In a recent study posted to the medRxiv* preprint server, researchers determined the nature and dynamics of mutations associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) French Marseille-4 variant during 10 months from its onset.
The study concluded that the heterogenicity associated with a SARS-CoV-2 lineage can possibly predict the end of an outbreak.
The characteristics of mutations associated with the SARS-CoV-2 variants leading to subsequent waves of the current coronavirus disease 2019 (COVID-19) pandemic are complex. The extinction of epidemics is linked to the development of herd immunity, decrease in viral load, and the implementation of therapeutic interventions such as vaccination. Moreover, sufficient data regarding factors and mechanisms associated with the emergence, transmission, and extinction of SARS-CoV-2 variants are not yet available.
About the study
In the current study, the researchers determined the kinetics of a new SARS-CoV-2 variant, called Marseille-4, identified from minks at IHU Méditerranée Infection, Marseille, France, in July 2020. The Marseille-4 variant has 20 mutations, with 13 specific mutations compared to the Wuhan-Hu-1 isolate and one among the seven non-synonymous mutations in the spike (S) glycoprotein region.
The study participants had the SARS-CoV-2 Marseille-4 variant infection and their clinical and epidemiological data were collected from the Assistance Publique-Hôpitaux de Marseille (APHM) information system.
The researchers investigated the epidemiological origin and characteristics of the Marseille-4 variant. Genetic data through 10 months from the origin to the extinction of this variant in April 2021 gathered via extensive SARS-CoV-2 genomic surveillance was analyzed using next-generation sequencing. Similarly, the 7,453 genomes of Marseille-4 obtained by next-generation sequencing were classified into lineages and subvariants. The truncated and untruncated forms of ORF8 protein were analyzed by generating a structural ORF8 protein model from the PDB 7JTL file.
The emergence, transmission, and disappearance of the SARS-CoV-2 Marseille-4 variant were determined using these gathered data.
Two subvariants of the SARS-CoV-2 Marseille-4 variant were identified in the study, namely Marseille-4A with 22 lineages from 50 genomes and Marseille-4B. During the study period, 9,616 cases associated with the Marseille-4 infection were identified using specific quantitative polymerase chain reaction (qPCR).
The average lifetime of these two variants was 4.1±1.4 months and during this period, around 4.1±2.6 mutations had developed. The growth rate was 0.010 to 0.173 in Marseille-4A.17 and Marseille-4A.15, respectively, and the average value of the growth rate was 0.079±0.045. All lineages showed a gamma distribution and were associated with the inactivation of ORF7a or ORF7b genes.
The mutations at unpredicted sites led to a new outbreak, and the accumulation of further mutations led to an increase in heterogenicity, diversity, and extinction of all lineages. None of the mutations were predicted to be probably associated with higher transmissibility, apart from those mutations in the S region.
Marseille-4B emerged after the extinction of all Marseille-4A lineages and its ORF8 gene was inhibited by a stop codon. Further, this subvariant was linked to a high number of SARS-CoV-2-associated hospitalizations and mortality, indicating that ORF8 was a non-virulence gene.
Structural analysis of the truncated form of the ORF8 gene confirmed that stop codon-induced large deletions resulted in a distinct protein that does not share any structural resemblance with the original ORF8 dimer. The average detection time for Marseille-4 lineages was around four months.
The study findings characterized the emergence, transmission, and vanishing of the Marseille-4 variant. The study reported heterogeneity of growth rate for various Marseille-4 subvariants and lineages and indicated that the heterogeneity associated with the SARS-CoV-2 lineage might predict the extinction of the outbreak.
Moreover, the finding suggested that SARS-CoV-2 follows the Black Queen hypothesis, stating that the loss of a gene confers a substantial advantage to the organism when the function of the gene can be dispensable.
The inhibition of the Marseille-4 genes suggested that SARS-CoV-2 originated from a distinct animal reservoir, and the ORF8 and ORF7a/b genes were not necessary to function in humans, pangolins, and minks and may be inhibited in them. The data regarding the inhibition of the ORF8 gene was in line with previous reports on several mink lineages and the Alpha variant.
Overall, it was concluded that the accumulation of beneficial mutations led to an increase in viral fitness, whereas non-beneficial mutations are associated with low viral fitness, transmissibility, and extinction of the lineage.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.