Fang, ShuyiLiu, ShengLu, Alex Z.Wang, Audrey K. Y.Zhang, YuchengLi, KailingLiu, JuliYang, LeiHu, Chang-DengWan, Jun2021-12-012021-12-012021-12Fang, S., Liu, S., Shen, J., Lu, A. Z., Wang, A. K. Y., Zhang, Y., Li, K., Liu, J., Yang, L., Hu, C.-D., & Wan, J. (2021). Updated SARS-CoV-2 single nucleotide variants and mortality association. Journal of Medical Virology, 93(12), 6525–6534. https://doi.org/10.1002/jmv.271910146-6615, 1096-9071https://hdl.handle.net/1805/27100This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.By analyzing newly collected SARS-CoV-2 genomes and comparing them with our previous study about SARS-CoV-2 single nucleotide variants (SNVs) before June 2020, we found that the SNV clustering had changed remarkably since June 2020. Apart from that the group of SNVs became dominant, which is represented by two nonsynonymous mutations A23403G (S:D614G) and C14408T (ORF1ab:P4715L), a few emerging groups of SNVs were recognized with sharply increased monthly incidence ratios of up to 70% in November 2020. Further investigation revealed sets of SNVs specific to patients' ages and/or gender, or strongly associated with mortality. Our logistic regression model explored features contributing to mortality status, including three critical SNVs, G25088T(S:V1176F), T27484C (ORF7a:L31L), and T25A (upstream of ORF1ab), ages above 40 years old, and the male gender. The protein structure analysis indicated that the emerging subgroups of nonsynonymous SNVs and the mortality-related ones were located on the protein surface area. The clashes in protein structure introduced by these mutations might in turn affect the viral pathogenesis through the alteration of protein conformation, leading to a difference in transmission and virulence. Particularly, we explored the fact that nonsynonymous SNVs tended to occur in intrinsic disordered regions of Spike and ORF1ab to significantly increase hydrophobicity, suggesting a potential role in the change of protein folding related to immune evasion.en-USPublic Health Emergencymortality risk factorVirulenceCOVID-19Polymorphism, Single NucleotideSpike Glycoprotein, CoronavirusArticle