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

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

doi:10.1016/j.isci.2023.106210

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

iScience. 2023 Mar 17;26(3):106210. doi: 10.1016/j.isci.2023.106210. Epub 2023 Feb 16.

Authors

Kosuke Takada^{1

2}, Mahoko Takahashi Ueda³, Shintaro Shichinohe¹, Yurie Kida¹, Chikako Ono^{4

5}, Yoshiharu Matsuura^{4

5}, Tokiko Watanabe^{1

5

6}, So Nakagawa^{2

7}

Affiliations

¹ Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
² Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
³ Department of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510, Japan.
⁴ Laboratory of Virus Control, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
⁵ Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka 565-0871, Japan.
⁶ Center for Advanced Modalities and DDS, Osaka University, Suita, Osaka 565-0871, Japan.
⁷ Bioinformation and DDBJ Center, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan.

Abstract

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.

Keywords: Evolutionary biology; Virology.