Introduction

Coronaviruses (CoVs) have been identified from a diverse range of birds and mammals, including humans [1, 2]. Most of the emerging CoVs, those have infected humans, are originated from animals or birds and have the potential to cause major outbreaks [2]. The CoVs have higher mutation rates and genetic variability in their genomes as a result of either recombination, genetic drift (point mutations), and lack of proofreading capacity by RNA-dependent polymerases (replicative fidelity and diversity) [3,4,21, 22]. Pangolin-, bat- and human-derived SARS-CoV-2 strains were distinct or distantly related in the phylogenetic analysis. However, as for the genetic divergence is concerned, bat- and human-derived SARS-CoV-2 strains were closer than pangolin-derived SARS-CoV-2 strains, indicating the emergence of variants from a common ancestor. Based upon genomic heterogeneity and clustering pattern, the study findings are in agreement with previous observations, suggesting a non-mosaic nature of the SARS-CoV-2 and its close relationship with bat-derived strain [12]. The analysis suggests that SARS-CoV-2 is not an exact variant which is causing a global pandemic in humans; however, the hypothesis of the emergence of the new variant from bats-derived CoVs is very likely. However, a controversy exists for a conceivable relationship among bats- and pangolin-derived hCoV-19 to human-originating SARS-CoV-2 strains. Instead of direct transmission from bats to humans, a study suggests the role of another animal as an intermediate host of the SARS-CoV-2 virus [23]. Taking into consideration the recent history of emerged CoVs (e.g., SARS-CoV and MERS-CoV) where bat acted as a natural reservoir, while other animals (e.g., civet and camels) served as intermediate hosts before their transmission to terminal host (human) [7, 8], it seems reasonable to speculate that there may involve an intermediate host other than bats for potential transmission of SARS-CoV-2 to human. This is important because the place where the outbreak was first escalated during December 2019, most of the bats usually kept themselves in hibernation at that time of the year. Added to this, there was no selling of bat at the Huanan seafood market, whereas other non-aquatic animals such as pangolins were available. Therefore, this particular aspect needs further epidemiological investigations.

Such supposition is also linked to the detection of SARS-like coronavirus in pangolins [24]. On the other hand, the genetic makeup and similarity between spike protein of pangolin- and human-derived SARS-CoV-2 strains is higher (90.15%) than what (99%) is observed between human- and civets-derived SARS-CoV strains, which is why civets were considered as intermediate host but such scenario is not applicable in case of pangolin as intermediate host of SARS-CoV-2 virus. Regarding this aspect, the current study pointed out that pet animals including dogs and cats may act as an intermediate or carrier host of SARS-CoV-2 in the future because of a high level of genomic similarity between dog-, cat- and human-derived hCoVs sequences. This speculation is also supported by the reports about the pet animals as intermediate/carrier hosts of other human emerging viruses [25, 26]. However, it should be cautioned that such speculation is biased because of a limited number of dog- and cat-originating SARS-CoV-2 strains. Recent studies also claimed very low or permissive susceptibility of dogs and cats to SARS-CoV-2 infection [27] and found negative for the existence of SARS-CoV-2-specific antibodies [28]. There are still controversies about the source of the virus and its potential intermediate host which still needs more evidence to be confirmed. Therefore, it is quite earlier to conclude or proclaim any pet animal as an intermediate or carrier host of the SARS-CoV-2 virus and a slew of deep genomic analysis along with disease surveillance, sero-surveillance, molecular epidemiology, pathobiology, and transmissibility investigations has yet to find a conclusive proof.

An occurrence of residue substitutions in coding regions of SARS-CoV-2 sequences reported from different hosts highlight the potential of the virus to mutate rapidly for the emergence of host-specific variants. Considering SARS-CoV-2 as a typical RNA virus, there is likely a chance of high mutation rate and subsequent speciation and evolution of novel variants. It is interesting to note that, among all the CoVs, SARS-CoV-2 possesses the longest genome that makes it more prone to errors during RNA transcription, and therefore the potential occurrence of mutations for the adaptation to novel hosts may very frequent. A significant number of residue substitutions were observed in RBD at spike protein of bat- and pangolin-derived SARS-CoV-2 strains. A vital role of mutations in the RBD region has been indicated for potential inter- and intra-species transmission of SARS-CoV [29]. Amino acid substitutions within the RBD can significantly affect the binding affinity of S protein to its receptor. Any substitution at critical binding sites significantly lowers the electrostatic stabilizing interactions and binding affinity between ACE2-RBD and subsequently alter tissue tropism [30]. Indeed, a minimum of 1–2 substitutions in the RBD is sufficient for a virus to alter its host receptor specificity and subsequent inter-species transmission [31]. Beside it was reported that the SARS-CoV-2 virus has a unique peptide (PRRA) insertion at 680 amino acid position, which may be involved in the proteolytic cleavage of the S protein by cellular proteases, and impact host range and transmissibility [32]. In the current comparative study, it is not found in the S proteins of the bat- and pangolin-derived SARS-CoV-2 strains. Comparative investigations to determine an in vitro impact of the mutations are prerequisites to explore species jump of the SARS-CoV-2 virus.

In conclusion, taken into consideration the intrinsic capacity of CoVs to adapt novel host species [33], the current study suggests the potential evolution of all SARS-CoV-2 strains from a common ancestor. Comparative analysis of human- and non-human-derived SARS-CoV-2 strains highlights the positive selection and continuous evolution in different hosts. Hence, the emergence of different variants with varying pathobiological characteristics is very likely for different host species living across the globe. In this regard, increased genetic diversity among SARS-CoV-2 infected patients suggests an adaptation as well as the evolution of the virus to the environment and the human population worldwide [34]. Therefore, an in-depth analysis of residue substitutions and genetic evolution of SARS-CoV-2 from a wide geographical region is ascertained in the future. Summarizing together, such comparative analysis enhances our understanding of the molecular epidemiology of the SARS-CoV-2 virus in a wide range of host species and future intervention strategies.