The increased EN-RAGE expression occurs specifically in monocytes of COVID-19 patients without inducing pro-inflammatory cytokines, which well correlates with its higher levels in the plasma. and SARS-CoV2. However, RmYN02 exhibits a low AA sequence identity (only 62.4%) to SARS-CoV2 in its RBD, and may not bind to the human ACE2 to cause contamination. A similarity plot, called Simplot has also showed that this RmYN02 is more similar to the SARS-CoV2 than RaTG13 in most genome regions [33]. Of note, the multiple AAs insertion at the junction site of the S1 and S2 subunits of the S protein characterized the RmYN02. Hence, insertion of AAs may occur naturally in CoVs to Sirt5 which SARS-CoV2 belongs. Thus we know that this COVID-19 is usually of bat origin but we do not have its confirmatory proof. We do not have a confirmatory report for the transmission of SARS-CoV2 from bats to humans. Open in a separate window Fig. 1 Origin of SARS-CoV2 contamination or COVID-19 in humans. The BatCoV RaTG13 and RmYN02 are most closely related to SARS-CoV2. However, they are not able to cause infection in their natural form. So different theories have emerged, including the use of secondary animal hosts (which are not confirmed yet) by the virus to evolve there to cause infection to humans. However, another theory suggest the RaTG13 and RmYN02 evolved or undergone positive episodic selection in horseshoe bats. Fruit bats and ferret can also get the SARS-CoV2 contamination through intranasal route. However, fruit bats do not develop visible symptoms and clear the infection, whereas ferrets can serve an animal model for asymptomatic SARS-CoV2 contamination of the humans as they develop subclinical symptoms. The severe contamination with SARS-CoV2 in humans causes severe pneumonia and the associated ALI/ARDS through generating the cytokine storm to cause death of the patient. Some researchers have also suggested its transmission to humans from snakes [(the many-banded krait) and (the Chinese cobra)] and pangolins via serving as secondary or reservoir hosts [34], [35], [36]. However, we do not have any evidence of SARS-CoV2 transmission from snakes to humans. SARS-CoV-2-like CoV (named Pangolin-CoV) isolated from dead Malayan pangolins is usually 91.02% and 90.55% identical to SARS-CoV2 and BatCoV RaTG13 at the whole genome level [36]. Another pangolin CoV, called pangolin-CoV2020 isolated from three sick Malayan pangolins does not provide the evidence of direct emergence of SARS-CoV2 from it [37]. Also, all the pangolin CoVs isolated to date have no polybasic (furin-like) S1//S2 cleavage site in their S protein like SARS-CoV2 [38]. Both, Pangolin-CoV and RaTG13 have lost their putative furin recognition sequence motif at S1/S2 cleavage site, which is present in SARS-CoV2 [36]. Only SARS-CoV2 has an unique peptide called PRRA, which may be involved in the proteolytic cleavage of the spike protein by cellular proteases to impact host range and transmissibility and pangolin CoVs lack it [39]. Hence, the RatTG13-CoV is usually more closer to SARS-CoV2 than CoVs obtained from two pangolin samples (SRR10168377 and SRR10168378) [39]. Thus, hypotheses supporting genetic recombination, convergence, and adaptation for the SARS-CoV2 evolution from these known sources of virus are still the hot topic for debate and need further investigation. A recent study has contrasted the role of positive selection and recombination in the? and also replicates there Fevipiprant [42]. However, contamination of SARS-CoV2 contamination in the horseshoe bats will be interesting to study as the natural presence of SARS-CoV2 and clinical contamination or symptoms in horseshoe Fevipiprant still needs experimental investigations. A phylogenetic and phylodynamic analysis of SARS-CoV2 has indicated the time to the most recent common ancestor (TMRCA) and evolutionary rate of Fevipiprant SARS-CoV-2 to be 12 November 2019 (95% BCI: 11 October 2019 and 09 December 2019) and 9.90??10?4 ?substitutions per site per year (95% Fevipiprant BCI: 6.29??10?4C1.35??10?3) [43]. Another study based on Bayesian time-scaled phylogenetic analysis using the tip-dating.