Abstract
Analysis of SARS-CoV-2 genetic diversity within infected hosts can provide insight into the generation and spread of new viral variants and may enable high resolution inference of transmission chains. However, little is known about temporal aspects of SARS-CoV-2 intrahost diversity and the extent to which shared diversity reflects convergent evolution as opposed to transmission linkage. Here we use high depth of coverage sequencing to identify within-host genetic variants in 325 specimens from hospitalized COVID-19 patients and infected employees at a single medical center. We validated our variant calling by sequencing defined RNA mixtures and identified viral load as a critical factor in variant identification. By leveraging clinical metadata, we found that intrahost diversity is low and does not vary by time from symptom onset. This suggests that variants will only rarely rise to appreciable frequency prior to transmission. Although there was generally little shared variation across the sequenced cohort, we identified intrahost variants shared across individuals who were unlikely to be related by transmission. These variants did not precede a rise in frequency in global consensus genomes, suggesting that intrahost variants may have limited utility for predicting future lineages. These results provide important context for sequence-based inference in SARS-CoV-2 evolution and epidemiology.
Highlights
Over the course of the SARS-CoV-2 pandemic, whole genome sequencing has been widely used to characterize patterns of broad geographic spread, transmission in local clusters, and the spread of specific viral variants [1,2,3,4,5,6]
The funders played no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript
Reports demonstrated that SARS-CoV-2 exhibits genetic diversity within infected hosts, but this has been less studied than consensus-level genomic diversity [7]
Summary
Over the course of the SARS-CoV-2 pandemic, whole genome sequencing has been widely used to characterize patterns of broad geographic spread, transmission in local clusters, and the spread of specific viral variants [1,2,3,4,5,6]. Reports demonstrated that SARS-CoV-2 exhibits genetic diversity within infected hosts, but this has been less studied than consensus-level genomic diversity [7]. Patterns of viral intrahost diversity throughout individual infections can suggest the relative importance of natural selection and stochastic genetic drift [8]. Studies of SARS-CoV-2 intrahost diversity may shed light on selective pressures applied at the individual level, such as antivirals and antibody-based therapeutics. While a clear understanding of within-host evolution can inform how SARS-CoV-2 spreads on broader scales, there have been relatively few comprehensive studies of intrahost dynamics [9,11,12]
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