Evolution of coronavirus frameshifting elements: Competing stem networks explain conservation and variability

Shuting Yan, Qiyao Zhu, Jenna Hohl, Alex Dong, Tamar Schlick

Research output: Contribution to journalArticlepeer-review


The frameshifting RNA element (FSE) in coronaviruses (CoVs) regulates the programmed −1 ribosomal frameshift (−1 PRF) mechanism common to many viruses. The FSE is of particular interest as a promising drug candidate. Its associated pseudoknot or stem loop structure is thought to play a large role in frameshifting and thus viral protein production. To investigate the FSE structural evolution, we use our graph theory-based methods for representing RNA secondary structures in the RNA-As-Graphs (RAG) framework to calculate conformational landscapes of viral FSEs with increasing sequence lengths for representative 10 Alpha and 13 Beta-CoVs. By following length-dependent conformational changes, we show that FSE sequences encode many possible competing stems which in turn favor certain FSE topologies, including a variety of pseudoknots, stem loops, and junctions. We explain alternative competing stems and topological FSE changes by recurring patterns of mutations. At the same time, FSE topology robustness can be understood by shifted stems within different sequence contexts and base pair coevolution. We further propose that the topology changes reflected by length-dependent conformations contribute to tuning the frameshifting efficiency. Our work provides tools to analyze virus sequence/structure correlations, explains how sequence and FSE structure have evolved for CoVs, and provides insights into potential mutations for therapeutic applications against a broad spectrum of CoV FSEs by targeting key sequence/structural transitions.

Original languageEnglish (US)
Article numbere2221324120
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number20
StatePublished - May 16 2023

ASJC Scopus subject areas

  • General


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