Analysis of SARS-CoV-2 Population Genetics from Samples Associated with Huanan Market and Early Cases Identifies Substitutions Associated with Future Variants of Concern.

SARS-CoV-2 began spreading through human-to-human transmission first within China and then worldwide, with increasing sequence diversity associated with time and the further spread of the virus. The spillover events in the Huanan market were associated with two lineages of SARS-CoV-2 (lineages A and B). Infecting virus populations and those in infected individuals consist of a dominant genomic sequence and minor genomic variants; these latter populations can indicate sites on the genome that may be subject to mutational changes-either neutral or advantageous sites and those that act as a reservoir for future dominant variants-when placed under selection pressure. The earliest deposited sequences with human infections associated with the Huanan market shared very close homology with each other and were all lineage B. However, there were minor genomic variants present in each sample that encompassed synonymous and non-synonymous changes. Fusion sequences characteristic of defective RNA were identified that could potentially link transmission chains between individuals. Although all the individuals appeared to have lineage B as the dominant sequence, nucleotides associated with lineage A could be found at very low frequencies. Several substitutions (but not deletions) associated with much later variants of concern (VoCs) were already present as minor genomic variants. This suggests that low-frequency substitutions at the start of a pandemic could be a reservoir of future dominant variants and/or provide information on potential sites within the genome associated with future plasticity.