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[Preprint]. 2020 Jun 10:2020.06.09.134460. [Version 1] doi: 10.1101/2020.06.09.134460

A Rare Deletion in SARS-CoV-2 ORF6 Dramatically Alters the Predicted Three-Dimensional Structure of the Resultant Protein

Marco A Riojas, Andrew M Frank, Nikhita P Puthuveetil, Beth Flores, Michael Parker, Stephen P King, Malik Peiris, Daniel K W Chu, Briana Benton, Rebecca Bradford, Manzour Hernando Hazbón, Sujatha Rashid
PMCID: PMC7302196  PMID: 32577643

Abstract

The function of the SARS-CoV-2 accessory protein p6, encoded by ORF6, is not fully known. Based upon its similarity to p6 from SARS-CoV, it may play a similar role, namely as an antagonist of type I interferon (IFN) signaling. Here we report the sequencing of a SARS-CoV-2 strain passaged six times after original isolation from a clinical patient in Hong Kong. The genome sequence shows a 27 nt in-frame deletion (Δ27,264-27,290) within ORF6, predicted to result in a 9 aa deletion ( ΔFKVSIWNLD ) from the central portion of p6. This deletion is predicted to result in a dramatic alteration in the three-dimensional structure of the resultant protein (p6 Δ22-30 ), possibly with significant functional implications. Analysis of the original clinical sample indicates that the deletion was not present, while sequencing of subsequent passages of the strain identifies the deletion as a majority variant. This suggests that the deletion originated ab initio during passaging and subsequently propagated into the majority, possibly due to the removal of selective pressure through the IFN-deficient Vero E6 cell line. The specific function of the SARS-CoV-2 p6 N-terminus, if any, has not yet been determined. However, this deletion is predicted to cause a shift from N-endo to N-ecto in the transmembrane localization of the SARS-CoV-2 p6 Δ22-30 N-terminus, possibly leading to the ablation of its native function.

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