Zhang Jingsong, Zhang Yang, Kang Jun-Yan, Chen Shuiye, He Yongqun, Han Benhao, Liu Mo-Fang, Lu Lina, Li Li, Yi Zhigang, Chen Luonan
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Cell Discov. 2021 Jun 15;7(1):44. doi: 10.1038/s41421-021-00282-1.
The presence of SARS-CoV-2 mutants, including the emerging variant B.1.1.7, has raised great concerns in terms of pathogenesis, transmission, and immune escape. Characterizing SARS-CoV-2 mutations, evolution, and effects on infectivity and pathogenicity is crucial to the design of antibody therapies and surveillance strategies. Here, we analyzed 454,443 SARS-CoV-2 spike genes/proteins and 14,427 whole-genome sequences. We demonstrated that the early variant B.1.1.7 may not have evolved spontaneously in the United Kingdom or within human populations. Our extensive analyses suggested that Canidae, Mustelidae or Felidae, especially the Canidae family (for example, dog) could be a possible host of the direct progenitor of variant B.1.1.7. An alternative hypothesis is that the variant was simply yet to be sampled. Notably, the SARS-CoV-2 whole-genome represents a large number of potential co-mutations. In addition, we used an experimental SARS-CoV-2 reporter replicon system to introduce the dominant co-mutations NSP12_c14408t, 5'UTR_c241t, and NSP3_c3037t into the viral genome, and to monitor the effect of the mutations on viral replication. Our experimental results demonstrated that the co-mutations significantly attenuated the viral replication. The study provides valuable clues for discovering the transmission chains of variant B.1.1.7 and understanding the evolutionary process of SARS-CoV-2.
包括新出现的B.1.1.7变体在内的SARS-CoV-2突变体的出现，在发病机制、传播和免疫逃逸方面引起了极大关注。表征SARS-CoV-2突变、进化及其对传染性和致病性的影响，对于抗体疗法和监测策略的设计至关重要。在此，我们分析了454,443个SARS-CoV-2刺突基因/蛋白和14,427个全基因组序列。我们证明，早期变体B.1.1.7可能并非在英国或人类群体中自发进化而来。我们的广泛分析表明，犬科、鼬科或猫科动物，尤其是犬科（如狗）可能是变体B.1.1.7直接祖先的潜在宿主。另一种假设是该变体只是尚未被采样。值得注意的是，SARS-CoV-2全基因组存在大量潜在的共突变。此外，我们使用实验性SARS-CoV-2报告基因复制子系统，将主要的共突变NSP12_c14408t、5'UTR_c241t和NSP3_c3037t引入病毒基因组，并监测这些突变对病毒复制的影响。我们的实验结果表明，这些共突变显著减弱了病毒复制。该研究为发现B.1.1.7变体的传播链和理解SARS-CoV-2的进化过程提供了有价值的线索。
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