Meta-Analysis and Structural Dynamics of the Emergence of Genetic Variants of SARS-CoV-2
Abstract
The novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) emerged in late December 2019 in Wuhan, China, and is the causative agent for the worldwide COVID-19 pandemic. SARS-CoV-2 is a positive-sense single-stranded RNA virus belonging to the betacoronavirus genus. Due to the error-prone nature of the viral RNA-dependent polymerase complex, coronaviruses are known to acquire new mutations at each cycle of genome replication. This constitutes one of the main factors driving the evolution of its relatively large genome and the emergence of new genetic variants. In the past few months, the identification of new B.1.1.7 (UK), B.1.351 (South Africa) and P.1 (Brazil) variants of concern (VOC) have highlighted the importance of tracking the emergence of mutations in the SARS-CoV-2 genome that impact transmissibility, virulence, and immune and neutralizing antibody escape. Here we analyzed the appearance and prevalence trajectory over time of mutations that appeared in all SARS-CoV-2 genes from December, 2019 to April, 2021. The goal of the study was to identify which genetic modifications are the most frequent and study the dynamics of their propagation, their incorporation into the consensus sequence, and their impact on virus biology. We also analyzed the structural properties of the spike glycoprotein of the B.1.1.7, B.1.351 and P.1 variants for its binding to the host receptor ACE2. This study offers an integrative view of the emergence, disappearance, and consensus sequence integration of successful mutations that constitute new SARS-CoV-2 variants and their impact on neutralizing antibody therapeutics and vaccines.
IMPORTANCE
SARS-CoV-2 is the etiological agent of COVID-19, which has caused > 3.4 million deaths worldwide as of April, 2021. Mutations occur in the genome of SARS-CoV-2 during viral replication and affect viral infectivity, transmissibility, and virulence. In early March 2020, the D614G mutation in the spike protein emerged, which increased viral transmissibility and is now found in over 90% of all SARS-CoV-2 genomic sequences in GISAID database. Between October and December 2020, B.1.1.7 (UK), B.1.351 (South Africa) and P.1 (Brazil) variants of concern (VOCs) emerged, which have increased neutralizing antibody escape capabilities because of mutations in the receptor binding domain of the spike protein. Characterizing mutations in these variants is crucial because of their effect on adaptive immune responses, neutralizing antibody therapy, and their impact on vaccine efficacy. Here we tracked and analyzed mutations in SARS-CoV-2 genes since the beginning of the pandemic and investigated their functional impact on the spike of these three VOCs.
Graphical Abstract
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