A selective sweep in the Spike gene has driven SARS-CoV-2 human adaptation

Abstract

The COVID-19 pandemic underscores the need to understand better animal-to-human transmission of coronaviruses and adaptive evolution within new hosts. We scanned over 182,000 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 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 (WT-SARS-CoV-2) enhanced replication in human lung cells relative to its putative ancestral variant (T372), an effect which was 20x greater than the well-known D614G mutation. Our findings suggest that this mutation likely contributed to SARS-CoV-2’s emergence from animal reservoirs or enabled sustained human-to-human transmission.

Loss of Spike N370 glycosylation as an important evolutionary event for the enhanced infectivity of SARS-CoV-2

“…Through comparisons with the closely related bat RaTG13 and pangolin PCoV_GX coronaviruses, we further supported our previous proposal that tight RBD–ACE2 binding and efficient RBD “down” to “up” conformational transition are both required for SARS-CoV-2 to efficiently infect and transmit among humans 5 . While this paper was under preparation for submission, Kang et al reported a scanning over 182,000 SARS-CoV-2 genomes for selective sweep signatures and the identification of the same T372A change 9 . They showed that the A372T reversion mutation resulted in decreased viral replication in human lung cells and proved a decreased binding of the A372T mutant S glycoprotein to ACE2 in an ELISA-based binding assay 9 .…”

“…While this paper was under preparation for submission, Kang et al reported a scanning over 182,000 SARS-CoV-2 genomes for selective sweep signatures and the identification of the same T372A change 9 . They showed that the A372T reversion mutation resulted in decreased viral replication in human lung cells and proved a decreased binding of the A372T mutant S glycoprotein to ACE2 in an ELISA-based binding assay 9 . The presence of the N370-linked glycans favoring the SARS-CoV-2 S glycoprotein to be in the closed state has also been proposed by Harbison et al 10 .…”

Research Article Temporal data series and logistic models reveal the dynamics of SARS-CoV-2 spike protein D614G variant in the COVID-19 pandemic

“…Nevertheless, we provide population study evidence for the hypothesis that combines a founder effect with selection. We hypothesize that G614 predominance over D614 is an example of selective sweep in a viral population (Kang et al, 2021).…”

“Multiomics” Approaches to Understand and Treat COVID-19: Mass Spectrometry and Next-Generation Sequencing

“…A study by Kang et al suggests that a mutation in the receptor-binding domain of the SARS-CoV-2 virus' spike domain is largely responsible for the emergence of the novel coronavirus from sarbecoviruses, a subgenus of coronaviruses. This mutation, a substitution of threonine (T372) in the studied sarbecoviruses to alanine (A372) in SARS-CoV-2, allows SARS-CoV-2 to more easily replicate in human lung cells [63].…”