Emergence of SARS-CoV-2 subgenomic RNAs that enhance viral fitness and immune evasion.

Summary

The study identifies convergently evolved, novel TRSs in SARS-CoV-2 that generate subgenomic RNAs—including a truncated N sgRNA—enhancing viral replication via antagonism of type I interferon. These RNA-level innovations occur across multiple lineages (e.g., B.1.1, Alpha, Gamma, Omicron), revealing a functional evolutionary layer beyond amino acid substitutions.

Key Findings

• Convergent emergence of novel TRSs upstream of Spike and Envelope in multiple lineages.
• A prevalent neo-TRS within Nucleocapsid (B.1.1 lineage and VOCs) generates a truncated N sgRNA that antagonizes type I interferon and enhances fitness.
• Distinct phenotypes arise when abrogating the TRS versus mutating N coding sequence, implicating functional RNA-level evolution.

Clinical Implications

Encourages genomic surveillance to track emergent TRSs; suggests considering TRS/sgRNA targets for therapeutics; highlights that variant risk cannot be judged by spike mutations alone.

Limitations

• In vivo relevance in humans inferred; direct clinical outcome correlations were not reported.
• Quantitative epidemiologic impact of each neo-TRS on transmission was not modeled.

Future Directions

Incorporate TRS/sgRNA features into variant risk assessment; develop inhibitors targeting TRS-mediated transcription; longitudinally link neo-TRS emergence to clinical severity and transmissibility.