiles of peripheral blood mononuclear cells of 24 MS patients within the first 4 weeks of IFN-b administration. We identified 1Leibniz Institute for Natural Product Research 121 genes that were significantly up- or downregulated compared with and Infection Biology—Hans-Knoell-Institute, baseline, with stronger changed expression at 1 week after start of therapy. Jena, Germany; 2University of Rostock, Institute of Immunology, Rostock, Germany and Eleven transcription factor-binding sites (TFBS) are overrepresented in the 3University of Rostock, Department of Neurology, regulatory regions of these genes, including those of IFN regulatory factors Rostock, Germany and NF-kB. We then applied TFBS-integrating least angle regression, a novel integrative algorithm for deriving gene regulatory networks from gene Correspondence: M Hecker, Leibniz Institute for Natural Product expression data and TFBS information, to reconstruct the underlying network Research and Infection Biology—Hans-Knoell- of molecular interactions. An NF-kB-centered sub-network of genes was Institute, Beutenbergstr.
    [Show full text]
  • Structural Basis for Cytosolic Double-Stranded RNA Surveillance by Human Oligoadenylate Synthetase 1
    Structural basis for cytosolic double-stranded RNA surveillance by human oligoadenylate synthetase 1 Jesse Donovan, Matthew Dufner, and Alexei Korennykh1 Department of Molecular Biology, Princeton University, Princeton, NJ 08540 Edited by Jennifer A. Doudna, University of California, Berkeley, CA, and approved December 19, 2012 (received for review October 23, 2012) The human sensor of double-stranded RNA (dsRNA) oligoadenylate Results and Discussion synthetase 1 (hOAS1) polymerizes ATP into 2′,5′-linked iso-RNA (2- Overview of the hOAS1•dsRNA•dATP Ternary Complex. To un- 5A) involved in innate immunity, cell cycle, and differentiation. We derstand how OAS1 recognizes dsRNA, we conducted cocrys- report the crystal structure of hOAS1 in complex with dsRNA and tallization screening with hOAS1 and dsRNA sequences derived 2′-deoxy ATP at 2.7 Å resolution, which reveals the mechanism of from RNA constructs known to activate the sensor (2). Single cytoplasmic dsRNA recognition and activation of oligoadenylate cocrystals were obtained only with dsRNA having 18 bp and a ser- synthetases. Human OAS1 recognizes dsRNA using a previously endipitously constructed sequence GGCUUUUGACCUUUAU- uncharacterized protein/RNA interface that forms via a conforma- GC. The structure of the ternary complex was determined at 2.7 Å tional change induced by binding of dsRNA. The protein/RNA in- resolution (Table S1). In the cocrystal structure, hOAS1 is bound to fi terface involves two minor grooves and has no sequence-speci c one face of the RNA double-helix (Fig. 1A and Figs. S1 and S2)and contacts, with the exception of a single hydrogen bond between the dsRNA termini are unobstructed by the protein (Table S2).
    [Show full text]
  • The Evolution of the Viral RNA Sensor OAS1 in Old World Monkeys and Cetartiodactyls
    City University of New York (CUNY) CUNY Academic Works All Dissertations, Theses, and Capstone Projects Dissertations, Theses, and Capstone Projects 2-2016 The Evolution of the Viral RNA Sensor OAS1 in Old World Monkeys and Cetartiodactyls Ian Fish Graduate Center, City University of New York How does access to this work benefit ou?y Let us know! More information about this work at: https://academicworks.cuny.edu/gc_etds/759 Discover additional works at: https://academicworks.cuny.edu This work is made publicly available by the City University of New York (CUNY). Contact: [email protected] The Evolution of the Viral RNA Sensor OAS1 in Old World Monkeys and Cetartiodactyls by Ian Fish The City University of New York 2016 i Copyright 2016 by Fish, Ian All rights reserved ii This manuscript has been read and accepted for the Graduate Faculty in Biology in satisfaction of the dissertation requirement for the degree of Doctor of Philosophy. ______________ ______________________________ Date Chair of Examining Committee Dr. Stéphane Boissinot ______________ ______________________________ Date Executive Officer Dr. Laurel Eckhardt Supervising Committee Members: ____________________________ Dr. Cathy Savage-Dunn, Queens College ____________________________ Dr. Susan Rotenberg, Queens College ____________________________ Dr. Shaneen Singh, Brooklyn College ____________________________ Dr. Margaret MacDonald, The Rockefeller University iii Abstract The Evolution of the Viral RNA Sensor OAS1 in Old World Monkeys and Cetartiodactyls author: Ian Fish advisor: Dr. Stéphane Boissinot Animals produce an array of sensors patrolling the intracellular environment poised to detect and respond to viral infection. The oligoadenylate synthetase family of enzymes comprises a crucial part of this innate immune response, directly signaling endonuclease activity responsible for inhibiting viral replication.
