SARS-CoV-2 has evolved variants with substitutions in the spike receptor-binding domain (RBD) that impact its affinity for ACE2 receptor and recognition by antibodies. These substitutions could also shape future evolution by modulating the effects of mutations at other sites—a phenomenon called epistasis. To investigate this possibility, we performed deep mutational scans to measure the effects on ACE2 binding of all single amino-acid mutations in the Wuhan-Hu-1, Alpha, Beta, Delta, and Eta variant RBDs. Some substitutions, most prominently N501Y, cause epistatic shifts in the effects of mutations at other sites. These epistatic shifts shape subsequent evolutionary change, for example enabling many of the antibody-escape substitutions in the Omicron RBD. These epistatic shifts occur despite high conservation of the overall RBD structure. Our data shed light on RBD sequence-function relationships and facilitate interpretation of ongoing SARS-CoV-2 evolution.

中文翻译：

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病毒进化过程中 SARS-CoV-2 受体结合域的突变限制发生变化

SARS-CoV-2 已进化出一些变异体，其刺突受体结合域 (RBD) 发生了取代，从而影响了其对 ACE2 受体的亲和力以及抗体的识别。这些取代还可以通过调节其他位点突变的影响来塑造未来的进化——这种现象称为上位性。为了研究这种可能性，我们进行了深度突变扫描，以测量 Wuu-Hu-1、Alpha、Beta、Delta 和 Eta 变体 RBD 中所有单个氨基酸突变对 ACE2 结合的影响。一些取代（最突出的是 N501Y）会导致其他位点的突变效应发生上位性变化。这些上位性转变塑造了随后的进化变化，例如在 Omicron RBD 中实现了许多抗体逃逸替代。尽管整个 RBD 结构高度保守，但这些上位性转变仍然发生。我们的数据揭示了 RBD 序列与功能的关系，并有助于解释正在进行的 SARS-CoV-2 进化。