Background SARS-CoV-2 began spreading in December 2019 and has since become a pandemic that has impacted many aspects of human society. Several issues concerning the origin, time of introduction to humans, evolutionary patterns, and underlying force driving the SARS-CoV-2 outbreak remain unclear. Method Genetic variation in 137 SARS-CoV-2 genomes and related coronaviruses as of 2/23/2020 was analyzed. Result After correcting for mutational bias, the excess of low frequency mutations on both synonymous and nonsynonymous sites was revealed which is consistent with the recent outbreak of the virus. In contrast to adaptive evolution previously reported for SARS-CoV during its brief epidemic in 2003, our analysis of SARS-CoV-2 genomes shows signs of relaxation. The sequence similarity in the spike receptor binding domain between SARS-CoV-2 and a sequence from pangolin is probably due to an ancient intergenomic introgression that occurred approximately 40 years ago. The current outbreak of SARS-CoV-2 was estimated to have originated on 12/11/2019 (95% HPD 11/13/2019–12/23/2019). The effective population size of the virus showed an approximately 20-fold increase from the onset of the outbreak to the lockdown of Wuhan (1/23/2020) and ceased to increase afterwards, demonstrating the effectiveness of social distancing in preventing its spread. Two mutations, 84S in orf8 protein and 251 V in orf3 protein, occurred coincidentally with human intervention. The former first appeared on 1/5/2020 and plateaued around 1/23/2020. The latter rapidly increased in frequency after 1/23/2020. Thus, the roles of these mutations on infectivity need to be elucidated. Genetic diversity of SARS-CoV-2 collected from China is two times higher than those derived from the rest of the world. A network analysis found that haplotypes collected from Wuhan were interior and had more mutational connections, both of which are consistent with the observation that the SARS-CoV-2 outbreak originated in China. Conclusion SARS-CoV-2 might have cryptically circulated within humans for years before being discovered. Data from the early outbreak and hospital archives are needed to trace its evolutionary path and determine the critical steps required for effective spreading.

bioRxiv preprint 23 impacted many aspects of human society. Here, we analyzed genetic variation of SARS- 24 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, 40 haplotypes collected from Wuhan city were at interior and have more mutational connections, 41 both of which are consistent with the observation that the outbreak of cov-19 was originated 42 from China. SUMMARY 44In contrast to adaptive evolution previously reported for SARS-CoV in its brief 45 epidemic, our analysis of SARS-CoV-2 genomes shows signs of relaxation of selection. The 46 sequence similarity of the spike receptor binding domain between SARS-CoV-2 and a 47 sequence from pangolin is probably due to an ancient intergenomic introgression. Therefore, 48 SARS-CoV-2 might have cryptically circulated within humans for years before being 49 recently noticed. Data from the early outbreak and hospital archives are needed to trace its 50 evolutionary path and reveal critical steps required for effective spreading. Two mutations, 51 84S in orf8 protein and 251V in orf3 protein, occurred coincidentally with human 52 intervention. The 84S first appeared on 1/5/2020 and reached a plateau around 1/23/2020, the 53 lockdown of Wuhan. 251V emerged on 1/21/2020 and rapidly increased its frequency. Thus, 54 the roles of these mutations on infectivity need to be elucidated. 55 56 57 A newly emerging coronavirus was detected in patients during an outbreak of 58 respiratory illnesses starting in mid-December of 2019 in Wuhan, the capital of Hubei 59 Province, China [1 , 2, 3]. Due to the similarity of its symptoms to those induced by the 60 severe acute respiratory syndro...

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Analyses of the genomic diversity of SARS-CoV-2 found that some sites across the genome appear to have mutated independently multiple times with frequency significantly higher than four-fold sites, which can be either due to mutational bias, i.e., elevated mutation rate in some sites of the genome, or selection of the variants due to antagonistic pleiotropy, a condition where mutations increase some components of fitness at a cost to others. To examine how different forces shaped evolution of SARS-CoV-2 in 2020–2021, we analyzed a large set of genome sequences (~ 2 million). Here we show that while evolution of SARS-CoV-2 during the pandemic was largely mutation-driven, a group of nonsynonymous changes is probably maintained by antagonistic pleiotropy. To test this hypothesis, we studied the function of one such mutation, spike M1237I. Spike I1237 increases viral assembly and secretion, but decreases efficiency of transmission in vitro. Therefore, while the frequency of spike M1237I may increase within hosts, viruses carrying this mutation would be outcompeted at the population level. We also discuss how the antagonistic pleiotropy might facilitate positive epistasis to promote virus adaptation and reconcile discordant estimates of SARS-CoV-2 transmission bottleneck sizes in previous studies.

Since the first report of SARS-CoV-2 in December 2019, Taiwan had gone through three local outbreaks. Unlike the first two, the spatial and temporal origin of the third outbreak (April 20 to November 5, 2021) is still unclear. We sequenced and reconstructed the phylogeny of SARS-CoV-2 genomes and find that the third outbreak was caused by a single virus lineage (T-III), which carries four genetic fingerprints, including spike M1237I (S-M1237I), and three silent changes. The T-III is closest to sequences derived from Turkey on February 8, 2021. The estimated date of divergence from the most recent common ancestor (TMRCA) of T-III is March 23, 2021 (95% HPD February 24 - April 13, 2021), almost one month before the first three confirmed cases on April 20, 2021. The effective population size of the T-III showed approximately 20-fold increase after the onset of the outbreak and reached a plateau in early June. Consequently, the lineage leading to the third outbreak most likely originated from Europe, perhaps Turkey, in February 2021. In addition, the T-III could have circulated in Taiwan in mid-March 2021. The virus was unnoticed while spreading within the community.

One of the unique features of SARS-CoV-2 is that it mainly evolved neutrally or under purifying selection during the early pandemic. This contrasts with the preceding epidemics of the closely related SARS-CoV and MERS-CoV, both of which evolved adaptively. It is possible that the SARS-CoV-2 exhibits a unique or adaptive feature which deviates from other coronaviruses. Alternatively, the virus may have been cryptically circulating in humans for a sufficient time to have acquired adaptive changes for efficient transmission before the onset of the current pandemic. In order to test the above scenarios, we analyzed the SARS-CoV-2 sequences from minks (Neovision vision) and parenteral human strains. In the early phase of the mink epidemic (April to May 2020), nonsynonymous to synonymous mutation ratios per site within the spike protein was 2.93, indicating a selection process favoring adaptive amino acid changes. In addition, mutations within this protein concentrated within its receptor binding domain and receptor binding motif. Positive selection also left a trace on linked neutral variation. An excess of high frequency derived variants produced by genetic hitchhiking was found during middle (June to July 2020) and early late (August to September 2020) phases of the mink epidemic, but quickly diminished in October and November 2020. Strong positive selection found in SARS-CoV-2 from minks implies that the virus may be not unique in super-adapting to a wide range of new hosts. The mink study suggests that SARS-CoV-2 already went through adaptive evolution in humans, and likely been circulating in humans at least six months before the first case found in Wuhan, China. We also discuss circumstances under which the virus can be well-adapted to its host but fail to induce an outbreak.

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