Constrained Mutational Sampling of Amino Acids in HIV-1 Protease Evolution.

Autor:	Boucher JI; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA., Whitfield TW; Department of Medicine, University of Massachusetts Medical School, Worcester, MA.; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA., Dauphin A; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA., Nachum G; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA., Hollins C; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA., Zeldovich KB; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA., Swanstrom R; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC., Schiffer CA; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA., Luban J; Department of Medicine, University of Massachusetts Medical School, Worcester, MA.; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA., Bolon DNA; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA.
Jazyk:	angličtina
Zdroj:	Molecular biology and evolution [Mol Biol Evol] 2019 Apr 01; Vol. 36 (4), pp. 798-810.
DOI:	10.1093/molbev/msz022
Abstrakt:	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 is 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 data set of 32,163 sequenced isolates from drug-naïve 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. (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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