    [Show full text]
  • A Neanderthal OAS1 Isoform Protects Against COVID-19 Susceptibility
    medRxiv preprint doi: https://doi.org/10.1101/2020.10.13.20212092; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . 1 A Neanderthal OAS1 isoform Protects Against COVID-19 Susceptibility and 2 Severity: Results from Mendelian Randomization and Case-Control Studies 3 4 5 Sirui Zhou1,2,* Guillaume Butler-Laporte1,2,* Tomoko Nakanishi1,3,4,5,* David Morrison1, Jonathan Afilalo1, 6 Marc Afilalo1, Laetitia Laurent1, Maik Pietzner6, Nicola Kerrison6, Kaiqiong Zhao1,2, Elsa Brunet- 7 Ratnasingham7, Danielle Henry1, Nofar Kimchi1, Zaman Afrasiabi1, Nardin Rezk1, Meriem Bouab1, Louis 8 Petitjean,1 Charlotte Guzman1, Xiaoqing Xue1, Chris Tselios,1 Branka Vulesevic1, Olumide Adeleye1, Tala 9 Abdullah1, Noor Almamlouk1, Yiheng Chen1, Michaël Chassé7, Madeleine Durand7, Michael Pollak1, Clare 10 Paterson8, Hugo Zeberg9, Johan Normark10, Robert Frithiof11, Miklós Lipcsey12,13, Michael Hultström11,13, 11 Celia M T Greenwood1,2, Claudia Langenberg6,14, Elin Thysell15, Vincent Mooser3, Vincenzo Forgetta1, 12 Daniel E. Kaufmann7,16, J Brent Richards1,2,3,17 13 14 Affiliations: 15 1) Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, 16 Canada 17 2) Department of Epidemiology, Biostatistics and Occupational Health, McGill 18 University, Montréal, Québec, Canada 19 3) Department of Human Genetics,
    [Show full text]
  • Supplementary Table 1: Gene List of 44 Upregulated Enzymes in Transformed Mesenchymal Stem Cell Cancer Model
    Supplementary Table 1: Gene list of 44 upregulated enzymes in transformed mesenchymal stem cell cancer model. Gene expression values for parental MSC (MSC 0) and transformed MSC (MSC5) are an average of three replicate log-2 transformed expression values from affymetrix U133 plus 2 genechip experiments with the log-fold change (LFC) indicating the difference (MSC5-MSC0). Supplementary Table 1 HGNC Symbol Alias Enzyme ID U133 plus2 probe set MSC0 MSC5 LFC Ttest pval # Gene rifs # Pubmed cites from Genecards (Sep 2007) Pathway / Function PharmGKB Drugs? Drug pathways? Therapeutic Target Database Thomson Pharma RNASEH2A AGS4; JUNB; RNHL; RNHIA; RNASEHI 3.1.26.- 203022_at 8.56 9.87 1.31 1.56E-05 0 11 RNA degradation none none none PPAP2C LPP2; PAP-2c; PAP2-g 3.1.3.4 209529_at 6.48 8.63 2.16 5.74E-03 2 13 Glycerolipid synthesis none none none ADARB1 ADAR2, ADAR2a, ADAR2a-L1, ADAR2a-L2, ADAR2a-L3, ADAR2b, ADAR2c 3.5.-.- 234799_at 6.36 8.15 1.79 2.03E-04 10 58 RNA pre-mRNA editing none none none ADARB1 3.5.-.- 203865_s_at 6.99 8.42 1.43 6.94E-03 10 58 RNA pre-mRNA editing none none none UAP1 AgX; AGX1; SPAG2 2.7.7.23 209340_at 11.17 12.45 1.28 2.46E-07 0 37 polysaccharide synthesis none none RNMT MET; RG7MT1; hCMT1c; KIAA0398; DKFZp686H1252 2.1.1.56 202684_s_at 5.70 6.78 1.08 8.15E-03 1 24 RNA (mRNA) capping none none GPD2 GDH2, mGPDH 1.1.1.8 211613_s_at 5.71 6.73 1.02 7.02E-03 2 37 glycolysis none none GCDH ACAD5, GCD 1.3.99.7 237304_at 5.38 6.39 1.01 2.44E-02 4 63 lys, hydroxy-lys, and trp metabolism none none ESPL1 3.4.22.49 38158_at 8.03
    [Show full text]
  • Cancer Upregulated Gene 2, a Novel Oncogene, Confers Resistance to Oncolytic Vesicular Stomatitis Virus Through STAT1-OASL2 Signaling
