The origin and underlying driving forces of the SARS-CoV-2 outbreak

Shu-Miaw Chaw; Jui-Hung Tai; Shi-Lun Chen; Chia-Hung Hsieh; Sui-Yuan Chang; Shiou-Hwei Yeh; Wei-Shiung Yang; Pei-Jer Chen; Hurng-Yi Wang

The spread of SARS-CoV-2 since December 2019 has become a pandemic and 23 impacted many aspects of human society. Here, we analyzed genetic variation of CoV-2 and its related coronavirus and found the evidence of intergenomic recombination. 25 After correction for mutational bias, analysis of 137 SARS-CoV-2 genomes as of 2/23/2020 26 revealed the excess of low frequency mutations on both synonymous and nonsynonymous 27 sites which is consistent with recent origin of the virus. In contrast to adaptive evolution 28 previously reported for SARS-CoV in its brief epidemic in 2003, our analysis of SARS-CoV-29 2 genomes shows signs of relaxation of selection. The sequence similarity of the spike 30 receptor binding domain between SARS-CoV-2 and a sequence from pangolin is probably 31 due to an ancient intergenomic introgression. Therefore, SARS-CoV-2 might have cryptically 32 circulated within humans for years before being recently noticed. Data from the early 33 outbreak and hospital archives are needed to trace its evolutionary path and reveal critical 34 steps required for effective spreading. Two mutations, 84S in orf8 protein and 251V in orf3 35 protein, occurred coincidentally with human intervention. The 84S first appeared on 1/5/2020 36 and reached a plateau around 1/23/2020, the lockdown of Wuhan. 251V emerged on 37 1/21/2020 and rapidly increased its frequency. Thus, the roles of these mutations on 38 infectivity need to be elucidated. Genetic diversity of SARS-CoV-2 collected from China was 39 two time higher than those derived from the rest of the world. In addition, in network analysis, Province, China [1 , 2, 3] . Due to the similarity of its symptoms to those induced by the 60 severe acute respiratory syndrome (SARS) and genome organization similarity, the causal 61 virus was named SARS-CoV-2 by the International Committee on Taxonomy of Viruses [4] . 62 As of 3/16/2020, 167,515 cases of SARS-CoV-2 infection have been confirmed in 114 63 countries, causing 6,606 fatalities. As a result, WHO declared the first pandemic caused by a 64 coronavirus on 3/11/2020 (https://www.who.int/emergencies/diseases/novel-coronavirus-65 2019/situation-reports). As the virus continues to spread, numerous strains have been isolated 66 and sequenced. On 3/18/2020, more than 500 complete or nearly complete genomes have 67 been sequenced and made publicly available.