Three adjacent nucleotide changes spanning two residues in SARS-CoV-2 nucleoprotein: possible homologous recombination from the transcription-regulating sequence

Shay Leary; Silvana Gaudieri; Abha Chopra; Suman Pakala; Eric Alves; Mina John; Suman Das; Simon Mallal; Phillips Jane Phillips

The rapid emergence of these closely linked polymorphisms in viruses may reflect strong selection pressure on this region of the genome in which the original mutation incurred a replicative capacity, or other fitness cost, which could be restored by a linked compensatory mutation. Evidence for such adaptations with closely linked compensatory mutations are known to occur under host immune pressure as is well established for other adaptable RNA viruses such as HIV 1,2 and Hepatitis C virus (HCV) 3 . These viruses have such a high rate of viral replication and error-prone reverse transciptase that a massive swarm of viral variants with ongoing recombination between residues is generated continuously. As a result selection pressure exerted by immune responses or other selective pressures effectively operate on each separate residue independently 4 . In contrast, coronaviruses encode proofreading machinery and have a propensity to adapt by homologous recombination between viruses rather than classic step-wise individual mutations driven by selective pressures operating on single viral residues. This, together with the routine nature of their cross-species transmission 5 , led Graham and Baric 6 to presciently warn in 2010 that it was a matter of when, rather than if, a pathogenic coronavirus pandemic would occur in humans. Also of note, the phenomena of compensatory fixation has been described in the area of HIV antiviral resistance in which the linked mutations cannot author/funder. All rights reserved. No reuse allowed without permission.