Evidence for Strong Mutation Bias toward, and Selection against, U Content in SARS-CoV-2: Implications for Vaccine Design.
SARS-CoV-2
mutation equilibrium
selection
synonymous mutations
vaccine design
viral attenuation
Journal
Molecular biology and evolution
ISSN: 1537-1719
Titre abrégé: Mol Biol Evol
Pays: United States
ID NLM: 8501455
Informations de publication
Date de publication:
04 01 2021
04 01 2021
Historique:
pubmed:
21
7
2020
medline:
13
1
2021
entrez:
21
7
2020
Statut:
ppublish
Résumé
Large-scale re-engineering of synonymous sites is a promising strategy to generate vaccines either through synthesis of attenuated viruses or via codon-optimized genes in DNA vaccines. Attenuation typically relies on deoptimization of codon pairs and maximization of CpG dinucleotide frequencies. So as to formulate evolutionarily informed attenuation strategies that aim to force nucleotide usage against the direction favored by selection, here, we examine available whole-genome sequences of SARS-CoV-2 to infer patterns of mutation and selection on synonymous sites. Analysis of mutational profiles indicates a strong mutation bias toward U. In turn, analysis of observed synonymous site composition implicates selection against U. Accounting for dinucleotide effects reinforces this conclusion, observed UU content being a quarter of that expected under neutrality. Possible mechanisms of selection against U mutations include selection for higher expression, for high mRNA stability or lower immunogenicity of viral genes. Consistent with gene-specific selection against CpG dinucleotides, we observe systematic differences of CpG content between SARS-CoV-2 genes. We propose an evolutionarily informed approach to attenuation that, unusually, seeks to increase usage of the already most common synonymous codons. Comparable analysis of H1N1 and Ebola finds that GC3 deviated from neutral equilibrium is not a universal feature, cautioning against generalization of results.
Identifiants
pubmed: 32687176
pii: 5873882
doi: 10.1093/molbev/msaa188
pmc: PMC7454790
doi:
Substances chimiques
COVID-19 Vaccines
0
RNA, Messenger
0
RNA, Viral
0
Uracil
56HH86ZVCT
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
67-83Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : European Research Council
ID : ERC-2014-ADG 669207
Pays : International
Organisme : Wellcome Trust
ID : 207507
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
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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