Department of Bioinformatics, Semmelweis University, Budapest, Hungary; TTK Momentum Cancer Biomarker Research Group, Budapest, Hungary.
Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary.
Int J Antimicrob Agents. 2021 Feb;57(2):106272. doi: 10.1016/j.ijantimicag.2020.106272. Epub 2020 Dec 23.
Genomic alterations in a viral genome can lead to either better or worse outcome and identifying these mutations is of utmost importance. Here, we correlated protein-level mutations in the SARS-CoV-2 virus to clinical outcome.
Mutations in viral sequences from the GISAID virus repository were evaluated by using "hCoV-19/Wuhan/WIV04/2019" as the reference. Patient outcomes were classified as mild disease, hospitalization and severe disease (death or documented treatment in an intensive-care unit). Chi-square test was applied to examine the association between each mutation and patient outcome. False discovery rate was computed to correct for multiple hypothesis testing and results passing FDR cutoff of 5% were accepted as significant.
Mutations were mapped to amino acid changes for 3,733 non-silent mutations. Mutations correlated to mild outcome were located in the ORF8, NSP6, ORF3a, NSP4, and in the nucleocapsid phosphoprotein N. Mutations associated with inferior outcome were located in the surface (S) glycoprotein, in the RNA dependent RNA polymerase, in ORF3a, NSP3, ORF6 and N. Mutations leading to severe outcome with low prevalence were found in the ORF3A and in NSP7 proteins. Four out of 22 of the most significant mutations mapped onto a 10 amino acid long phosphorylated stretch of N indicating that in spite of obvious sampling restrictions the approach can find functionally relevant sites in the viral genome.
We demonstrate that mutations in the viral genes may have a direct correlation to clinical outcome. Our results help to quickly identify SARS-CoV-2 infections harboring mutations related to severe outcome.
病毒基因组中的基因组改变可能导致更好或更差的结果，识别这些突变至关重要。在这里，我们将 SARS-CoV-2 病毒的蛋白质水平突变与临床结果相关联。
通过使用“hCoV-19/Wuhan/WIV04/2019”作为参考，评估来自 GISAID 病毒库的病毒序列中的突变。患者的结局分为轻症、住院和重症（死亡或在重症监护病房接受有记录的治疗）。应用卡方检验来检验每个突变与患者结局之间的关系。应用假发现率来校正多重假设检验，通过 FDR 截断值为 5%的结果被认为具有统计学意义。
共映射了 3733 个非同义突变的氨基酸变化。与轻症结局相关的突变位于 ORF8、NSP6、ORF3a、NSP4 和核衣壳磷蛋白 N 中。与不良结局相关的突变位于表面（S）糖蛋白、RNA 依赖的 RNA 聚合酶、ORF3a、NSP3、ORF6 和 N 中。导致严重结局且发生率较低的突变发生在 ORF3A 和 NSP7 蛋白中。22 个最重要的突变中有 4 个映射到 N 上的 10 个氨基酸长的磷酸化区域，这表明尽管存在明显的采样限制，但该方法可以在病毒基因组中找到具有功能相关性的位点。
我们证明病毒基因中的突变可能与临床结果直接相关。我们的研究结果有助于快速识别携带与严重后果相关突变的 SARS-CoV-2 感染。
