title: An experimentally informed evolutionary model improves phylogenetic fit to divergent lactamase homologs.
abstract: Phylogenetic analyses of molecular data require a quantitative model for how sequences evolve. Traditionally, the details of the site-specific selection that governs sequence evolution are not known a priori, making it challenging to create evolutionary models that adequately capture the heterogeneity of selection at different sites. However, recent advances in high-throughput experiments have made it possible to quantify the effects of all single mutations on gene function. I have previously shown that such high-throughput experiments can be combined with knowledge of underlying mutation rates to create a parameter-free evolutionary model that describes the phylogeny of influenza nucleoprotein far better than commonly used existing models. Here, I extend this work by showing that published experimental data on TEM-1 beta-lactamase (Firnberg E, Labonte JW, Gray JJ, Ostermeier M. 2014. A comprehensive, high-resolution map of a gene's fitness landscape. Mol Biol Evol. 31:1581-1592) can be combined with a few mutation rate parameters to create an evolutionary model that describes beta-lactamase phylogenies much better than most common existing models. This experimentally informed evolutionary model is superior even for homologs that are substantially diverged (about 35% divergence at the protein level) from the TEM-1 parent that was the subject of the experimental study. These results suggest that experimental measurements can inform phylogenetic evolutionary models that are applicable to homologs that span a substantial range of sequence divergence.
authors: Division of Basic Sciences and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA jbloom@fhcrc.org.
authors: Jesse D
authors: JD
authors: Bloom
mesh_terms: D000465:Algorithms; D004252:DNA Mutational Analysis; D056084:Genetic Fitness; D008958:Models, Molecular; D059645:Mutation Rate; D010802:Phylogeny; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D001618:beta-Lactamases / Q000235:genetics*
chemical_list: D001618:beta-Lactamases; C034413:beta-lactamase TEM-1
keywords: deep mutational scanning; lactamase; phylogenetics; protein evolution; substitution model