Abstract
Since the first case of COVID-19 in December 2019 in Wuhan, China, SARS-CoV-2 has spread worldwide and within a year and a half has caused 3.56 million deaths globally. With dramatically increasing infection numbers, and the arrival of new variants with increased infectivity, tracking the evolution of its genome is crucial for effectively controlling the pandemic and informing vaccine platform development. Our study explores evolution of SARS-CoV-2 in a representative cohort of sequences covering the entire genome in the United States, through all of 2020 and early 2021. Strikingly, we detected many accumulating Single Nucleotide Variations (SNVs) encoding amino acid changes in the SARS-CoV-2 genome, with a pattern indicative of RNA editing enzymes as major mutators of SARS-CoV-2 genomes. We report three major variants through October of 2020. These revealed 14 key mutations that were found in various combinations among 14 distinct predominant signatures. These signatures likely represent evolutionary lineages of SARS-CoV-2 in the U.S. and reveal clues to its evolution such as a mutational burst in the summer of 2020 likely leading to a homegrown new variant, and a trend towards higher mutational load among viral isolates, but with occasional mutation loss. The last quartile of 2020 revealed a concerning accumulation of mostly novel low frequency replacement mutations in the Spike protein, and a hypermutable glutamine residue near the putative furin cleavage site. Finally, end of the year data and 2021 revealed the gradual increase to prevalence of known variants of concern, particularly B.1.1.7, that have acquired additional Spike mutations. Overall, our results suggest that predominant viral genomes are dynamically evolving over time, with periods of mutational bursts and unabated mutation accumulation. This high level of existing variation, even at low frequencies and especially in the Spike-encoding region may become problematic when super-spreader events, akin to serial Founder Events in evolution, drive these rare mutations to prominence.
Highlights
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which causes the Coronavirus disease 2019 (COVID-19), was first detected in December 2019 in Wuhan, China, when a number of severe pneumonia cases were reported [1]
For low frequency Spike mutations or add-on spike mutations in the variants of concern (VOC), we considered Spike missense mutations present in more than 0.1% of the genomes
The number of sequences per collection date and locations from which they are obtained are shown in S1 Fig. The number of Single Nucleotide Variations (SNVs) per viral isolate increases progressively over time (Fig 1A), indicating the virus is not keeping a static genome during the course of the pandemic and is instead accumulating diversity
Summary
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which causes the Coronavirus disease 2019 (COVID-19), was first detected in December 2019 in Wuhan, China, when a number of severe pneumonia cases were reported [1]. SARS-CoV-2 is an enveloped, single-stranded, positive-sense RNA virus and a member of the betacoronavirus genera, of the Coronaviridae family [4]. The viral envelope of SARS-CoV2 consists of the membrane (M), envelope (E), nucleocapsid (N) and spike (S) proteins (encoded by the ORF5, ORF4 and ORF2 respectively), crucial components of the viral structure, and necessary for the packaging of the viral RNA genome, and for viral infectivity [5]. The S protein ( known as the spike glycoprotein), is a major contributor to COVID-19’s pathogenesis and tropism, as it is responsible for SARS-CoV-2’s recognition, fusion and entrance into host cells. The infection process initiates when the Receptor Binding Domain (RBD; S1 subunit) of the S protein recognizes and binds the angiotensin-converting enzyme 2 (ACE2) receptor of the host, leading to fusion of the viral envelope with the cellular membrane thanks to a hydrophobic fusion peptide sequence found in the spike’s S2 subunit [6]
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