SARS-CoV-2 Is Evolving Rapidly Due To Human Host Factors

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Two recently published study findings are indicating that the SARS-CoV-2 virus is evolving in the human host due to a multitude of factors and hence will give rise to more genetic variants.

In the first study, scientists explored severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) ribonucleic acid (RNA) editing in host cells.
The study findings were published in the peer reviewed journal: PLOS Genetics.
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1010130


The rapid spread of coronavirus disease 19 (COVID-19) across the world represents an urgent healthcare emergency. By January 2022, the virus had infected >352 million people and caused >5.6 million deaths globally, and these numbers continue to increase. COVID-19 is caused by a novel coronavirus designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1,2].

In the past two years, extensive efforts have been made to characterize this highly contagious virus: the genomes from thousands of infected patients have been sequenced, and the transcriptome architecture has been determined. The genome of SARS-CoV-2 is a positive-sense, single-stranded RNA of ~30 kb and contains ten canonical RNA products in addition to a few unknown ORFs [1–3].

These results have provided a key foundation for elucidating the evolutionary pattern and pathogenicity of SARS-CoV-2 and for developing effective treatment strategies. However, our knowledge of nucleotide variation and plasticity of this viral genome is still limited, especially RNA modifications induced in human host cells.

RNA editing is a widespread nucleotide modification mechanism through which specific nucleotides are modified by RNA editing enzymes at the RNA level without altering template genomic DNA [4]. Adenosine to inosine (A-to-I) is the most prevalent editing type in humans [5]. The A-to-I conversion is catalyzed by adenosine deaminases that act on RNA (ADARs), and the resulting inosines are recognized as G by the translational machinery [6,7].

The other known RNA editing type is cytidine to uridine (C-to-U), which is catalyzed by APOBEC1 [8]. Upon entering human cells, whether and to what extent SARS-CoV-2 is subjected to the activities of human RNA editing enzymes remains largely unexplored. This knowledge is of importance for at least two reasons. First, as the virus employs its negative-strand RNA as a replication template [9] (Fig 1A shows the example of A-to-I RNA editing), the nucleotide changes thus induced could become a direct source of genetic variations inherited from generation to generation.

Second, in sharp contrast to the human genome, the vast majority of the SARS-CoV-2 genome is protein-coding, and thus, RNA editing events would have a much higher probability of causing amino acid changes, thereby modifying protein products. Although identifying RNA editing events from RNA-sequencing data has been well described in many species, including humans, such an analysis for an RNA virus is not trivial.

This is because, without the DNA sequence for comparison, it is almost impossible to distinguish single nucleotide variants (SNVs) caused by spontaneous mutation processes from those due to RNA editing, solely based on alignment-based sequence analysis. In this study, our strategy was to first identify a high-confidence nucleotide variant candidate pool from metatranscriptomic sequencing reads of COVID-19 patient samples using a robust bioinformatics pipeline and then test whether real RNA editing signals were enriched in the candidate pool.

To do so, we evaluated multiple RNA editing-specific characteristics of the candidate sites in comparison to other A/T sites in the SARS-CoV-2 genome, including (i) ADAR1 binding affinity predicted by a deep-learning model based on ADAR1 CLIP-seq data; (ii) cause-effect relationship between ADAR1 expression and the global RNA editing level based on a drug-treated human cell line perturbation experiment, (iii) local clustering patterns of candidate sites from a distance-based analysis, and (iv) RNA secondary structure propensity inferred from an established computational algorithm.

The results from these analyses strongly suggest that an appreciable proportion of the RNA variants we identified result from the ADAR1-mediated A-to-I RNA editing process.


In the second study by Italian researchers, a large-scale analysis of SARS-CoV-2 synonymous mutations revealed the adaptation to the human codon usage during the virus evolution. The study findings showed that synonymous SARS-CoV-2 mutations related to the activity of different mutational processes may positively impact viral evolution by increasing its adaptation to the human codon usage.

The study findings were published in the peer journal: Virus Evolution. https://academic.oup.com/ve/article/8/1/veac026/6553895

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Many large national and transnational studies have been dedicated to the analysis of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) genome, most of which focused on missense and nonsense mutations.

However, approximately 30 per cent of the SARS-CoV-2 variants are synonymous, therefore changing the target codon without affecting the corresponding protein sequence.

By performing a large-scale analysis of sequencing data generated from almost 400,000 SARS-CoV-2 samples, we show that silent mutations increasing the similarity of viral codons to the human ones tend to fixate in the viral genome overtime.

This indicates that SARS-CoV-2 codon usage is adapting to the human host, likely improving its effectiveness in using the human aminoacyl-tRNA set through the accumulation of deceitfully neutral silent mutations.

One-Sentence Summary. Synonymous SARS-CoV-2 mutations related to the activity of different mutational processes may positively impact viral evolution by increasing its adaptation to the human codon usage.

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