Heterogeneous evolution among SARS-CoV-2 genes and variants of concern

Despite the progress made through vaccination, relevant challenges remain about the influence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on public health. The current attention is increasingly focused on what the future with the SARS-CoV-2 could look like. Predictions require the understanding of the molecular evolution of the virus, especially with respect to proteins targeted by therapies, where some discrepancies can be found across studies. Thus, we analyzed thousands of SARS-CoV-2 genomes to assess the rates of evolution and adaptation of the protein-coding regions. Our findings showed an overall low nucleotide diversity along the genome, which fluctuated over time and among genomic regions, and showed a clear increase in the recent Omicron Variant of Concern (VOC), particularly in the S and ORF6 genes. We estimated an overall rate of evolution of approximately 10-3 substitutions per site per year, which varied among genes and over time. Actually, most of the genomic regions did not fit with the strict molecular clock. Regarding molecular adaptation, the protein-coding genes overall showed evidence of purifying selection, with local diversifying selection detected in a few genes directly related to virus transmission and replication. Altogether, the molecular evolution of SARS-CoV-2 presents spatial and temporal heterogeneity, with fluctuations of the rate of evolution and molecular adaptation among genomic regions and over time. These finding suggest that forecasting SARS-CoV-2 molecular evolution is complex and remarks the importance of monitoring the evolution of this virus.