ABSTRACT
As the SARS-CoV-2 has spread and the pandemic has dragged on, the virus continued to evolve rapidly resulting in the emergence of new highly transmissible variants that can be of public health concern. The evolutionary mechanisms that drove this rapid diversity are not well understood but neutral evolution should open the first insight. The neutral theory of evolution states that most mutations in the nucleic acid sequences are random and they can be fixed or disappear by purifying selection. Herein, we performed a neutrality test to better understand the selective pressures exerted over SARS-CoV-2 Spike protein, as well as in four of the identified health concern variants. Lys and Thr have higher occurrence rate on the Receptor Binding Domain (RBD) than in the overall sequence whereas Cys, His, and importantly Arg have low occurrence rate both in the whole protein and the RBD. Amino acids that have lower occurrence than the expected neutral control influence in the stability and or functionality of the protein. Our results show that most unique mutations either for SARS-CoV-2 or the variants of health concern are under selective pressures, which could be related either to the evasion of the immune system, increasing the virus’ fitness or altering protein – protein interactions with host proteins. Altogether all these forces have shaped the Spike protein. Understanding the evolutionary forces that act upon Spike protein may help designing better treatments and vaccines that target variants of health concern.