A team of Brazilian scientists recently conducted a genomic and phylogenetic analysis of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome to better understand the process of viral evolution. Their analysis revealed that the E484K mutation variant of SARS-CoV-2 was present in three different lineages in four regions of Brazil and that the mutation could serve as a general solution for viral evolution. Studies are currently available at bioRxiv* preprint server.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the pathogen that causes Coronavirus disease 2019 (COVID-19), is a member of the Coronaviridae family, which is enveloped in positive sense single-strand RNA viruses with a larger genome size of about 30 kb. Since its appearance in December 2019 in China, researchers around the world have sequenced nearly 4.10,000 SARS-CoV-2 genomes and have shared information in the Global Initiative on Sharing All Influenza Data (GISAID) database.
Several epidemiological studies of the SARS-CoV-2 genomics have been conducted, with the majority focusing on viral mutations. spike protein, surface glycoproteins SARS-CoV-2 is responsible for binding to the host angiotensin-converting enzyme 2 (ACE2) and initiating viral entry. Current research mainly focuses on three viral lineages, B.1.1.7, B.1.351, and P.1. because of its significant impact on viral transmission and pathogenicity. From this lineage, the P.1 lineage is prevalent in Brazil with three mutations (K417T, E484K, and N501Y) in the spike receptor binding (RBD) domain. In Brazil, many viral genomes harbor the E484K mutation, which is associated with increased viral transmission and immune evasion.
In the current study, scientists evaluated mutation characteristics and phylogenetic relationships in currently known lineages in Brazil to understand the adaptive evolutionary process of SARS-CoV-2.
A mutation histogram frequently observed in the Brazilian SARS-CoV-2 genome that stores the E484K mutation. The red label above the bar indicates the absolute nucleotide position and the blue label indicates the effect of this mutation on the corresponding protein. Since P.1 has only 19 represented genomes and a handful of mutations, only the major mutations of concern were highlighted. UTR: Areas that haven’t been translated; Syn: Synonym substitution; del: deletion; ORF: Open Reading Frame; Nsp: Non-structural protein; S: Surge; E: Envelope; M: Membrane; N: Nucleocapsid.
An important observation
The results revealed that the SARS-CoV-2 variant with the E484K mutation was widespread in many regions in Brazil. This mutation was introduced in Brazil in October 2020. Because the E484K mutation was found in different viral lineages at the same time as other mutations, scientists suggest that this particular amino acid substitution could act as a general driver for viral evolution in different genetic variants of SARS. -CoV-2. In the E484K mutation, a negatively charged amino acid (glutamic acid) is replaced by a positively charged amino acid (lysine). Thus, it is hoped that mutations will have a significant impact on viral survival and adaptive evolution.
Structural analysis revealed that a new site for ACE2 (75 amino acid) binding was generated due to the E484K mutation. This appears to create a significantly stronger interaction between ACE2 and the native binding site located at the RBD and ACE2 interface (amino acid 501).
A very diverse range of genetic mutations was observed in all Brazilian lineages with the E484K mutation. On average, about 19 and 30 mutations were observed in lineages B.1.1.33 and P.1, respectively. Further genomic analysis of the most recently emerging P.2 lineage showed that the P.1 and P.2 lineages were rapidly developing and had been circulating in Brazil for a longer period.
A new specific single substitution analysis was also carried out in this study. One such mutation, A27V, is present in the N-terminal domain (NTD) of the spike protein. Research has suggested that mutations in the NTD spike can allosterically change the dynamics of the spike RBD-ACE2 interaction and facilitate immune evasion. In addition, evidence suggests that viral lineages carrying the E484K mutation are associated with increased escape from antibody-mediated neutralization. Although the true impact of E484K and other substitutes on immune avoidance remains unclear, scientists argue that the E484K mutation is associated with improved viral fitness under pressure of natural selection.
Overall, the study suggests that the E484K mutation acts as an important evolutionary event for different viral lineages in terms of increased viral fitness. The E484K mutation has the potential to increase the infectivity and immune-avoidance potential of SARS-CoV-2. According to scientists, further research investigating the effectiveness of human serum anti-SARS-CoV-2 against the E484K mutation variant of SARS-CoV-2 is urgently needed.
* Important Notice
bioRxiv publishes a preliminary scientific report that is not peer reviewed and, therefore, should not be construed as a conclusion, a guide to health-related clinical / behavioral practice, or be treated as prescribed information