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

Area of Science:

• Genetics
• Virology
• Molecular Biology

Background:

• Polymorphisms near the interferon lambda 3 (IFNL3) gene are strong predictors of spontaneous and therapeutic hepatitis C virus (HCV) clearance.
• A specific variant, rs4803217 G/T, within the IFNL3 mRNA 3' untranslated region (UTR) is associated with enhanced HCV clearance.

Purpose of the Study:

• To investigate the functional impact of the rs4803217 variant on IFNL3 mRNA translation and RNA structure.
• To elucidate the molecular mechanisms by which this non-coding variant influences HCV clearance.

Main Methods:

• Analysis of IFNL3 mRNA structure using SHAPE-MaP (Selective 2′-Hydroxyl Acylation analyzed by Primer Extension and Mutational Profiling) at nucleotide resolution.
• Assessment of translational regulation modulated by the rs4803217 variant in the IFNL3 3' UTR.

Main Results:

• The IFNL3 3' UTR was shown to repress mRNA translation.
• The protective G allele of rs4803217 results in a well-defined 3' UTR structure, while the T allele exhibits a more dynamic structure.
• These structural differences, induced by a single nucleotide change, significantly alter translational regulation.

Conclusions:

• Non-coding genetic variants can exert significant functional effects by modulating RNA structure.
• The rs4803217 variant influences HCV clearance through allele-specific alterations in IFNL3 mRNA structure and subsequent translational control.