    Cancer Gene Therapy (2013) 20, 125–132 & 2013 Nature America, Inc. All rights reserved 0929-1903/13 www.nature.com/cgt ORIGINAL ARTICLE Cancer upregulated gene 2, a novel oncogene, confers resistance to oncolytic vesicular stomatitis virus through STAT1-OASL2 signaling W Malilas1, SS Koh2, R Srisuttee1, W Boonying1, I-R Cho1, C-S Jeong3, RN Johnston4 and Y-H Chung1 We have recently found a novel oncogene, named cancer upregulated gene 2 (CUG2), which activates Ras and mitogen-activated protein kinases (MAPKs), including ERK, JNK and p38 MAPK. Because activation of these signaling pathways has previously been shown to enhance cancer cell susceptibility to oncolysis by certain viruses, we examined whether vesicular stomatitis virus (VSV) could function as a potential therapeutic agent by efficiently inducing cytolysis in cells transformed by CUG2. Unexpectedly, NIH3T3 cells stably expressing CUG2 (NIH-CUG2) were resistant to VSV because of the activation of signal transducers and activators of transcription 1 (STAT1). The result was supported by evidence showing that suppression of STAT1 with short interference RNA (siRNA) renders cells susceptible to VSV. Furthermore, 20–50 oligoadenylate synthetase-like (OASL) 2 was the most affected by STAT1 expression level among anti-viral proteins and furthermore suppression of OASL2 mRNA level caused NIH-CUG2 cells to succumb to VSV as seen in NIH-CUG2 cells treated with STAT1 siRNA. In addition, Colon26L5 carcinoma cells stably expressing CUG2 (Colon26L5-CUG2) exhibited resistance to VSV, whereas Colon26L5 stably expressing a control vector yielded to VSV infection. Moreover, Colon26L5-CUG2 cells stably suppressing STAT1 succumbed to VSV infection, resulting in apoptosis.
    [Show full text]
  • 14498 OAS1 (D1W3A) Rabbit Mab
    Revision 1 C 0 2 - t OAS1 (D1W3A) Rabbit mAb a e r o t S Orders: 877-616-CELL (2355) [email protected] 8 Support: 877-678-TECH (8324) 9 4 Web: [email protected] 4 www.cellsignal.com 1 # 3 Trask Lane Danvers Massachusetts 01923 USA For Research Use Only. Not For Use In Diagnostic Procedures. Applications: Reactivity: Sensitivity: MW (kDa): Source/Isotype: UniProt ID: Entrez-Gene Id: WB, IP H Endogenous 40, 44 Rabbit IgG P00973 4938 Product Usage Information Application Dilution Western Blotting 1:1000 Immunoprecipitation 1:50 Storage Supplied in 10 mM sodium HEPES (pH 7.5), 150 mM NaCl, 100 µg/ml BSA, 50% glycerol and less than 0.02% sodium azide. Store at –20°C. Do not aliquot the antibody. Specificity / Sensitivity OAS1 (D1W3A) Rabbit mAb recognizes endogenous levels of total OAS1 protein. This antibody cross-reacts with an unidentified protein of 100 kDa in some cell lines. Species Reactivity: Human Source / Purification Monoclonal antibody is produced by immunizing animals with a synthetic peptide corresponding to residues surrounding Asp90 of human OAS1 protien. Background 2’-5’-oligoadenylate synthetase 1 (OAS1) is an antiviral protein induced by type 1 interferon that plays a key role in the cellular innate immune response (1). The OAS family of proteins includes OAS1, OAS2, OAS3, and OASL in humans (2). The OAS1 enzyme produces the second messenger 2’-5’-linked oligoadenylate in response to cytosolic dsRNA. These 2’-5’-linked oligoadenylates bind to the ribonuclease RNase L, which then degrades viral and cellular RNA (3). Research studies indicate that the OAS1 system inhibits protein synthesis and induces apoptosis in virally infected cells, which limits viral infection (4).
