How mutation-driven predisposition shapes the accelerated adaptive trajectory of SARS-CoV-2: the role of NSP4 T492I

Recent evolve-and-resequence experiments demonstrate that the historical SARS-CoV-2 non-structural protein 4 (NSP4) mutation T492I mutation may accelerate viral evolution toward the Omicron variants via enhancing viral replication, altering the expression of DNA-editing enzymes, and exerting a positive epistatic effect to other adaptive mutations. These findings suggest the existence and importance of natural driver mutation and predisposition to adaptive variants in viral evolution. However, previous studies have primarily focus on result demonstration, and there is a need for a more systematic summary, further theoretical speculation and a detailed review of relevant background based on previous work. Addressing these issues, we have searched relevant documents published up to 2026 in PubMed, Web of Science, and Scopus. Based on these, this study comprehensively reviews previous research on predisposition and mutation-driven evolution, and discusses how a potential driver mutation, NSP4 T492I, may accelerate adaptive evolution and shape the evolutionary trajectory of SARS-CoV-2. These contribute to understanding the evolutionary trajectory of virus and the mechanisms underlying mutation-driven evolution, which could benefit future predictions of viral evolution and vaccine development.