Abstract
The genus Betacoronavirus, consisting of four main subgenera (Embecovirus, Merbecovirus, Nobecovirus, and Sarbecovirus), encompasses all clinically significant coronaviruses (CoVs), including SARS, MERS, and the SARS-CoV-2 virus responsible for current COVID-19 pandemic. Very few molecular characteristics are known that are specific for the genus Betacoronavirus or its different subgenera. In this study, our analyses of the sequences of four essential proteins of CoVs, viz., spike, nucleocapsid, envelope, and RNA-dependent RNA polymerase (RdRp), identified ten novel molecular signatures consisting of conserved signature indels (CSIs) in these proteins which are specific for the genus Betacoronavirus or its subgenera. Of these CSIs, two 14-aa-conserved deletions found within the heptad repeat motifs 1 and 2 of the spike protein are specific for all betacoronaviruses, except for their shared presence in the highly infectious avian coronavirus. Six additional CSIs present in the nucleocapsid protein and one CSI in the RdRp protein are distinctive characteristics of either the Merbecovirus, Nobecovirus, or Sarbecovirus subgenera. In addition, a 4-aa insert is present in the spike protein, which is uniquely shared by all viruses from the subgenera Merbecovirus, Nobecovirus, and Sarbecovirus, but absent in Embecovirus and all other genera of CoVs. This molecular signature provides evidence that viruses from the three subgenera sharing this CSI are more closely related to each other, and they evolved after the divergence of embecoviruses and other CoVs. As all CSIs specific for different groups of CoVs are flanked by conserved regions, their sequences provide novel means for identifying the above groups of CoVs and for developing novel diagnostic tests. Furthermore, our analyses of the structures of the spike and nucleocapsid proteins show that all identified CSIs are localized in the surface-exposed loops of these protein. It is postulated that these surface loops, through their interactions with other cellular proteins/ligands, play important roles in the biology/pathology of these viruses.
Highlights
Coronaviruses (CoVs) are a part of the subfamily Orthocoronavirinae [1,2]
Within the genus Betacoronavirus, four main clusters corresponding to its four subgenera i.e., Embecovirus, Sarbecovirus, Merbecovirus, and Nobecovirus are observed
CoVs have been responsible for three major outbreaks in the past 20 years including the current COVID-19 pandemic caused by the SARS-CoV-2 virus, which has infected >307 million people worldwide leading to >5.6 million deaths
Summary
Coronaviruses (CoVs) are a part of the subfamily Orthocoronavirinae [1,2] The members of this family have been divided into four genera, viz., Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus, based on their branching in phylogenetic trees and genomic structures [1,2,3,4]. The genus Betacoronavirus is made up of four main lineages, which are recognized as distinct subgenera with the names Embecovirus, Merbecovirus, Nobecovirus, and Sarbecovirus [1,2,3,4,5] Of these four subgenera, SARS coronavirus (SARSCoV) and the COVID-19 virus (named as SARS-CoV-2) are both members of the subgenus Sarbecovirus, whereas the MERS-CoV is a part of the Merbecovirus subgenus [1,3,5,6]. It is of much interest to identify molecular markers that are specific for different genera/subgenera of CoVs [1,2,7]
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