    [Show full text]
  • A Prenylated Dsrna Sensor Protects Against Severe COVID-19 and Is Absent in Horseshoe Bats
    medRxiv preprint doi: https://doi.org/10.1101/2021.05.05.21256681; this version posted May 9, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . @WilsonlabCVR Wickenhagen et al., A Prenylated dsRNA Sensor Protects Against Severe COVID-19 and is ABsent in Horseshoe Bats A Prenylated dsRNA Sensor Protects on global health, culture and prosperity. SARS-CoV-2 is Against Severe COVID-19 and is Absent in particularly sensitive to inhibition by type I interferons (IFNs) and there is great interest in understanding how individual Horseshoe Bats IFN-stimulated genes (ISGs) inhibit SARS-CoV-2, as type I IFNs play a major role in governing COVID-19 disease Arthur Wickenhagen1, Elena Sugrue1*, Spyros Lytras1*, 1* 1 1 outcome. Specifically, inborn errors (Zhang et al., 2020) Srikeerthana Kuchi , Matthew L Turnbull , Colin Loney , and single nucleotide polymorphisms (Pairo-Castineira et 1 1 1 Vanessa Herder , Jay Allan , Innes Jarmson , Natalia al., 2020) within the IFN system are linked with more severe 1 1 1 Cameron-Ruiz , Margus Varjak , Rute M Pinto , Douglas G COVID-19. Moreover, neutralizing anti-IFN autoantibodies 1 1 1 Stewart , Simon Swingler , Marko Noerenberg , Edward J likely prevent host IFN responses from controlling SARS- 2 2 1 D Greenwood , Thomas W M Crozier , Quan Gu , Sara CoV-2 replication, again resulting in severe COVID-19 3 3 4 Clohisey , Bo Wang , Fabio Trindade Maranhão Costa , disease (Bastard et al., 2020).
    [Show full text]
  • Real-Time 2-5A Kinetics Suggest That Interferons Β and Λ Evade Global Arrest of Translation by Rnase L
    Real-time 2-5A kinetics suggest that interferons β and λ evade global arrest of translation by RNase L Alisha Chitrakara,1, Sneha Ratha,1, Jesse Donovana, Kaitlin Demaresta, Yize Lib, Raghavendra Rao Sridharc,d, Susan R. Weissb, Sergei V. Kotenkoc,d, Ned S. Wingreena, and Alexei Korennykha,2 aDepartment of Molecular Biology, Princeton University, Princeton, NJ 08544; bDepartment of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; cDepartment of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ 07103; and dCenter for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ 07103 Edited by Peter Walter, University of California, San Francisco, CA, and approved December 14, 2018 (received for review October 24, 2018) Cells of all mammals recognize double-stranded RNA (dsRNA) as a of a dimeric endoribonuclease active site (21–23). This dimer foreign material. In response, they release interferons (IFNs) and further assembles into high-order oligomers (24) that cleave viral activate a ubiquitously expressed pseudokinase/endoribonuclease RNAs (16, 18) and all components of the translation apparatus, RNase L. RNase L executes regulated RNA decay and halts global including mRNAs (25), tRNAs (26), and 28S/18S rRNAs (27, translation. Here, we developed a biosensor for 2′,5′-oligoadeny- 28). The resulting action of RNase L inhibits global translation, late (2-5A), the natural activator of RNase L. Using this biosensor, which puts all proteins, including IFNs, at risk for arrest during a we found that 2-5A was acutely synthesized by cells in response to cellular response to dsRNA. dsRNA sensing, which immediately triggered cellular RNA cleav- The impact of translational shutdown by RNase L on IFN age by RNase L and arrested host protein synthesis.
