Molecular chaperones, also known as heat-shock proteins, refold misfolded proteins and help other proteins reach their native conformation. Thanks to these abilities, some chaperones, such as the Hsp90 protein or the chaperonin GroEL, can buffer the deleterious phenotypic effects of mutations that alter protein structure and function. Hsp70 chaperones use a chaperoning mechanism different from Hsp90 and GroEL, and it is not known whether they can also buffer mutations. Here, we show that they can. To this end, we performed a mutation accumulation experiment in Escherichia coli, followed by whole-genome resequencing. Our sequence data shows that overexpression of the Hsp70 chaperone DnaK increases the tolerance of its clients for nonsynonymous nucleotide substitutions and nucleotide insertions and deletions. We also show that this elevated mutational buffering on short evolutionary time scales translates into differences in evolutionary rates on intermediate and long evolutionary time scales. To this end, we compared the evolutionary rates of DnaK clients and nonclients using the genomes of E. coli, Salmonella typhimurium, and 83 other gamma-proteobacterial species. We find that clients that interact strongly with DnaK evolve faster than weakly interacting clients. Our results imply that all three major chaperone classes can buffer mutations and affect protein evolution. They illustrate how an individual protein like a chaperone can have a disproportionate effect on proteome evolution.
Family-joining: A fast distance-based method for constructing generally labeled trees
Prabhav Kalaghatgi, Nico Pfeifer, Thomas Lengauer
The widely used model for evolutionary relationships is a bifurcating tree with all taxa/observations placed at the leaves. This is not appropriate for taxa that have been densely sampled across evolutionary time and may be in a direct ancestral relationship. In this paper, we present a fast distance-based agglomeration method called family-joining (FJ) for constructing so-called generally labeled trees in which taxa may be placed at internal vertices and the tree may contain polytomies. FJ constructs such trees on the basis of pairwise distances and a distance threshold. We tested two methods for threshold selection, FJ-BIC and FJ-CV, which minimize BIC and CV error, respectively. When compared with related methods on simulated data, FJ-BIC was among the best at reconstructing the correct tree across a wide range of simulation scenarios. FJ-BIC was applied to HIV sequences sampled from individuals involved in a known transmission chain. The FJ-BIC tree was found to be compatible with almost all transmission events. On average, internal branches in the FJ-BIC tree have higher bootstrap support than branches in the leaf-labeled bifurcating tree constructed using RAxML. 36% and 25% of the internal branches in the FJ-BIC tree and RAxML tree, respectively, have bootstrap support greater than 70%. To the best of our knowledge the method presented here is the first attempt at modeling the evolutionary relationships of densely sampled pathogens using generally labeled trees.