Genomic diversity of SARS-CoV-2 can be accelerated by mutations in the nsp14 gene (Watanabe Lab, iScience)

Coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), encode a proofreading exonuclease, nonstructural protein 14 (nsp14), that helps ensure replication competence at a low evolutionary rate compared with other RNA viruses. In the current pandemic, SARS-CoV-2 has accumulated diverse genomic mutations including in nsp14. Here, to clarify whether amino acid substitutions in nsp14 affect the genomic diversity and evolution of SARS-CoV-2, we searched for amino acid substitutions in nature that may interfere with nsp14 function. We found that viruses carrying a proline-to-leucine change at position 203 (P203L) have a high evolutionary rate and that a recombinant SARS-CoV-2 virus with the P203L mutation acquired more diverse genomic mutations than wild-type virus during its replication in hamsters. Our findings suggest that substitutions, such as P203L, in nsp14 may accelerate the genomic diversity of SARS-CoV-2, contributing to virus evolution during the pandemic.


  • Amino acids of nonstructural protein 14 (nsp14) are well conserved in coronaviruses
  • P203L in nsp14 was not detected among coronaviruses but observed in SARS-CoV-2
  • Genome analysis suggested P203L nsp14 variants have a higher evolutionary rate
  • In vivo studies confirmed that the P203L nsp14 accelerates genomic diversity


This article was published in iScience on February 2023

Title: Genomic diversity of SARS-CoV-2 can be accelerated by mutations in the nsp14 gene

Authors: Kosuke Takada, Mahoko Takahashi Ueda, Shintaro Shichinohe, Yurie Kida, Chikako Ono, Yoshiharu Matsuura, Tokiko Watanabe, So Nakagawa