RNA sequencing of SARS-CoV-2 mutations in 1,000+ individuals underlines the need for continued monitoring

An analysis of SARS-CoV-2 genome diversity in more than 1,000 people in the United Kingdom suggests that if viral mutations do arise, they can be transmitted in some cases but they rarely persist in subsequent transmissions.

“Our observations indicate the within-host emergence of vaccine- and therapeutic-escape mutations is likely to be relatively rare,” say the authors, “at least during early infection when viral loads are high.”

However, because mutations that can escape therapies like antibodies were identified, including in higher viral load samples, the authors encourage continued monitoring and vigilance, particularly as vaccines and therapeutics that put “pressure” on viruses to adapt are rolled out more widely. Most analyses of mutations in SARS-CoV-2 to date have been focused on mutations observed in individuals that represent the dominant variants. However, new mutations are emerging in infected individuals, too, and knowledge of the full underlying diversity of viruses in human hosts – how frequently they emerge, and whether they are transmitted – is important for understanding viral adaption and patterns of spread.

To better characterize diversity in single human hosts, Katrina Lythgoe and colleagues used veSEQ, an RNA sequencing approach based on a quantitative targeted enrichment strategy which we previously validated for other viruses, to analyze 1,390 SARS-CoV-2 genomes from 1,313 nasopharyngeal swabs sampled mostly from symptomatic patients in the UK who had gotten sick between March and June 2020 (the first global wave of infection). The authors observed only one or two variants in most individuals, but a few patients carried many variants. Most of these were lost at the point of transmission, though a small number initiated ongoing transmission and wider dissemination. Too, there were very few cases of virus transmission between households in the studied genomes. These results suggest that during early infection, mutations that can increase the virus’s chances of escaping therapies rarely emerge and transmit. Even so, the authors did identify variants that can give the virus an advantage, including in high viral load samples. This indicates that naturally occurring variants would have the opportunity to spread as population selection pressure from vaccine rollout increases. The findings underline the need for continued monitoring, they say.

Characterization of iSNV frequencies

(A) Distribution of number of identified iSNV sites in each sample against number of unique mapped reads. The colors represent different minor allele frequency (MAF) thresholds; an iSNV site is identified within a sample if the MAF is greater than the threshold. (B) Distribution of mean MAF in each sample against number of unique mapped reads, with no MAF threshold applied. The black line is the estimated mean value by linear regression, with the green ribbon the 95% confidence interval. (C) Distribution of number of identified iSNV sites, at 3% MAF threshold, when subsampling from high-depth samples. Each color represents a different high-depth sample.

SourceAmerican Association for the Advancement of Science

Lythgoe KA, Hall M, Ferretti L et al. (2021) SARS-CoV-2 within-host diversity and transmission. Science [Epub ahead of print]. [article]

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