    [Show full text]
  • Supplementary Tables: Table S1
    Supplementary Tables: Table S1. Differences of ADG and other performance traits between groups of high (n = 6) and low ADG steers (n = 6) of the three breeds. Angus Charolais KC Trait L_ADG±SE H_ADG±SE P-value L_ADG±SE H_ADG±SE P-value L_ADG±SE H_ADG±SE P-value ADG/kg/day 1.54±0.02 2.1±0.09 8.06E-04* 1.48±0.02 1.93±0.05 7.2E-05* 1.23±0.04 1.88±0.09 4.8E-05* RFI/kg/day 0.63±0.35 0.37±0.39 0.63 -0.032±0.40 0.33±0.28 0.48 -0.65±0.3 -0.06±0.56 0.37 DMI/kg/day 12.2±0.34 13.45±0.34 0.03 11.06±0.48 11.7±0.34 0.30 9.57±0.31 11.12±0.78 0.10 MWT/kg 115±2.33 120.26±2.19 0.13 122.31±2.06 117.76±2.25 0.22 98.45±1.66 103.53±3.02 0.17 FUREA/cm2 83.08±2.89 82.88±2.95 0.96 94.78±4.91 91.59±3.83 0.73 65.34±1.62 74.45±1.49 0.002* FUFAT/mm 10.57±0.93 10.18±0.98 0.78 6.38±0.71 5.73±0.37 0.44 8.28±0.94 8.83±0.32 0.59 HCW/lb 752.95±21.68 786.53±16.14 0.24 859.33 ±21.22 836.17±16.34 0.41 657.67±20.83 703.33±26.7 0.21 AFAT/mm 12±1.13 11.33±1.31 0.71 6.67±0.67 7.17±0.4 0.53 11.17±1.78 9.83±0.95 0.52 CREA/cm2 73.17±2.87 75.5±4.09 0.65 95.33±3.17 90.33±5.18 0.43 66.83±3.33 77.17±2.98 0.04 LMY/% 55.08±1.17 55.61±1.66 0.80 62.01±0.79 60.93±0.84 0.37 55.55±1.36 58.02±0.94 0.17 Marbling 448.33±24.96 416.67±24.32 0.39 365±19.05 381.67±25.23 0.58 372.5±9.64 380±18.08 0.72 Slaughter age/day 491.67±7.52 493.5±4.43 0.84 525.5 ±1.28 504±8.98 0.06 470.83±8.35 448.5±6.14 0.06 “*” indicates significant difference (P-value < 0.0042, Bonferroni Correction for 12 multiple testing analyses at P<0.05).
    [Show full text]
  • IL36RN Mutations
    The University of Manchester Research IL-36 Promotes Systemic IFN-I Responses in Severe Forms of Psoriasis DOI: 10.1016/j.jid.2019.08.444 Document Version Accepted author manuscript Link to publication record in Manchester Research Explorer Citation for published version (APA): Catapano, M., Vergnano, M., Romano, M., Mahil, S. K., Choon, S., Burden, A. D., Young, H. S., Carr, I. M., Lachmann, H. J., Lombardi, G., Smith, C. H., Ciccarelli, F. D., Barker, J. N., & Capon, F. (2019). IL-36 Promotes Systemic IFN-I Responses in Severe Forms of Psoriasis. Journal of Investigative Dermatology. https://doi.org/10.1016/j.jid.2019.08.444 Published in: Journal of Investigative Dermatology Citing this paper Please note that where the full-text provided on Manchester Research Explorer is the Author Accepted Manuscript or Proof version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version. General rights Copyright and moral rights for the publications made accessible in the Research Explorer 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. Takedown policy If you believe that this document breaches copyright please refer to the University of Manchester’s Takedown Procedures [http://man.ac.uk/04Y6Bo] or contact [email protected] providing relevant details, so we can investigate your claim. Download date:03.
    [Show full text]