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Constrained mutational sampling of amino acids in HIV-1 protease evolution
Authors
Boucher, Jeffrey I.Whitfield, Troy W.
Dauphin, Ann
Nachum, Gily S.
Hollins, Carl III
Zeldovich, Konstantin B.
Swanstrom, Ronald
Schiffer, Celia A.
Luban, Jeremy
Bolon, Daniel N A
UMass Chan Affiliations
Schiffer LabProgram in Molecular Medicine
Program in Bioinformatics and Integrative Biology
Department of Medicine
Department of Biochemistry and Molecular Pharmacology
Document Type
Journal ArticlePublication Date
2019-02-04Keywords
fitness landscapemutation
HIV
Amino Acids, Peptides, and Proteins
Biochemistry, Biophysics, and Structural Biology
Ecology and Evolutionary Biology
Genetic Phenomena
Genetics and Genomics
Nucleic Acids, Nucleotides, and Nucleosides
Viruses
Metadata
Show full item recordAbstract
The evolution of HIV-1 protein sequences should be governed by a combination of factors including nucleotide mutational probabilities, the genetic code, and fitness. The impact of these factors on protein sequence evolution are interdependent, making it challenging to infer the individual contribution of each factor from phylogenetic analyses alone. We investigated the protein sequence evolution of HIV-1 by determining an experimental fitness landscape of all individual amino acid changes in protease. We compared our experimental results to the frequency of protease variants in a publicly available dataset of 32,163 sequenced isolates from drug-naive individuals. The most common amino acids in sequenced isolates supported robust experimental fitness, indicating that the experimental fitness landscape captured key features of selection acting on protease during viral infections of hosts. Amino acid changes requiring multiple mutations from the likely ancestor were slightly less likely to support robust experimental fitness than single mutations, consistent with the genetic code favoring chemically conservative amino acid changes. Amino acids that were common in sequenced isolates were predominantly accessible by single mutations from the likely protease ancestor. Multiple mutations commonly observed in isolates were accessible by mutational walks with highly fit single mutation intermediates. Our results indicate that the prevalence of multiple base mutations in HIV-1 protease is strongly influenced by mutational sampling.Source
Mol Biol Evol. 2019 Feb 4. pii: 5306343. doi: 10.1093/molbev/msz022. [Epub ahead of print] Link to article on publisher's site
DOI
10.1093/molbev/msz022Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29381PubMed ID
30721995Related Resources
ae974a485f413a2113503eed53cd6c53
10.1093/molbev/msz022