A selective sweep in the Spike gene has driven SARS-CoV-2 human adaptation.
A selective sweep in the Spike gene has driven SARS-CoV-2 human adaptation.
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DOI：
10.1016/j.cell.2021.07.007
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发表时间：
2021-08-19
期刊：
影响因子：
64.5
通讯作者：
Weger-Lucarelli J
中科院分区：
文献类型：
--
作者：
Kang L;He G;Sharp AK;Wang X;Brown AM;Michalak P;Weger-Lucarelli J
2019 年冠状病毒病 (COVID-19) 大流行凸显了需要更好地了解冠状病毒从动物到人类的传播以及新宿主内的适应性进化。我们扫描了超过 182,000 个严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 基因组的选择性扫描特征，发现了位于刺突蛋白受体结合域 (RBD) 内非同义变化 (A1114G；T372A) 周围的独特正选择足迹，预计会消除糖基化并增加与细胞受体人 ACE2 (hACE2) 的结合。这种变化存在于所有人类 SARS-CoV-2 序列中，但不存在于密切相关的蝙蝠和穿山甲病毒中。正如预测的那样，T372A RBD 在实验结合测定中以更高的亲和力结合 hACE2。我们设计了回复突变体 (A372T)，发现 A372（野生型 [WT]-SARS-CoV-2）相对于其假定的祖先变体 (T372) 增强了人肺细胞中的复制，其效果比众所周知的 D614G 突变强 20 倍。我们的研究结果表明，这种突变可能导致 SARS-CoV-2 从动物宿主中出现或实现持续的人际传播。与假定的祖先变体（T372）相比，人类 SARS-CoV-2 刺突蛋白 RBD 内的非同义变化（T372A）显示出与 hACE2 更高的结合亲和力，并增强了在人肺细胞中的复制，这提供了病毒突变的证据，这种突变可能是实现人际传播所必需的。
The coronavirus disease 2019 (COVID-19) pandemic underscores the need to better understand animal-to-human transmission of coronaviruses and adaptive evolution within new hosts. We scanned more than 182,000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes for selective sweep signatures and found a distinct footprint of positive selection located around a non-synonymous change (A1114G; T372A) within the spike protein receptor-binding domain (RBD), predicted to remove glycosylation and increase binding to human ACE2 (hACE2), the cellular receptor. This change is present in all human SARS-CoV-2 sequences but not in closely related viruses from bats and pangolins. As predicted, T372A RBD bound hACE2 with higher affinity in experimental binding assays. We engineered the reversion mutant (A372T) and found that A372 (wild-type [WT]-SARS-CoV-2) enhanced replication in human lung cells relative to its putative ancestral variant (T372), an effect that was 20 times greater than the well-known D614G mutation. Our findings suggest that this mutation likely contributed to SARS-CoV-2 emergence from animal reservoirs or enabled sustained human-to-human transmission. A non-synonymous change (T372A) within the spike protein RBD of human SARS-CoV-2 shows higher binding affinity to hACE2 and enhanced replication in human lung cells compared with its putative ancestral variant (T372), providing evidence of a viral mutation that is likely to have been necessary to enable human-to-human transmission.
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