Phylogenomics and population genomics of SARS-CoV-2 in Mexico reveals variants of interest (VOI) and a mutation in the Nucleocapsid protein associated with symptomatic versus asymptomatic carriers

Understanding the evolution of SARS-CoV-2 virus in various regions of the world during the Covid19 pandemic is of the utmost importance 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 RT-qPCR screening and phylogenomics reconstructions directed a sequence/structure analysis of the Spike glycoprotein, revealing 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 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 postulated variants of interest (VOIs) 20B/478K.V1 and P.3. Moreover, the population patterns of Single Nucleotide Variants (SNVs) from symptomatic and asymptomatic carriers sampled with a self-sampling scheme, revealed a bimodal distribution of polymorphisms in all three sampled localities from central Mexico, and confirmed the presence of several fixed variants, mostly from the 241T-3037T-14408T-23403G haplotype common in Asia. Despite gene flow among Mexican localities, we found differences in both the allelic frequencies among localities and the allelic imbalance of the mutation S194L of the nucleocapsid protein between symptomatic and asymptomatic carriers. Our results highlight the dual 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 in Mexico. IMPACT STATEMENTFollowing self-sampling, screening of mutations of concern, and a combined phylogenomic and population genetics pipeline, we reveal the occurrence of two variants of interest with mutations in the Spike protein, P.3 (B.1.1.28.3) and 20B/478K.V1 (B.1.1.222, recently named B.1.1.519) in Mexico during the pre-vaccination stage, plus a mutation in the Nucleocapsid protein, S194L, that associates only with symptomatic patients versus asymptomatic carriers in the population investigated. Our research can aid epidemiological genomics efforts during the vaccination stage in Mexico by contributing with a combined analytical platform and information about variants within different genetic backgrounds. DATA SUMMARYThe Mexstrain-Nextstrain data can be found at: http://www.ira.cinvestav.mx/ncov.evol.mex.aspx. Data generated and used in this study is provided as supplementary Tables: Table S1. Self-sampling performance validation data generated in 58 volunteers. Table S2. Metadata of SARS-CoV-2 genomes generated and investigated. Table S3. Complete dataset of the population genomics analysis of SARS-CoV-2.