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Virology Journal
Published in: Virology Journal 1/2023

Open Access 01-12-2023 | SARS-CoV-2 | Research

Analysis of 3.5 million SARS-CoV-2 sequences reveals unique mutational trends with consistent nucleotide and codon frequencies

Authors: Sarah E. Fumagalli, Nigam H. Padhiar, Douglas Meyer, Upendra Katneni, Haim Bar, Michael DiCuccio, Anton A. Komar, Chava Kimchi-Sarfaty

Published in: Virology Journal | Issue 1/2023

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Abstract

Background

Since the onset of the SARS-CoV-2 pandemic, bioinformatic analyses have been performed to understand the nucleotide and synonymous codon usage features and mutational patterns of the virus. However, comparatively few have attempted to perform such analyses on a considerably large cohort of viral genomes while organizing the plethora of available sequence data for a month-by-month analysis to observe changes over time. Here, we aimed to perform sequence composition and mutation analysis of SARS-CoV-2, separating sequences by gene, clade, and timepoints, and contrast the mutational profile of SARS-CoV-2 to other comparable RNA viruses.

Methods

Using a cleaned, filtered, and pre-aligned dataset of over 3.5 million sequences downloaded from the GISAID database, we computed nucleotide and codon usage statistics, including calculation of relative synonymous codon usage values. We then calculated codon adaptation index (CAI) changes and a nonsynonymous/synonymous mutation ratio (dN/dS) over time for our dataset. Finally, we compiled information on the types of mutations occurring for SARS-CoV-2 and other comparable RNA viruses, and generated heatmaps showing codon and nucleotide composition at high entropy positions along the Spike sequence.

Results

We show that nucleotide and codon usage metrics remain relatively consistent over the 32-month span, though there are significant differences between clades within each gene at various timepoints. CAI and dN/dS values vary substantially between different timepoints and different genes, with Spike gene on average showing both the highest CAI and dN/dS values. Mutational analysis showed that SARS-CoV-2 Spike has a higher proportion of nonsynonymous mutations than analogous genes in other RNA viruses, with nonsynonymous mutations outnumbering synonymous ones by up to 20:1. However, at several specific positions, synonymous mutations were overwhelmingly predominant.

Conclusions

Our multifaceted analysis covering both the composition and mutation signature of SARS-CoV-2 gives valuable insight into the nucleotide frequency and codon usage heterogeneity of SARS-CoV-2 over time, and its unique mutational profile compared to other RNA viruses.
Appendix
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Metadata
Title
Analysis of 3.5 million SARS-CoV-2 sequences reveals unique mutational trends with consistent nucleotide and codon frequencies
Authors
Sarah E. Fumagalli
Nigam H. Padhiar
Douglas Meyer
Upendra Katneni
Haim Bar
Michael DiCuccio
Anton A. Komar
Chava Kimchi-Sarfaty
Publication date
01-12-2023
Publisher
BioMed Central
Keyword
SARS-CoV-2
Published in
Virology Journal / Issue 1/2023
Electronic ISSN: 1743-422X
DOI
https://doi.org/10.1186/s12985-023-01982-8

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