Phylogenomics and population genomics of SARS-CoV-2 in Mexico during the pre-vaccination stage reveals variants of interest B.1.1.28.4 and B.1.1.222 or B.1.1.519 and the nucleocapsid mutation S194L associated with symptoms.

Understanding the evolution of the SARS-CoV-2 virus in various regions of the world during the Covid-19 pandemic is essential to help mitigate the effects of this devastating disease. We describe the phylogenomic and population genetic patterns of the virus in Mexico during the pre-vaccination stage, including asymptomatic carriers. A real-time quantitative PCR screening and phylogenomic reconstructions directed at sequence/structure analysis of the spike glycoprotein revealed mutation of concern E484K in genomes from central Mexico, in addition to the nationwide prevalence of the imported variant 20C/S:452R (B.1.427/9). Overall, the detected variants in Mexico show spike protein mutations in the N-terminal domain (i.e. R190M), in the receptor-binding motif (i.e. T478K, E484K), within the S1-S2 subdomains (i.e. P681R/H, T732A), and at the basis of the protein, V1176F, raising concerns about the lack of phenotypic and clinical data available for the variants of interest we postulate: 20B/478K.V1 (B.1.1.222 or B.1.1.519) and 20B/P.4 (B.1.1.28.4). Moreover, the population patterns of single nucleotide variants from symptomatic and asymptomatic carriers obtained with a self-sampling scheme confirmed the presence of several fixed variants, and differences in allelic frequencies among localities. We identified the mutation N:S194L of the nucleocapsid protein associated with symptomatic patients. Phylogenetically, this mutation is frequent in Mexican sub-clades. Our results highlight the dual and complementary role of spike and nucleocapsid proteins in adaptive evolution of SARS-CoV-2 to their hosts and provide a baseline for specific follow-up of mutations of concern during the vaccination stage.