The Development of SARS-CoV-2 Variants: The Gene Makes the Disease

Abstract

A novel coronavirus (SARS-CoV-2) emerged towards the end of 2019 that caused a severe respiratory disease in humans called COVID-19. It led to a pandemic with a high rate of morbidity and mortality that is ongoing and threatening humankind. Most of the mutations occurring in SARS-CoV-2 are synonymous or deleterious, but a few of them produce improved viral functions. The first known mutation associated with higher transmissibility, D614G, was detected in early 2020. Since then, the virus has evolved; new mutations have occurred, and many variants have been described. Depending on the genes affected and the location of the mutations, they could provide altered infectivity, transmissibility, or immune escape. To date, mutations that cause variations in the SARS-CoV-2 spike protein have been among the most studied because of the protein’s role in the initial virus–cell contact and because it is the most variable region in the virus genome. Some concerning mutations associated with an impact on viral fitness have been described in the Spike protein, such as D614G, N501Y, E484K, K417N/T, L452R, and P681R, among others. To understand the impact of the infectivity and antigenicity of the virus, the mutation landscape of SARS-CoV-2 has been under constant global scrutiny. The virus variants are defined according to their origin, their genetic profile (some characteristic mutations prevalent in the lineage), and the severity of the disease they produce, which determines the level of concern. If they increase fitness, new variants can outcompete others in the population. The Alpha variant was more transmissible than previous versions and quickly spread globally. The Beta and Gamma variants accumulated mutations that partially escape the immune defenses and affect the effectiveness of vaccines. Nowadays, the Delta variant, identified around March 2021, has spread and displaced the other variants, becoming the most concerning of all lineages that have emerged. The Delta variant has a particular genetic profile, bearing unique mutations, such as T478K in the spike protein and M203R in the nucleocapsid. This review summarizes the current knowledge of the different mutations that have appeared in SARS-CoV-2, mainly on the spike protein. It analyzes their impact on the protein function and, subsequently, on the level of concern of different variants and their importance in the ongoing pandemic.

Interpretable and Predictive Deep Modeling of the SARS-CoV-2 Spike Protein Sequence

“…8 shows a spike at position 484, which is where the E484K mutation has been found to lead to substantial antibody escape. [126] Other positions, such as 417, 501, and 681 have also been associated with potential immune-evasive mutations (i.e., N501Y, K417N/T, L452R) [172]. Interestingly, focusing on site 346, we found that a relatively greater reduction in predicted activity was associated with Omicron sequences which include of the R346K mutation.…”

Genomics of Post-Vaccination SARS-CoV-2 Infections During the Delta Dominated Second Wave of COVID-19 Pandemic, from Mumbai Metropolitan Region (MMR), India

“…4 and 5). The orf1a: P2287S mutation is present in the nsp3 PLpro papain-like protease whose function is to block host innate immune response and promote cytokine expression [33]. The increasing frequency of orf1a: P2287S mutation and its association in mild cases could possibly indicate an enhanced host immune response and reduced cytokine expression (potentially mitigating cytokine storm), leading to less severe disease.…”

“…However, the limitation of the meagre number of partially vaccinated patients (n=23) in this study should be noted before drawing any conclusion. The third mutation in orf1a (T3255I) is present in the nsp4 protein, whose function is to produce double-membrane vesicles required to form a replication-transcription complex [33]. This mutation may play a role in reducing the formation of active replication-transcription complexes in the host cell, in turn reducing the viral load and explaining its association with the milder disease form.…”

“…Of the 150 samples sequenced, the sequence data of 136 samples were considered for further analysis. Fourteen samples were excluded due to low sequence coverage either because the Ct values were high (n=13; Ct between [30][31][32][33] or there was a high number of ambiguous bases were observed (n=1). All further analyses were carried out on the genomic data of the 136 samples (Fig.…”

Efficient Neutralization of SARS-CoV-2 Omicron and Other VOCs by a Broad Spectrum Antibody 8G3

“…The mutation rate of SARS-CoV-2 is ~10 -6 mutations/site/cycle, which is sufficient to cause more than one mutation per site during an infection period 1 . Especially, the frequency of manifold mutations in the spike (S) region is three times that of the entire genome 2 . With the vaccination starting from the end of 2020, the pandemic has been effectively alleviated.…”