PDF(Pubmed)
Abstract：
Over the course of the COVID-19 pandemic, several SARS-CoV-2 variants have emerged that may exhibit different etiological effects such as enhanced transmissibility and infectivity. However, genetic variations that reduce virulence and deteriorate viral fitness have not yet been thoroughly investigated. The present study sought to evaluate the effects of viral genetic makeup on COVID-19 epidemiology in Pakistan, where the infectivity and mortality rate was comparatively lower than other countries during the first pandemic wave. For this purpose, we focused on the comparative analyses of 7096 amino-acid long polyprotein pp1ab. Comparative sequence analysis of 203 SARS-CoV-2 genomes, sampled from Pakistan during the first wave of the pandemic revealed 179 amino acid substitutions in pp1ab. Within this set, 38 substitutions were identified within the Nsp3 region of the pp1ab polyprotein. Structural and biophysical analysis of proteins revealed that amino acid variations within Nsp3\'s macrodomains induced conformational changes and modified protein-ligand interactions, consequently diminishing the virulence and fitness of SARS-CoV-2. Additionally, the epistatic effects resulting from evolutionary substitutions in SARS-CoV-2 proteins may have unnoticed implications for reducing disease burden. In light of these findings, further characterization of such deleterious SARS-CoV-2 mutations will not only aid in identifying potential therapeutic targets but will also provide a roadmap for maintaining vigilance against the genetic variability of diverse SARS-CoV-2 strains circulating globally. Furthermore, these insights empower us to more effectively manage and respond to potential viral-based pandemic outbreaks of a similar nature in the future.
摘要：
在COVID-19大流行的过程中，已经出现了几种SARS-CoV-2变体，它们可能表现出不同的病因，例如传染性和传染性增强。然而,降低毒力和恶化病毒适应性的遗传变异尚未得到彻底研究。本研究试图评估病毒基因构成对巴基斯坦COVID-19流行病学的影响，在第一次大流行浪潮中，传染性和死亡率相对低于其他国家。为此,我们专注于7096个氨基酸长的多蛋白pp1ab的比较分析。203个SARS-CoV-2基因组的比较序列分析,在第一波大流行期间从巴基斯坦取样，发现pp1ab中有179个氨基酸取代。在这个集合中，在pp1ab多蛋白的Nsp3区域内鉴定了38个取代。蛋白质的结构和生物物理分析显示，Nsp3巨域内的氨基酸变异诱导构象变化和修饰的蛋白质-配体相互作用，因此降低了SARS-CoV-2的毒力和适应性。此外,SARS-CoV-2蛋白的进化取代导致的上位效应可能对降低疾病负担具有未被注意到的意义.根据这些发现,对此类有害SARS-CoV-2突变的进一步鉴定不仅有助于确定潜在的治疗靶点,还将为保持对全球传播的多种SARS-CoV-2毒株的遗传变异性的警惕提供路线图.此外，这些见解使我们能够更有效地管理和应对未来类似性质的潜在的基于病毒的大流行暴发。
