SARS-CoV-2 continuously optimizes its codon usage to adapt to human lung environment.

Viruses need to utilize the resources from host cells to reproduce themselves. RNA translation rate, which is largely determined by codon usage, is the rate-limiting step across the life cycle of viruses. Adapting to the codon usage of hosts would help virus better proliferate. We retrieved the time-course mutation profile of millions of world-wide SARS-CoV-2 sequences. For synonymous mutations, we defined whether a mutation elevate or reduce the relative synonymous codon usage (RSCU). We found that if a synonymous mutation in SARS-CoV-2 increases the RSCU (calculated from human lungs), denoted as delta RSCU > 0, then this mutation is positively selected because the allele frequency (AF) of this mutation increases with time, and vice versa. The results suggest that in SARS-CoV-2, the synonymous mutations that increase codon optimality are beneficial to the virus and are favored by natural selection. For the first time, we used the dynamics of allele frequency to demonstrate that SARS-CoV-2 is continuously optimizing its codon usage to adapt to human lungs. Nevertheless, adaptation to other human tissues cannot be excluded. These results warn us that under this global pandemic, synonymous mutations in SARS-CoV-2 should not be automatically ignored since they indeed change the fitness of the virus.