Functional Constraint Profiling of a Viral Protein Reveals Discordance of Evolutionary Conservation and Functionality

Nicholas C. Wu, C. Anders Olson, Yushen Du, Shuai Le, Kevin Tran, Roland Remenyi, Danyang Gong, Laith Q. Al-Mawsawi, Hangfei Qi, Ting Ting Wu, Ren Sun

Research output: Contribution to journalArticlepeer-review


Viruses often encode proteins with multiple functions due to their compact genomes. Existing approaches to identify functional residues largely rely on sequence conservation analysis. Inferring functional residues from sequence conservation can produce false positives, in which the conserved residues are functionally silent, or false negatives, where functional residues are not identified since they are species-specific and therefore non-conserved. Furthermore, the tedious process of constructing and analyzing individual mutations limits the number of residues that can be examined in a single study. Here, we developed a systematic approach to identify the functional residues of a viral protein by coupling experimental fitness profiling with protein stability prediction using the influenza virus polymerase PA subunit as the target protein. We identified a significant number of functional residues that were influenza type-specific and were evolutionarily non-conserved among different influenza types. Our results indicate that type-specific functional residues are prevalent and may not otherwise be identified by sequence conservation analysis alone. More importantly, this technique can be adapted to any viral (and potentially non-viral) protein where structural information is available.

Original languageEnglish (US)
Article numbere1005310
JournalPLoS genetics
Issue number7
StatePublished - Jul 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research


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