IFNL3 mRNA structure is remodeled by a functional non-coding polymorphism associated with hepatitis C virus clearance.

Autor: Lu YF; 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., Mauger DM; Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599-3290, USA., Goldstein DB; Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA., Urban TJ; Center for Pharmacogenomics and Individualized Therapy, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7361, USA., Weeks KM; Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599-3290, USA., Bradrick SS; 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.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2015 Nov 04; Vol. 5, pp. 16037. Date of Electronic Publication: 2015 Nov 04.
DOI: 10.1038/srep16037
Abstrakt: 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.
Databáze: MEDLINE
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