About: Fitness barriers limit reversion of a proofreading-deficient coronavirus

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An Entity of Type : schema:ScholarlyArticle, within Data Space : covidontheweb.inria.fr associated with source document(s)

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
title	Fitness barriers limit reversion of a proofreading-deficient coronavirus
Creator	Lu, Xiaotao Agostini, Maria Graepel, Kevin Sexton, Nicole Denison,
source	BioRxiv; MedRxiv
abstract	The 3′-to-5′ exoribonuclease in coronavirus (CoV) nonstructural protein 14 (nsp14-ExoN) mediates RNA proofreading during genome replication. ExoN catalytic residues are arranged in three motifs: I (DE), II (E), III (D). Alanine substitution of the motif I residues (AA-E-D, four nucleotide substitutions) in murine hepatitis virus (MHV) and SARS-CoV yields viable mutants with impaired replication and fitness, increased mutation rates, and attenuated virulence in vivo. Despite these impairments, MHV- and SARS-CoV ExoN motif I AA mutants (ExoN-AA) have not reverted at motif I in diverse in vitro and in vivo environments, suggesting that profound fitness barriers prevent motif I reversion. To test this hypothesis, we engineered MHV-ExoN-AA with 1, 2 or 3 nucleotide mutations along genetic pathways to AA-to-DE reversion. We show that engineered intermediate revertants were viable but had no increased replication or competitive fitness compared to MHV-ExoN-AA. In contrast, a low passage (P10) MHV-ExoN-AA showed increased replication and competitive fitness without reversion of ExoN-AA. Finally, engineered reversion of ExoN-AA to ExoN-DE in the presence of ExoN-AA passage-adaptive mutations resulted in significant fitness loss. These results demonstrate that while reversion is possible, at least one alternative adaptive pathway is more rapidly advantageous than intermediate revertants and may alter the genetic background to render reversion detrimental to fitness. Our results provide an evolutionary rationale for lack of ExoN-AA reversion, illuminate potential multi-protein replicase interactions and coevolution, and support future studies aimed at stabilizing attenuated CoV ExoN-AA mutants. Coronaviruses encode an exoribonuclease (ExoN) that is important for viral replication, fitness, and virulence, yet coronaviruses with a defective ExoN (ExoN-AA) have not reverted under diverse experimental conditions. In this study, we identify multiple impediments to MHV-ExoN-AA reversion. We show that ExoN-AA reversion is possible but evolutionarily unfavorable. Instead, compensatory mutations outside of ExoN-AA motif I are more accessible and beneficial than partial reversion. We also show that coevolution between replicase proteins over long-term passage partially compensates for ExoN-AA motif I but renders the virus inhospitable to a reverted ExoN. Our results reveal the evolutionary basis for the genetic stability of ExoN-inactivating mutations, illuminate complex functional and evolutionary relationships between coronavirus replicase proteins, and identify potential mechanisms for stabilization of ExoN-AA coronavirus mutants.
has issue date	2019-04-26(xsd:dateTime)
bibo:doi	10.1101/618249
has license	medrxiv
sha1sum (hex)	d82fe700418fb6494ffb9a2c0cf4f6b8012b3824
schema:url	https://doi.org/10.1101/618249
resource representing a document's title	Fitness barriers limit reversion of a proofreading-deficient coronavirus
schema:publication	bioRxiv
resource representing a document's body	covid:d82fe700418fb6494ffb9a2c0cf4f6b8012b3824#body_text
is schema:about of	named entity 'replication' named entity 'motif' named entity 'nucleotide' named entity 'illuminate' named entity 'background' »more»

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