Scanning electron micrograph of an apoptotic cell (green) heavily infected with SARS-COV-2 virus particles (purple), isolated from a patient sample. Image captured and color-enhanced at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Image credit: NIAID (CC BY 2.0)
Tracking and characterizing mutations in a fast-evolving virus such as SARS-CoV-2, the cause of COVID-19, are valuable for an effective public health response and for developing treatments and vaccines that work well against mutated viruses. Mutations in the SARS-CoV-2 genome happen when errors are made as the RNA genetic material is copied.
The SARS-CoV-2 genome is made of an RNA chain consisting of four units called nucleotides, known as A, C, G, and U. Unlike DNA, where all nucleotides of one strand are paired with the other strand, RNA usually consists of a single strand. However, the SARS-CoV-2 genome folds into a compact and dynamic structure where some RNA nucleotides form pairs with others within the same strand, similar to the double-stranded DNA molecules.
Many mutations have no effect, but some can increase the ability of the virus to spread from person to person. This increased ‘viral fitness’ is difficult to predict, but understanding which mutations are more likely to occur can help scientists estimate risks. For example, a common type of mutation causes one RNA nucleotide – A, U, C or G – to be replaced by another. In SARS-CoV-2, the most common mutations involve C being replaced by U.
To find out if the pairing of RNA nucleotides affects how likely it is for a mutation to occur, Hensel looked at the rates of tens of thousands of different mutations, previously estimated from millions of publicly available sequences of the SARS-CoV-2 genome. He analyzed how often different types of mutations happen in paired versus unpaired RNA nucleotides. Only mutations that change the nucleotide sequence and not the protein sequences (so-called ‘neutral’ mutations) were considered in this analysis.
Hensel observed that C to U and G to U mutations are about four times more likely in unpaired nucleotides compared to paired ones. Other types of ‘neutral’ mutations, like A to G, were found to be equally likely, regardless of being paired or unpaired. Understanding that certain unpaired nucleotides mutate more often can help explain why some mutations are much more common than others. This should be considered in future models of the evolution of SARS-CoV-2 and other RNA viruses. A better understanding of mutation rates will also inform vaccine development and improve our estimates of viral fitness, potentially improving future public health responses.
