title: IFNL3 mRNA structure is remodeled by a functional non-coding polymorphism associated with hepatitis C virus clearance.
abstract: Polymorphisms near the interferon lambda 3 (IFNL3) gene strongly predict clearance of hepatitis C virus (HCV) infection. We analyzed a variant (rs4803217 G/T) located within the IFNL3 mRNA 3' untranslated region (UTR); the G allele (protective allele) is associated with elevated therapeutic HCV clearance. We show that the IFNL3 3' UTR represses mRNA translation and the rs4803217 allele modulates the extent of translational regulation. We analyzed the structures of IFNL3 variant mRNAs at nucleotide resolution by SHAPE-MaP. The rs4803217 G allele mRNA forms well-defined 3' UTR structure while the T allele mRNA is more dynamic. The observed differences between alleles are among the largest possible RNA structural alterations that can be induced by a single nucleotide change and transform the UTR from a single well-defined conformation to one with multiple dynamic interconverting structures. These data illustrate that non-coding genetic variants can have significant functional effects by impacting RNA structure.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham NC, 27710, USA.|Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Lu
authors.affiliation: Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599-3290, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Mauger
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
authors.affiliation: Center for Pharmacogenomics and Individualized Therapy, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7361, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Urban
authors.affiliation: Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599-3290, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Weeks
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham NC, 27710, USA.|Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Shelton S
authors.initials: SS
authors.lastname: Bradrick
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000998:Antiviral Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006367:HeLa Cells; D016174:Hepacivirus; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics* / Q000821:virology; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D000095022:Interferon Lambda
chemical_list: D020413:3' Untranslated Regions; D000998:Antiviral Agents; D007372:Interferons; D007378:Interleukins; D012333:RNA, Messenger; C000624353:interferon-lambda, human; D000095022:Interferon Lambda