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Updated: Nov 16, 2025
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Probing RNA Structure with Dimethyl Sulfate Mutational Profiling with Sequencing In Vitro and in Cells
Published on: December 9, 2022
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Genome-scale deconvolution of RNA structure ensembles
Edoardo Morandi1,2, Ilaria Manfredonia1, Lisa M Simon2
1Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, Groningen, the Netherlands.
Nature Methods
|February 23, 2021
Summary
RNA structure heterogeneity poses challenges for chemical probing. DRACO, a new algorithm, deconvolutes coexisting RNA conformations from mutational profiling, revealing alternative structures in the SARS-CoV-2 genome.
Area of Science:
- Computational Biology
- Structural Biology
- Virology
Background:
- Understanding RNA structure is crucial for biological function, but heterogeneity complicates analysis.
- Chemical probing methods provide insights into RNA structure but struggle with deconvoluting mixed conformations.
- The SARS-CoV-2 genome's structural dynamics are vital for its replication and pathogenesis.
Purpose of the Study:
- To develop a computational algorithm, DRACO, for deconvoluting coexisting RNA conformations from chemical probing data.
- To apply DRACO to analyze the structural heterogeneity of the SARS-CoV-2 genome.
- To identify and characterize alternative RNA structures within the viral genome.
Main Methods:
- Development of DRACO (Deconvolution of RNA Conformations) algorithm.
- Application of dimethyl sulfate mutational profiling with sequencing (DMS-MaPseq) to the SARS-CoV-2 genome.
- Integration of DRACO with DMS-MaPseq data for computational analysis of RNA structure.
Main Results:
- DRACO successfully deconvolutes coexisting RNA conformations from mutational profiling experiments.
- Analysis revealed multiple regions in the SARS-CoV-2 genome that exist in two mutually exclusive conformations.
- A conserved structural switch in the 3' untranslated region was identified as exhibiting conformational heterogeneity.
Conclusions:
- DRACO provides a powerful computational approach to dissect RNA structure heterogeneity.
- The SARS-CoV-2 genome exhibits significant conformational flexibility, particularly in its 3' untranslated region.
- This work advances the ability to study the complex RNA structurome, with implications for understanding viral biology.
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