Comparative study of SARS, MERS, BAT-SARS and SARS-CoV-2

Scientists have found that several viruses belonging to the Coronaviridae family can infect a wide range of hosts, including birds, humans and other mammals. These viruses are positive-sense single-stranded RNA viruses ranging in size from 27 to 32 kb. They are divided into four categories namely, alpha, beta, delta and gamma.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of the ongoing coronavirus pandemic 2019 (COVID-19), was first identified in China’s Wuhan province in December 2019. Due to its high infectivity and death rate, the World Health Organization announced that COVID-19 is a pandemic on March 11, 2020.

Since viruses undergo genomic mutation, it is first and foremost important to identify the mutation site for vaccine development. Several tree-based phylogenetic analyzes have been conducted to understand the evolutionary relationship of SARS-CoV-2 with other beta coronaviruses. A previous study built a phylogenetic tree and found that the genomic sequence of SARS-CoV-2 is 88% identical to that of BAT-CoV. In another study, scientists isolated about 70 SARS-CoV-2 genomic sequences from COVID-19 patients and studied the advanced glycoprotein gene. This study also reported that the BetaCoV-bat-Yunnan-RaTG13-2013 virus is almost identical to SARS-CoV-2.

Even though a comparative study on the genomic sequences of SARS-CoV, MERS-CoV and SARS-CoV-2 is available, there is a gap in the research regarding the comparison between four types of coronavirus, namely , SARS-CoV, MERS-CoV, BAT-CoV and SARS-CoV-2. A new study, which deals with the genomic comparison between the sequence of the aforementioned four types of coronavirus, has been published in the Journal of Medical Virology. This study used several genetic markers, including single nucleotide polymorphisms (SNPs), whole genome sequence phylogeny, mutations in proteins, and microsatellites. These were compared to the SARS-CoV-2 reference genomic sequence known as the Wuhan strain (Wuhan-Wu-I). All sequences were obtained from NCBI Genbank.

The SARS-CoV, MERS-CoV and SARS-CoV-2 sequences were obtained from homo sapiens (host), while BAT-CoV sequences were collected from eight different types of bats. The results of this study are described below.

Phylogenetic analysis

For the phylogenetic analysis of the sequence of the different coronaviruses, a maximum likelihood approach with 1000 bootstrap values ​​was used. Phylogenetic analysis revealed different lineages of coronavirus. The phylogenetic analysis based on the genome as a whole showed that MERS-CoV belonged to external species, while the other three were classified as endogroup species. Within the ingroup, two lines were found, namely one line consisting of SARS-CoV-2 and another consisting of SARS-CoV and BAT-CoV. Branches of the phylogenetic tree indicated that SARS-CoV diverged from BAT-CoV very early on. The tree also revealed an independent divergence of SARS-CoV-2 from BAT-CoV. The phylogeny also showed that SARS-CoV-2 was more closely related to BAT-CoV and SARS-CoV than MERS-CoV. Simplot software was used to visualize the similarity graph between the four selected species. It revealed approximately 98% homology of BAT-CoV with the reference sequence, i.e. the Wuhan stain of SARS-CoV-2. However, 92% similarity was obtained between SARS-CoV and the reference sequence, and 58% similarity between MERS-CoV and the Wuhan strain.

Analysis of genetic variants

Variant-based analysis showed that the MERS-CoV genome differed from the Wuhan reference strain at 134.21 sites, the BAT-CoV genome differed at 136.72 sites, the SARS-CoV genome differed at 26.64 sites and the SARS-CoV-2 genome differed at 0.66 sites. In addition, the present study also found that the probability of mutations at missense sites of MERS-CoV and SARS-CoV-2 is higher than that of SARS-CoV and BAT-CoV. This is due to the reduced number of missense variations in SARS-CoV and BAT-CoV, which occurred due to selection pressure on missense sites.

The number of mutations in Spike protein (S), envelope protein (E), membrane protein (M), core protein (N) and structural proteins was calculated. SNPs were filtered out from the S, M, E and N gene regions by a python script. The S, M, E and N genes revealed the presence of a varying number of SNPs. The Multialin online tool was used to detect similarities between four coronaviruses selected for the current study.

Microsatellite analysis

Microsatellite analysis is used to determine repetitive sequences in the genome. These sequences have a significant impact on the appearance of diseases and their evolution. In this study, microsatellite analysis was performed using the IMEX (Imperfect Microsatellite Extractor) and FMSD (Fast Microsatellite Discovery) online tools. No significant presence of microsatellite was found using IMEX. However, the FMSD revealed the presence of more microsatellite in MERS-CoV. The SARS-CoV-2 genome showed the presence of the highest incidence of compound microsatellites.

In summary, analysis of the phylogenetic tree has shown that SARS-CoV-2 is closely related to BAT-CoV and its second closest relative is SARS-CoV. All strains of MERS-CoV showed a distal relationship with SARS-CoV-2. In the analysis of genetic variants, more mutations were found in MERS-CoV compared to SARS-CoV and BAT-CoV. Phylogenetic analysis, the study of genetic variation, multisequence and microsatellite analysis, have shown that the bat is the native host of SARS-CoV-2. In addition, he also concluded that BAT-CoV is closely related to SARS-CoV-2. There is a possibility of the presence of an intermediate host to initiate transmission of COVID-19 from BAT to humans. However, more research is needed to validate this hypothesis. The FMSD tool revealed that SARS-CoV is more closely associated with SARS-CoV-2 than with BAT-CoV.