Abstract
Challenges persist regarding the influence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on public health, with growing interest in future viral molecular variants. In this context, accurate predictions demand a thorough understanding of the virus's molecular evolution, especially proteins targeted by therapies, where certain discrepancies among studies exist. We analyzed thousands of SARS-CoV-2 genomes to assess the rate of evolution and molecular adaptation in the various SARS-CoV-2 coding regions. We found an overall low genetic diversity along the genome, with fluctuations over time and among genomic regions, and a notable increase in the Omicron variant, especially in the S and ORF6 genes. We also estimated an overall rate of molecular evolution of approximately 10(-3) substitutions per site per year, though it varied among genomic regions and over time. Actually, most genomic regions did not follow the strict molecular clock. Regarding selective pressures, the protein-coding regions of SARS-CoV-2 generally exhibited evidence of purifying selection, with local diversifying selection associated with virus transmission and replication. Overall, the molecular evolution of SARS-CoV-2 displays heterogeneity among genomic regions and over time. These findings suggest that forecasting SARS-CoV-2 molecular evolution is not straightforward and remark the importance of continuing to monitor SARS-CoV-2 evolution.