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Abstract：
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Understanding the influence of mutations in the SARS-CoV-2 gene on clinical outcomes is critical for treatment and prevention. Here, we analyzed all high-coverage complete SARS-CoV-2 sequences from GISAID database from January 1, 2020, to January 1, 2021, to mine the mutation hotspots associated with clinical outcome and developed a model to predict the clinical outcome in different epidemic strains. Exploring the cause of mutation based on RNA-dependent RNA polymerase (RdRp) and RNA-editing enzyme, mutation was more likely to occur in severe and mild cases than in asymptomatic cases, especially A > G, C > T, and G > A mutations. The mutations associated with asymptomatic outcome were mainly in open reading frame 1ab (ORF1ab) and N genes; especially R6997P and V30L mutations occurred together and were correlated with asymptomatic outcome with high prevalence. D614G, Q57H, and S194L mutations were correlated with mild and severe outcome with high prevalence. Interestingly, the single-nucleotide variant (SNV) frequency was higher with high percentage of nt14408 mutation in RdRp in severe cases. The expression of ADAR and APOBEC was associated with clinical outcome. The model has shown that the asymptomatic percentage has increased over time, while there is high symptomatic percentage in Alpha, Beta, and Gamma. These findings suggest that mutation in the SARS-CoV-2 genome may have a direct association with clinical outcomes and pandemic. Our result and model are helpful to predict the prevalence of epidemic strains and to further study the mechanism of mutation causing severe disease.
摘要：
严重急性呼吸道综合症冠状病毒2（SARS-CoV-2）是正在进行的2019年冠状病毒病（COVID-19）大流行的原因。了解SARS-CoV-2基因突变对临床结果的影响对于治疗和预防至关重要。这里,我们分析了2020年1月1日至2021年1月1日GISAID数据库中所有高覆盖率的SARS-CoV-2完整序列,以挖掘与临床结局相关的突变热点,并建立了预测不同流行毒株临床结局的模型.探索基于RNA依赖性RNA聚合酶（RdRp）和RNA编辑酶的突变原因，严重和轻度病例比无症状病例更容易发生突变，尤其是A>G,C>T,和G>A突变。与无症状结局相关的突变主要在开放阅读框1ab（ORF1ab）和N基因中；尤其是R6997P和V30L突变一起发生，并且与无症状结局相关，患病率高。D614G,Q57H,S194L突变与轻度和重度结局相关,且患病率高.有趣的是,在严重病例中,单核苷酸变异(SNV)频率较高,RdRp中nt14408突变的百分比较高.ADAR和APOBEC的表达与临床预后有关。该模型表明，随着时间的推移，无症状百分比有所增加，虽然阿尔法有很高的症状百分比，Beta,还有Gamma.这些发现表明，SARS-CoV-2基因组中的突变可能与临床结果和大流行直接相关。我们的结果和模型有助于预测流行菌株的流行率和进一步研究突变引起严重疾病的机制。
