Evaluating the Effect of SARS-CoV-2 Spike Mutations by Causal Inference

Abstract

Abstract Driven by various mutations on the viral Spike protein, diverse variants of SARS-CoV-2 have emerged and prevailed repeatedly, which necessitates the identification of key Spike mutations for fitness enhancement. To address the need, this manuscript formulates a principled framework of causal inference for evaluating Spike mutations. In the context of large-scale genomes of SARS-CoV-2, it estimates the contribution of mutations to viral fitness across lineages and validates mutational effects on the Spike stability, receptor-binding affinity, and potential for immune escape. Key fitness-enhancing mutations and protein regions are recognized and studied. The transmission capacity of any new variant possessing these mutations can be predicted based on our model, solely based on the viral sequence. This research produces an innovative and systematic insight into SARS-CoV-2 and promotes functional studies of its key mutations.