Synonymous Mutations at the Beginning of the Influenza A Virus Hemagglutinin Gene Impact Experimental Fitness
AuthorsCanale, Aneth S.
Venev, Sergey V.
Whitfield, Troy W.
Caffrey, Daniel R.
Marasco, Wayne A.
Schiffer, Celia A.
Kowalik, Timothy F.
Jensen, Jeffrey D.
Finberg, Robert W.
Zeldovich, Konstantin B.
Wang, Jennifer P.
Bolon, Daniel N.
UMass Chan AffiliationsSchiffer Lab
Department of Microbiology and Physiological Systems
Department of Medicine
Program in Bioinformatics and Integrative Biology
Department of Biochemistry and Molecular Pharmacology
Document TypeJournal Article
Keywordsdeep mutational scanning
influenza A virus
Ecology and Evolutionary Biology
Medicinal Chemistry and Pharmaceutics
Nucleic Acids, Nucleotides, and Nucleosides
MetadataShow full item record
AbstractThe fitness effects of synonymous mutations can provide insights into biological and evolutionary mechanisms. We analyzed the experimental fitness effects of all single-nucleotide mutations, including synonymous substitutions, at the beginning of the influenza A virus hemagglutinin (HA) gene. Many synonymous substitutions were deleterious both in bulk competition and for individually isolated clones. Investigating protein and RNA levels of a subset of individually expressed HA variants revealed that multiple biochemical properties contribute to the observed experimental fitness effects. Our results indicate that a structural element in the HA segment viral RNA may influence fitness. Examination of naturally evolved sequences in human hosts indicates a preference for the unfolded state of this structural element compared to that found in swine hosts. Our overall results reveal that synonymous mutations may have greater fitness consequences than indicated by simple models of sequence conservation, and we discuss the implications of this finding for commonly used evolutionary tests and analyses.
J Mol Biol. 2018 Apr 13;430(8):1098-1115. doi: 10.1016/j.jmb.2018.02.009. Epub 2018 Feb 18. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/48881