The key evolutionary step leading to the pandemic virus was the acquisition of the PRRA furin cleavage motif at the spike glycoprotein S1/S2 junction by a progenitor of SARS-CoV-2. Two of its features draw attention: (i) it is absent in other known lineage B beta-coronaviruses, including the newly discovered coronaviruses in bats from Laos and Vietnam, which are the closest known relatives of the covid virus; and, (ii) it introduced the pair of arginine codons (CGG-CGG), whose usage is extremely rare in coronaviruses. With an occurrence rate of only 3%, the arginine CGG codon is considered a minority in SARS CoV-2. On the other hand, Laos and Vietnam bat coronaviruses contain receptor-binding domains that are almost identical to that of SARS-CoV-2 and can therefore infect human cells despite the absence of the furin cleavage motif. Based on these data, the aim of this work is to provide a detailed sequence analysis between the SARS-CoV-2 S gene insert encoding PRRA and the human mRNA transcripts. The result showed a 100% match to several mRNA transcripts. The set of human genes whose mRNAs match this S gene insert are ubiquitous and highly expressed, e.g., the ATPase F1 (ATP5F1) and the ubiquitin specific peptidase 21 (USP21) genes; or specific genes of target organs or tissues of the SARS-CoV-2 infection (e.g., MEMO1, SALL3, TRIM17, CWC15, CCDC187, FAM71E2, GAB4, PRDM13). Results suggest that a recombination between the genome of a SARS-CoV-2 progenitor and human mRNA transcripts could be the origin of the S gene 12-nucleotide insert encoding the S protein PRRA motif. The hypothesis of probable human origin of the SARS-CoV-2 polybasic furin cleavage motif is supported by: (i) the nature of human genes whose mRNA sequence 100% match the S gene insert; (ii) the synonymous base substitution in the arginine codons (CGG-CGG); and (iii) further spike glycoprotein PRRA-like insertions suggesting that the acquisition of PRRA may not have been a single recombination event.

中文翻译：

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SARS-CoV-2 多元弗林蛋白酶切割基序可能源自人类

导致大流行病毒的关键进化步骤是 SARS-CoV-2 的祖先在刺突糖蛋白 S1/S2 连接处获得 PRRA 弗林蛋白酶切割基序。它的两个特征引起了人们的关注：（i）它在其他已知的 B 谱系 β 冠状病毒中不存在，包括在老挝和越南的蝙蝠中新发现的冠状病毒，它们是已知的新冠病毒最近的亲属；(ii)它引入了一对精氨酸密码子（CGG-CGG），其在冠状病毒中的使用极为罕见。精氨酸 CGG 密码子的出现率仅为 3%，被认为是 SARS CoV-2 中的少数。另一方面，老挝和越南蝙蝠冠状病毒含有与 SARS-CoV-2 几乎相同的受体结合域，因此尽管不存在弗林蛋白酶裂解基序，但仍可以感染人类细胞。基于这些数据，这项工作的目的是提供编码 PRRA 的 SARS-CoV-2 S 基因插入片段和人类 mRNA 转录本之间的详细序列分析。结果显示与多个 mRNA 转录本 100% 匹配。mRNA 与该 S 基因插入片段相匹配的一组人类基因是普遍存在且高度表达的，例如 ATPase F1 (ATP5F1) 和泛素特异性肽酶 21 (USP21) 基因；或 SARS-CoV-2 感染的靶器官或组织的特定基因（例如 MEMO1、SALL3、TRIM17、CWC15、CCDC187、FAM71E2、GAB4、PRDM13）。结果表明，SARS-CoV-2 祖细胞基因组与人类 mRNA 转录本之间的重组可能是编码 S 蛋白 PRRA 基序的 S 基因 12 核苷酸插入片段的起源。SARS-CoV-2 多碱基弗林蛋白酶切割基序可能起源于人类的假设得到以下支持：(i) 人类基因的性质，其 mRNA 序列与 S 基因插入片段 100% 匹配；(ii) 精氨酸密码子中的同义碱基取代(CGG-CGG)；(iii) 进一步刺入糖蛋白 PRRA 样插入，表明 PRRA 的获得可能不是单一重组事件。