Contrasting Epidemiology and Population Genetics of COVID-19 Infections Defined by Multilocus Genotypes in SARS-CoV-2 Genomes Sampled Globally

Abstract

Since its emergence in 2019, SARS-CoV-2 has spread and evolved globally, with newly emerged variants of concern (VOCs) accounting for more than 500 million COVID-19 cases and 6 million deaths. Continuous surveillance utilizing simple genetic tools is needed to measure the viral epidemiological diversity, risk of infection, and distribution among different demographics in different geographical regions. To help address this need, we developed a proof-of-concept multilocus genotyping tool and demonstrated its utility to monitor viral populations sampled in 2020 and 2021 across six continents. We sampled globally 22,164 SARS-CoV-2 genomes from GISAID (inclusion criteria: available clinical and demographic data). They comprised two study populations, “2020 genomes” (N = 5959) sampled from December 2019 to September 2020 and “2021 genomes” (N = 16,205) sampled from 15 January to 15 March 2021. All genomes were aligned to the SARS-CoV-2 reference genome and amino acid polymorphisms were called with quality filtering. Thereafter, 74 codons (loci) in 14 genes including orf1ab polygene (N = 9), orf3a, orf8, nucleocapsid (N), matrix (M), and spike (S) met the 0.01 minimum allele frequency criteria and were selected to construct multilocus genotypes (MLGs) for the genomes. At these loci, 137 mutant/variant amino acids (alleles) were detected with eight VOC-defining variant alleles, including N KR203&204, orf1ab (I265, F3606, and L4715), orf3a H57, orf8 S84, and S G614, being predominant globally with > 35% prevalence. Their persistence and selection were associated with peaks in the viral transmission and COVID-19 incidence between 2020 and 2021. Epidemiologically, older patients (≥20 years) compared to younger patients (<20 years) had a higher risk of being infected with these variants, but this association was dependent on the continent of origin. In the global population, the discriminant analysis of principal components (DAPC) showed contrasting patterns of genetic clustering with three (Africa, Asia, and North America) and two (North and South America) continental clusters being observed for the 2020 and 2021 global populations, respectively. Within each continent, the MLG repertoires (range 40–199) sampled in 2020 and 2021 were genetically differentiated, with ≤4 MLGs per repertoire accounting for the majority of genomes sampled. These data suggested that the majority of SARS-CoV-2 infections in 2020 and 2021 were caused by genetically distinct variants that likely adapted to local populations. Indeed, four GISAID clade-defined VOCs - GRY (Alpha), GH (Beta), GR (Gamma), and G/GK (Delta variant) were differentiated by their MLG signatures, demonstrating the versatility of the MLG tool for variant identification. Results from this proof-of-concept multilocus genotyping demonstrates its utility for SARS-CoV-2 genomic surveillance and for monitoring its spatiotemporal epidemiology and evolution, particularly in response to control interventions including COVID-19 vaccines and chemotherapies.

Innate Immunity in Cardiovascular Diseases – Identification of Novel Molecular Players and Targets

“…Thus, a protective HLA extended haplotype was found to outweigh the major COVID-19 risk factor inherited from Neanderthals in the Sardinian population [126]. Another large study [128] conducted multilocus genotyping of SARS-CoV-2 genomes sampled globally and found evidence the majority of SARS-CoV-2 infections in 2020 and 2021 caused by genetically distinct variants that likely adapted to local populations. For further information on novel insights into genome structure and function we may refer the reader to a series of recent landmark papers and websites [129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145].…”

“…Genetic factors contributing to COVID-19 susceptibility and severity may provide new biological insights into disease pathogenesis and identify mechanistic targets for therapeutic development or drug repurposing, as treating the disease remains a highly important goal despite the recent development of vaccines. A large number of genome-wide association studies (GWAS) addressing the contribution of common genetic variation to COVID-19 in different populations worldwide have provided support for the involvement of several genomic loci associated with COVID-19 severity and susceptibility [128,179,[189][190][191][192]. The global COVID-19 Host Genetics Initiative (COVID-19 HGI) (https://www.covid19hg.org/) [225] recently reported the results of meta-analyses of 46 studies from 19 countries for host genetic effects [192].…”

Innate Immunity in Cardiovascular Diseases – Identification of Novel Molecular Players and Targets

“…Thus, a protective HLA extended haplotype was found to outweigh the major COVID-19 risk factor inherited from Neanderthals in the Sardinian population [126]. Another large study [128] conducted multilocus genotyping of SARS-CoV-2 genomes sampled globally and found evidence the majority of SARS-CoV-2 infections in 2020 and 2021 caused by genetically distinct variants that likely adapted to local populations. For further information on novel insights into genome structure and function we may refer the reader to a series of recent landmark papers and websites [62,[129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144].…”

“…Genetic factors contributing to COVID-19 susceptibility and severity may provide new biological insights into disease pathogenesis and identify mechanistic targets for therapeutic development or drug repurposing, as treating the disease remains a highly important goal despite the recent development of vaccines. A large number of genome-wide association studies (GWAS) addressing the contribution of common genetic variation to COVID-19 in different populations worldwide have provided support for the involvement of several genomic loci associated with COVID-19 severity and susceptibility [128,178,[188][189][190][191][196][197][198][199][200][201][202]. The global COVID-19 Host Genetics Initiative (COVID-19 HGI) (https://www.covid19hg.org/) [203] recently reported the results of meta-analyses of 46 studies from 19 countries for host genetic effects [191].…”

“…Another type of contribution of large-scale molecular genetic analyses to better understand the variable clinical expression of SARS-CoV-2 infections, and the global dynamics of virus evolution, has been published by Chan et al [128]. They have described the contrasting epidemiology and population genetics of COVID-19 infections defined by multilocus genotyping of the SARS-CoV-2 genomes.…”