Duncan NRI Faculty and Staff Publications
Language
English
Publication Date
5-1-2024
Journal
Nature Microbiology
DOI
10.1038/s41564-024-01655-4
PMID
38649410
PMCID
PMC11384275
PubMedCentral® Posted Date
5-1-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
RNA viruses, like SARS-CoV-2, depend on their RNA-dependent RNA polymerases (RdRp) for replication, which is error-prone. Monitoring replication errors is crucial for understanding the virus’s evolution. Current methods lack the precision to detect rare de novo RNA mutations, particularly in low-input samples such as those from patients. Here, we introduce a new targeted Accurate RNA Consensus sequencing method (tARC-seq) to accurately determine the mutation frequency and types in SARS-CoV-2, both in cell culture and clinical samples. Our findings show an average of 2.68×10−5 new errors per cycle with a C>T bias that cannot be solely attributed to APOBEC editing. We identified hotspots and cold spots throughout the genome, correlating with high or low GC content, and pinpointed transcription regulatory sites as regions more susceptible to errors. tARC-seq captured template switching events including insertions, deletions, and complex mutations. These insights shed light on the genetic diversity generation and evolutionary dynamics of SARS-CoV-2.
Keywords
SARS-CoV-2, Humans, Virus Replication, COVID-19, Genome, Viral, RNA, Viral, Mutation, Sequence Analysis, RNA, Evolution, Molecular, Mutation Rate
Published Open-Access
yes
Recommended Citation
Bradley, Catherine C; Wang, Chen; Gordon, Alasdair J E; et al., "Targeted Accurate RNA Consensus Sequencing (tARC-Seq) Reveals Mechanisms of Replication Error Affecting SARS-CoV-2 Divergence" (2024). Duncan NRI Faculty and Staff Publications. 158.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/158
Included in
Clinical Epidemiology Commons, Community Health and Preventive Medicine Commons, COVID-19 Commons, Genetic Phenomena Commons, Medical Genetics Commons, Neurology Commons, Neurosciences Commons