ΦX174 Attenuation by Whole-Genome Codon Deoptimization.
bacteriophage
codon bias
epistasis
fitness landscape
live-attenuated vaccine
synthetic biology
Journal
Genome biology and evolution
ISSN: 1759-6653
Titre abrégé: Genome Biol Evol
Pays: England
ID NLM: 101509707
Informations de publication
Date de publication:
03 02 2021
03 02 2021
Historique:
accepted:
07
10
2020
pubmed:
13
10
2020
medline:
24
12
2021
entrez:
12
10
2020
Statut:
ppublish
Résumé
Natural selection acting on synonymous mutations in protein-coding genes influences genome composition and evolution. In viruses, introducing synonymous mutations in genes encoding structural proteins can drastically reduce viral growth, providing a means to generate potent, live-attenuated vaccine candidates. However, an improved understanding of what compositional features are under selection and how combinations of synonymous mutations affect viral growth is needed to predictably attenuate viruses and make them resistant to reversion. We systematically recoded all nonoverlapping genes of the bacteriophage ΦX174 with codons rarely used in its Escherichia coli host. The fitness of recombinant viruses decreases as additional deoptimizing mutations are made to the genome, although not always linearly, and not consistently across genes. Combining deoptimizing mutations may reduce viral fitness more or less than expected from the effect size of the constituent mutations and we point out difficulties in untangling correlated compositional features. We test our model by optimizing the same genes and find that the relationship between codon usage and fitness does not hold for optimization, suggesting that wild-type ΦX174 is at a fitness optimum. This work highlights the need to better understand how selection acts on patterns of synonymous codon usage across the genome and provides a convenient system to investigate the genetic determinants of virulence.
Identifiants
pubmed: 33045052
pii: 5921183
doi: 10.1093/gbe/evaa214
pmc: PMC7881332
pii:
doi:
Substances chimiques
Codon
0
Viral Vaccines
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIGMS NIH HHS
ID : P20 GM104420
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM076040
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
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