key: cord-0705964-jer4jwwf
authors: Seyran, Murat; Pizzol, Damiano; Adadi, Parise; El‐Aziz, Tarek M. A.; Hassan, Sk. Sarif; Soares, Antonio; Kandimalla, Ramesh; Lundstrom, Kenneth; Tambuwala, Murtaza; Aljabali, Alaa A. A.; Lal, Amos; Azad, Gajendra K.; Choudhury, Pabitra P.; Uversky, Vladimir N.; Sherchan, Samendra P.; Uhal, Bruce D.; Rezaei, Nima; Brufsky, Adam M.
title: Questions concerning the proximal origin of SARS‐CoV‐2
date: 2020-12-30
journal: J Med Virol
DOI: 10.1002/jmv.26478
sha: 34a4f432909b5b805de2fb23486fca29c47818aa
doc_id: 705964
cord_uid: jer4jwwf

There is a consensus that Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) originated naturally from Bat coronaviruses (CoVs), in particular RaTG13. However, the SARS-CoV-2 host tropism/adaptation pattern has significant discrepancies compared to other CoVs, raising questions concerning the proximal origin of SARS-CoV-2. This article is protected by copyright. All rights reserved.

There is a consensus that severe acute respiratory syndrome cor- The "Canyon Hypothesis" explains the development of canyons, depression zones, or cavities on the surfaces of influenza virus, human rhinovirus, and Meningo viruses. 6 In CoVs (except SARS-CoV-2), the S protein NTD domain has several predicted glycan-binding domains, with a common feature being the hidden localization of these glycan-binding domains to cavities to limit their access to antibodies and immune cells. 5 This pattern of CoVs is thought to be an evolutionary measure to restrict the recognition of these active sites by host immune system. 4 HCoVs can evade detection by host glycan-binding immune receptors. Comparative genomic analysis of six HCoVs with their corresponding native bat or rodent CoVs suggests compatibility with the "Canyon Hypothesis" resulting from various adaptive S protein NTD nonsynonymous mutations near or at the glycan-binding domain which are predicted to result in these NTD domains being hidden below the protein surface. 5 The predicted flat, nonsunken pattern of the SARS-CoV-2 S protein NTD glycan-binding domains conflicts with this evolutionary host tropism/adaptation strategy. 7 A template-switching mechanism is presumably responsible for the high rate of RNA recombination in CoVs. In host cells, CoV RNAs show discontinuous RNA synthesis materialized by pauses of the RNA-dependent complex and subsequent jumps to downstream template acceptor sequences. This process results in subgenomic minus-strand RNAs which serve as templates for subgenomic messenger RNAs. Due to the mechanistic similarity to recombination, this process might be at the origin of recombinant CoVs co-opting other CoV or even host-related sequences. 8 Instances include the mouse hepatitis coronavirus S protein NTD sialic acid-binding domain, likely arising from recombination of viral RNA with human galectin RNA sequences. 8 The furin recognition motif present at the SARS-CoV2 S1/S2 junction has no analogy in other "linage B" beta-coronaviruses, including neither pangolin-CoV nor RaTG13. 1 This indicates that the S protein S1/S2 junction is not a hot spot for RNA recombination termination that depends on a pattern swapping templates (copy-choice). 8 In addition, clinical isolates of SARS-CoV-2 S protein have not indicated any further recombination in this S1/S2 area, suggesting that the addition of a motif for S1/S2 site furin cleavage constituted a unique recombination occurrence. Finally, the CoV-unique insertion of four aminoacids creating a novel RRAR furin cleavage site introduces two arginine codons CGG-CGG, whose usage is extremely rare in CoVs, further supporting the hypothesis of a unique recombination occurrence.

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