The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has resulted in 92 million cases in a span of 1 year. The study focuses on understanding population-specific variations attributing its high rate of infections in specific geographical regions particularly in the United States. Rigorous phylogenomic network analysis of complete SARS-CoV-2 genomes (245) inferred five central clades named a (ancestral), b, c, d, and e (subtypes e1 and e2). Clade d and subclade e2 were found exclusively comprised of U.S. strains. Clades were distinguished by 10 co-mutational combinations in Nsp3, ORF8, Nsp13, S, Nsp12, Nsp2, and Nsp6. Our analysis revealed that only 67.46% of single nucleotide polymorphism (SNP) mutations were at the amino acid level. T1103P mutation in Nsp3 was predicted to increase protein stability in 238 strains except for 6 strains which were marked as ancestral type, whereas co-mutation (P409L and Y446C) in Nsp13 were found in 64 genomes from the United States highlighting its 100% co-occurrence. Docking highlighted mutation (D614G) caused reduction in binding of spike proteins with angiotensin-converting enzyme 2 (ACE2), but it also showed better interaction with the TMPRSS2 receptor contributing to high transmissibility among U.S. strains. We also found host proteins, MYO5A, MYO5B, and MYO5C, that had maximum interaction with viral proteins (nucleocapsid [N], spike [S], and membrane [M] proteins). Thus, blocking the internalization pathway by inhibiting MYO5 proteins which could be an effective target for coronavirus disease 2019 (COVID-19) treatment. The functional annotations of the host-pathogen interaction (HPI) network were found to be closely associated with hypoxia and thrombotic conditions, confirming the vulnerability and severity of infection. We also screened CpG islands in Nsp1 and N conferring the ability of SARS-CoV-2 to enter and trigger zinc antiviral protein (ZAP) activity inside the host cell.

中文翻译：

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比较基因组学和综合网络方法揭示了 SARS-CoV-2 中的非定向系统发育模式、共突变热点、功能串扰和监管相互作用

严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 大流行在一年内导致 9200 万病例。该研究的重点是了解特定地理区域（尤其是美国）感染率高的特定人群变异。对完整的 SARS-CoV-2 基因组 (245) 进行严格的系统发育网络分析，推断出五个名为 a（祖先）、b、c、d 和 e（亚型 e1 和 e2）的中央进化枝。发现进化枝 d 和子进化枝 e2 完全由美国菌株组成。通过 Nsp3、ORF8、Nsp13、S、Nsp12、Nsp2 和 Nsp6 中的 10 种共突变组合区分进化枝。我们的分析表明，只有 67.46% 的单核苷酸多态性 (SNP) 突变处于氨基酸水平。预测 Nsp3 中的 T1103P 突变会增加 238 个菌株的蛋白质稳定性，除了 6 个标记为祖先类型的菌株，而在来自美国的 64 个基因组中发现了 Nsp13 的共突变（P409L 和 Y446C），突出了其 100% co-发生。对接突出突变 (D614G) 导致刺突蛋白与血管紧张素转换酶 2 (ACE2) 的结合减少，但它也显示出与 TMPRSS2 受体更好的相互作用，有助于美国菌株之间的高传播性。我们还发现宿主蛋白 MYO5A、MYO5B 和 MYO5C，它们与病毒蛋白（核衣壳 [N]、刺突 [S] 和膜 [M] 蛋白）的相互作用最大。因此，通过抑制 MYO5 蛋白来阻断内化途径，这可能是 2019 年冠状病毒病（COVID-19）治疗的有效靶点。发现宿主-病原体相互作用（HPI）网络的功能注释与缺氧和血栓形成密切相关，证实了感染的脆弱性和严重程度。我们还筛选了 Nsp1 和 N 中的 CpG 岛，这些岛赋予 SARS-CoV-2 进入并触发宿主细胞内锌抗病毒蛋白 (ZAP) 活性的能力。