The Early Cryptic Transmission and Evolution of SARS-CoV-2 in Human Hosts

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is first identified in Wuhan City at the end of December 2019 and responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic. So far this pandemic has claimed more than one million lives all over the world and its origin is still unknown. Methods: In this study, we developed a method to search the least mutated strain using SARS-CoV-2 whole genome sequences. By parsimony principle, the least mutated strain should be the phylogenetic root for all SARS-CoV-2s. We further investigated the SARS-CoV-2’s adaptive evolutionary process in human hosts using the least mutated strain as the phylogenetic root and analyzed its strain diversity in different countries/regions. Findings: According to their coding region identity, we classified 4571 SARS-CoV-2 genome sequences into 2449 viral strains collected from human hosts between December 2019 and July 2020. We found that the SARS-CoV-2 (NC_045512) strain first identified in Wuhan is not the least mutated strain. There are 41 SARS-CoV-2 strains harboring fewer global point mutations than the NC_045512 strain in our dataset. The least mutated strain can be found in eight countries across four continents due to SARS-CoV-2’s low mutability. Eight positive selection sites are identified in five SARS-CoV-2’s genes and four of them were present in the early stage of SARS-CoV-2’s human-to-human transmission. The NC_045512 strain has two positive selection sites, one in RNA-dependent RNA polymerase (L314P) and the other in spike protein (G614D). The statistical analysis of the SARS-CoV-2’s strain diversity in different countries/regions shows that the Indian subcontinent has the highest strain diversity. Furthermore, based on the SARS-CoV-2’s mutation rate, we estimate that the earliest SARS-CoV-2 transmission in human hosts could be traced back to July or August of 2019. Interpretation: Our result shows that Wuhan is not the place where human-to-human SARS-CoV-2 transmission first happened. Before it spread to Wuhan, SARS-CoV-2 has already experienced adaptive evolution during its human-to-human transmission. The positive selection sites could contribute to the different clinical features of different SARS-CoV-2 strains. Both the least mutated strain’s geographic information and the strain diversity suggest that the Indian subcontinent might be the place where the earliest human-to-human SARS-CoV-2 transmission occurred, which was three or four months prior to the Wuhan outbreak. Our study helps to elucidate the early cryptic transmission and evolution of SARS-CoV-2 in human hosts and provide the new thinking for the global management of the COVID-19 pandemic. Funding Statement: None to declare. Declaration of Interests: None to declare.