Symons Jori, Chung Claire, Verheijen Bert M, Shemtov Sarah J, de Jong Dorien, Amatngalim Gimano, Nijhuis Monique, Vermulst Marc, Gout Jean-Francois
Translational Virology, Department of Medical Microbiology, University Medical Center, Utrecht, The Netherlands.
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
Nat Commun. 2025 Jul 11;16(1):6425. doi: 10.1038/s41467-025-61555-x.
Although vaccines and treatments have strengthened our ability to combat the COVID-19 pandemic, new variants of SARS-CoV-2 continue to emerge in human populations. Because the evolution of SARS-CoV-2 is driven by mutation, a better understanding of its mutation rate and spectrum could improve our ability to forecast the trajectory of the pandemic. Here, we use circular RNA consensus sequencing (CirSeq) to determine the mutation rate of six SARS-CoV-2 variants and perform a short-term evolution experiment to determine the impact of these mutations on viral fitness. Our analyses indicate that the SARS-CoV-2 genome mutates at a rate of ∼1.5 × 10/base per viral passage and that the spectrum is dominated by C → U transitions. Moreover, we find that the mutation rate is significantly reduced in regions that form base-pairing interactions and that mutations that affect these secondary structures are especially harmful to viral fitness. In this work, we show that the biased mutation spectrum of SARS-CoV-2 is likely a result of frequent cytidine deamination and that the secondary structure of the virus plays an important role in this process, providing new insight into the parameters that guide viral evolution and highlighting fundamental weaknesses of the virus that may be exploited for therapeutic purposes.
尽管疫苗和治疗方法增强了我们抗击新冠疫情的能力，但严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的新变种仍在人群中不断出现。由于SARS-CoV-2的进化是由突变驱动的，更好地了解其突变率和突变谱可以提高我们预测疫情发展轨迹的能力。在这里，我们使用环状RNA一致性测序（CirSeq）来确定6种SARS-CoV-2变种的突变率，并进行短期进化实验以确定这些突变对病毒适应性的影响。我们的分析表明，SARS-CoV-2基因组在每次病毒传代时的突变率约为1.5×10⁻³/碱基，且突变谱以C→U转换为主。此外，我们发现形成碱基配对相互作用的区域突变率显著降低，而影响这些二级结构的突变对病毒适应性尤其有害。在这项工作中，我们表明SARS-CoV-2有偏向性的突变谱可能是频繁胞嘧啶脱氨的结果，并且病毒的二级结构在此过程中起重要作用，这为指导病毒进化的参数提供了新见解，并突出了病毒可能被用于治疗目的的基本弱点。
