Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant
Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant
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DOI：
10.1186/s12967-020-02344-6
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发表时间：
2020-04-22
影响因子：
7.4
通讯作者：
Ippodrino, Rudy
中科院分区：
文献类型：
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作者：
Pachetti, Maria;Marini, Bruna;Ippodrino, Rudy
背景SARS-CoV-2是一种RNA冠状病毒，导致严重急性呼吸系统综合征（COVID-19）大流行。RNA病毒的特点是突变率高，比其宿主高出100万倍。病毒的致突变能力取决于几个因素，包括复制核酸的病毒酶的保真度，如SARS-CoV-2 RNA依赖性RNA聚合酶（RdRp）。突变率驱动病毒进化和基因组变异，从而使病毒能够逃避宿主免疫并产生耐药性。方法我们分析了GISAID数据库中2019年12月至2020年3月中旬全球SARS-CoV-2感染患者的220个基因组序列。SARS-CoV-2参考基因组来自GenBank数据库。使用Clustal Omega进行基因组比对。使用Mann-Whitney和Fisher精确检验评估统计学显著性。结果我们鉴定了SARS-CoV-2的8个新的复发突变，分别位于1397、2891、14408、17746、17857、18060、23403和28881位。在2891、3036、14408、23403和28881位置的突变主要在欧洲观察到，而位于17746、17857和18060位置的突变仅存在于北美。我们于2020年2月9日在英国首次注意到RdRp基因的沉默突变，而2020年2月20日在意大利（伦巴第）出现了RdRp改变其氨基酸组成的不同突变。具有RdRp突变的病毒具有3个点突变的中值[范围：2-5]，否则它们具有1个突变的中值[范围：0-3]（p值< 0.001）。结论这些发现表明，该病毒正在进化，欧洲，北美和亚洲毒株可能共存，每种毒株的特征在于不同的突变模式。需要研究突变的RdRp对这种现象的贡献。迄今为止，几种靶向RdRp酶的药物被用于SARS-CoV-2感染的治疗。它们中的一些在SARS-CoV-2 RdRp疏水裂缝中具有预测的结合部分，该疏水裂缝与我们鉴定的14408突变相邻。因此，研究和表征SARS-CoV-2 RdRp突变以评估可能的耐药病毒表型是重要的。同样重要的是要认识到某些突变的存在是否可能与不同的SARS-CoV-2死亡率相关。
Background SARS-CoV-2 is a RNA coronavirus responsible for the pandemic of the Severe Acute Respiratory Syndrome (COVID-19). RNA viruses are characterized by a high mutation rate, up to a million times higher than that of their hosts. Virus mutagenic capability depends upon several factors, including the fidelity of viral enzymes that replicate nucleic acids, as SARS-CoV-2 RNA dependent RNA polymerase (RdRp). Mutation rate drives viral evolution and genome variability, thereby enabling viruses to escape host immunity and to develop drug resistance. Methods We analyzed 220 genomic sequences from the GISAID database derived from patients infected by SARS-CoV-2 worldwide from December 2019 to mid-March 2020. SARS-CoV-2 reference genome was obtained from the GenBank database. Genomes alignment was performed using Clustal Omega. Mann-Whitney and Fisher-Exact tests were used to assess statistical significance. Results We characterized 8 novel recurrent mutations of SARS-CoV-2, located at positions 1397, 2891, 14408, 17746, 17857, 18060, 23403 and 28881. Mutations in 2891, 3036, 14408, 23403 and 28881 positions are predominantly observed in Europe, whereas those located at positions 17746, 17857 and 18060 are exclusively present in North America. We noticed for the first time a silent mutation in RdRp gene in England (UK) on February 9th, 2020 while a different mutation in RdRp changing its amino acid composition emerged on February 20th, 2020 in Italy (Lombardy). Viruses with RdRp mutation have a median of 3 point mutations [range: 2-5], otherwise they have a median of 1 mutation [range: 0-3] (p value < 0.001). Conclusions These findings suggest that the virus is evolving and European, North American and Asian strains might coexist, each of them characterized by a different mutation pattern. The contribution of the mutated RdRp to this phenomenon needs to be investigated. To date, several drugs targeting RdRp enzymes are being employed for SARS-CoV-2 infection treatment. Some of them have a predicted binding moiety in a SARS-CoV-2 RdRp hydrophobic cleft, which is adjacent to the 14408 mutation we identified. Consequently, it is important to study and characterize SARS-CoV-2 RdRp mutation in order to assess possible drug-resistance viral phenotypes. It is also important to recognize whether the presence of some mutations might correlate with different SARS-CoV-2 mortality rates.