SARS-CoV-2 genomics beyond the consensus sequence: evidence for circulating mixed viral populations

SARS-CoV-2, the causative agent of COVID-19, emerged in late 2019 causing a global pandemic, with the United Kingdom (UK) one of the hardest hit countries. Rapid sequencing and publication of consensus genomes have enabled phylogenetic analysis of the virus, demonstrating SARS-CoV-2 evolves relatively slowly, but with multiple sites in the genome that appear inconsistent with the overall consensus phylogeny. To understand these discrepancies, we used veSEQ, a targeted RNA-seq approach, to quantify minor allele frequencies in 413 clinical samples from two UK locations. We show that SARS-CoV-2 infections are characterised by extensive within-host diversity, which is frequently shared among infected individuals with patterns consistent with geographical structure. These results were reproducible in data from other sequencing locations around the UK, where we find evidence of mixed infection by major circulating lineages with patterns that cannot readily be explained by artefacts in the data. We conclude that SARS-CoV-2 diversity is transmissible, and propose that geographic patterns are generated by co-circulation of distinct viral populations. Co-transmission of mixed populations fundamentally changes our understanding of transmission of SARS-CoV-2 and could prove significant for treatment and vaccine design, as well as opening opportunities for resolving clusters of transmission and understanding pathogenesis.