Functional Constraint Profiling of a Viral Protein Reveals Discordance of Evolutionary Conservation and Functionality
By Nicholas C. Wu, C. A. Olson, Yushen Du, Shuai Le, K. Tran, Roland Remenyi, D. Gong, Laith Q. Al‐Mawsawi, Hangfei Qi, Ting-Ting Wu and 1 more. 2015
66 citations recorded by the source corpus.
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.
Subfields: Epidemiology, Molecular Biology
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Citations in the corpus
- Using deep mutational scanning to benchmark variant effect predictors and identify disease mutations (2020, unknown): “Viral replication assays, performed by quantitative sequencing after a certain time point, were applied to all of the viral proteins (Wu et al , 2015; Doud & Bloom, 2016; Haddox et al , 2016; Lee et al , 2018).”
- Accurate Measurement of the Effects of All Amino-Acid Mutations on Influenza Hemagglutinin (2016, background): “A second strategy is to reduce the impact of bottlenecks by shrinking the complexity of the libraries, such as by only mutating a small portion of a viral gene [18,19].”