The B.1.1.7 variant (also known as Alpha) of SARS-CoV-2, the cause of the COVID-19 pandemic, emerged in the UK in the summer of 2020. The prevalence of this variant increased rapidly owing to an increase in infection and/or transmission efficiency¹. The Alpha variant contains 19 nonsynonymous mutations across its viral genome, including 8 substitutions or deletions in the spike protein that interacts with cellular receptors to mediate infection and tropism. Here, using a reverse genetics approach, we show that of the 8 individual spike protein substitutions, only N501Y resulted in consistent fitness gains for replication in the upper airway in a hamster model as well as in primary human airway epithelial cells. The N501Y substitution recapitulated the enhanced viral transmission phenotype of the eight mutations in the Alpha spike protein, suggesting that it is a major determinant of the increased transmission of the Alpha variant. Mechanistically, the N501Y substitution increased the affinity of the viral spike protein for cellular receptors. As suggested by its convergent evolution in Brazil, South Africa and elsewhere^2,3, our results indicate that N501Y substitution is an adaptive spike mutation of major concern.

SARS-CoV-2 的 B.1.1.7 变体（也称为 Alpha）是导致 COVID-19 大流行的原因，于 2020 年夏天在英国出现。由于增加在感染和/或传播效率方面¹. Alpha 变体在其病毒基因组中包含 19 个非同义突变，包括与细胞受体相互作用以介导感染和趋向性的刺突蛋白中的 8 个替换或缺失。在这里，我们使用反向遗传学方法显示，在 8 个单独的刺突蛋白替代物中，只有 N501Y 导致在仓鼠模型的上气道以及原代人气道上皮细胞中复制的一致适应度增益。N501Y 替代概括了 Alpha 刺突蛋白中 8 个突变增强的病毒传播表型，表明它是 Alpha 变体传播增加的主要决定因素。从机制上讲，N501Y 取代增加了病毒刺突蛋白对细胞受体的亲和力。^2,3，我们的结果表明，N501Y 替代是主要关注的适应性尖峰突变。