SARS-CoV-2 Mutations and COVID-19 Clinical Outcome: Mutation Global Frequency Dynamics and Structural Modulation Hold the Key

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had an enormous burden on the healthcare system worldwide as a consequence of its new emerging variants of concern (VOCs) since late 2019. Elucidating viral genome characteristics and its influence on disease severity and clinical outcome has been one of the crucial aspects toward pandemic management. Genomic surveillance holds the key to identify the spectrum of mutations vis-à-vis disease outcome. Here, in our study, we performed a comprehensive analysis of the mutation distribution among the coronavirus disease 2019 (COVID-19) recovered and mortality patients. In addition to the clinical data analysis, the significant mutations within the two groups were analyzed for their global presence in an effort to understand the temporal dynamics of the mutations globally in comparison with our cohort. Interestingly, we found that all the mutations within the recovered patients showed significantly low global presence, indicating the possibility of regional pool of mutations and the absence of preferential selection by the virus during the course of the pandemic. In addition, we found the mutation S194L to have the most significant occurrence in the mortality group, suggesting its role toward a severe disease progression. Also, we discovered three mutations within the mortality patients with a high cohort and global distribution, which later became a part of variants of interest (VOIs)/VOCs, suggesting its significant role in enhancing viral characteristics. To understand the possible mechanism, we performed molecular dynamics (MD) simulations of nucleocapsid mutations, S194L and S194*, from the mortality and recovered patients, respectively, to examine its impacts on protein structure and stability. Importantly, we observed the mutation S194* within the recovered to be comparatively unstable, hence showing a low global frequency, as we observed. Thus, our study provides integrative insights about the clinical features, mutations significantly associated with the two different clinical outcomes, its global presence, and its possible effects at the structural level to understand the role of mutations in driving the COVID-19 pandemic.

Prevalence of symptoms, comorbidities, and reinfections in individuals infected with Wild-Type SARS-CoV-2, Delta, or Omicron variants: a comparative study in western Mexico

“…Even though there is extensive research on the impact of the virus mutation in its transmission and receptor affinity, information regarding the association of specific symptoms with a particular VOC is meager. Nevertheless, some mutations present in VOCs, such as the mutation S194L found in the Nucleocapsid gene, have been associated with symptomatic patients ( 17 ) or a higher frequency of fatal outcomes ( 18 ). This could indicate the crucial role of some variants in elevating the pathogenicity of the virus, thereby contributing to increased symptoms of disease severity ( 8 ).…”

SARS-CoV-2 Genetic Variants and Patient Factors Associated with Hospitalization Risk

“…Other candidate variants found by two or more prior studies include nsp6 amino acid variant L37F, which was associated with asymptotic or mild symptoms (2, 6, 9); spike protein (S) variant V1176F (2, 4) and open reading frame 3a (ORF3a) variant Q57H (2, 10), which were associated with more severe symptoms; and S variant D614G, which was associated with more severe symptoms in three papers (2, 10, 11) and less severe outcomes in another paper (3). None of these were identified in our study.…”

“…Multiple studies have investigated associations between SARS-CoV-2 genomic variation and COVID severity in different times and places during the pandemic and collectively have identified a diverse set of candidate genetic variants (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)). These studies have either used data from GISAID (2, 4-6, 9, 11, 16-18) or from individual hospitals (3,10,(12)(13)(14)(15)). The GISAID-based studies use COVID-19 severity metrics that classify samples into two or more severity categories, such as 'asymptomatic' and 'severe', based on patient status descriptions.…”

Genetic features of SARS-CoV-2 Alpha, Delta, and Omicron variants and their association with the clinical severity of COVID-19 in Vietnam

“…RNA viruses have a faster rate of mutation than DNA viruses, leading to a wide range of mutations across the entire genome [8] . In patients with COVID-19, cumulative alterations between the viral genomes of the parent and its progeny may contribute to the differences in symptoms and clinical course with each viral replication cycle at different time points [9] . There have been statistical reports on new variants, with the hypothesis of increased contagiousness, disease severity, proportion of patients requiring hospitalization for medical care, decreased antibody response ability, and antibody response, as well as preventive vaccines, posing challenges in disease control and vaccine production [10] .…”