An experimentally informed evolutionary model improves phylogenetic fit to divergent lactamase homologs.

Publication Type:

Journal Article


Molecular biology and evolution, Volume 31, Issue 8, p.1956-78 (2014)


2014, August 2014, Basic Sciences Division, Center-Authored Paper, Genomics Core Facility, Public Health Sciences Division, Shared Resources


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 et al., 2014) can be combined with a few mutation rate parameters to create an evolutionary model that describes beta-lactamase phylogenies much 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.