Synonymous Mutations at the Beginning of the Influenza A Virus Hemagglutinin Gene Impact Experimental Fitness

Aneth S. Canale, Sergey V. Venev, Troy W. Whitfield, Daniel R. Caffrey, Wayne A. Marasco, Celia A. Schiffer, Timothy F. Kowalik, Jeffrey Jensen, Robert W. Finberg, Konstantin B. Zeldovich, Jennifer P. Wang, Daniel N.A. Bolon

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


The 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.

Original languageEnglish (US)
Pages (from-to)1098-1115
Number of pages18
JournalJournal of molecular biology
Issue number8
StatePublished - Apr 13 2018


  • deep mutational scanning
  • experimental evolution
  • influenza A virus
  • selection
  • synonymous mutations

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Molecular Biology


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