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

Area of Science:

• Virology
• Evolutionary Biology
• Genomics

Background:

• The COVID-19 pandemic highlights the need to understand virus evolution and animal-to-human transmission.
• Coronaviruses, particularly SARS-CoV-2, have demonstrated significant adaptability to new hosts.

Purpose of the Study:

• To investigate the evolutionary mechanisms driving SARS-CoV-2 adaptation and transmission.
• To identify specific genetic mutations contributing to the virus's success in humans.

Main Methods:

• Genome-wide analysis of over 182,000 SARS-CoV-2 genomes to detect positive selection.
• Identification of a specific mutation (T372A) in the spike protein's receptor-binding domain (RBD).
• Experimental validation of the mutation's impact on ACE2 binding and viral replication in human lung cells.

Main Results:

• A distinct footprint of positive selection was found around the T372A mutation in the SARS-CoV-2 spike protein RBD.
• This mutation is present in all human SARS-CoV-2 strains but absent in related bat and pangolin viruses.
• The T372A mutation significantly increased binding affinity to human ACE2 and enhanced viral replication in human lung cells, surpassing the effect of the D614G mutation.

Conclusions:

• The T372A mutation likely played a critical role in the emergence of SARS-CoV-2 in humans or its sustained human-to-human transmission.
• Understanding such adaptive mutations is crucial for predicting and mitigating future zoonotic threats.