SNPs or RNA modifications? Concerns on mutation-based evolutionary studies of SARS-CoV-2

Area of Science:

• Virology
• Genomics
• Molecular Biology

Background:

• The ongoing global pandemic necessitates understanding SARS-CoV-2 evolution.
• Previous evolutionary studies relied heavily on RNA sequencing (RNA-seq) data to identify single nucleotide polymorphisms (SNPs).
• Distinguishing viral RNA modifications from genetic mutations in RNA-seq data is challenging.

Purpose of the Study:

• To investigate the presence and significance of RNA modifications in SARS-CoV-2.
• To highlight the potential misinterpretation of RNA modifications as SNPs in evolutionary analyses of RNA viruses.
• To emphasize the need for rigorous validation of mutation origins in SARS-CoV-2 research.

Main Methods:

• Analysis of public SARS-CoV-2 RNA-seq datasets.
• Detection of specific base modifications (A-to-G) using high signal-to-noise ratio methods.
• Comparative analysis of mutation spectra to differentiate between RNA modifications and SNPs.

Main Results:

• Reliable detection of A-to-G RNA modifications in SARS-CoV-2 RNA-seq data.
• These modifications are likely host-induced, potentially by deamination enzymes.
• Inherent difficulty in distinguishing RNA modifications from SNPs in RNA viruses using RNA-seq alone.

Conclusions:

• RNA modifications can be erroneously identified as SNPs in SARS-CoV-2 evolutionary studies.
• The origin of mutations (RNA modification vs. genetic mutation) must be clarified before inferring evolutionary patterns.
• This distinction is critical for accurate understanding of RNA virus evolution, unlike DNA-based organisms.