Molecular Chaperones Accelerate the Evolution of Their Protein Clients in Yeast

Abstract

Protein stability is a major constraint on protein evolution. Molecular chaperones, also known as heat-shock proteins, can relax this constraint and promote protein evolution by diminishing the deleterious effect of mutations on protein stability and folding. This effect, however, has only been stablished for a few chaperones. Here, we use a comprehensive chaperone-protein interaction network to study the effect of all yeast chaperones on the evolution of their protein substrates, that is, their clients. In particular, we analyze how yeast chaperones affect the evolutionary rates of their clients at two very different evolutionary time scales. We first study the effect of chaperone-mediated folding on protein evolution over the evolutionary divergence of Saccharomyces cerevisiae and S. paradoxus. We then test whether yeast chaperones have left a similar signature on the patterns of standing genetic variation found in modern wild and domesticated strains of S. cerevisiae. We find that genes encoding chaperone clients have diverged faster than genes encoding non-client proteins when controlling for their number of protein-protein interactions. We also find that genes encoding client proteins have accumulated more intraspecific genetic diversity than those encoding non-client proteins. In a number of multivariate analyses, controlling by other well-known factors that affect protein evolution, we find that chaperone dependence explains the largest fraction of the observed variance in the rate of evolution at both evolutionary time scales. Chaperones affecting rates of protein evolution mostly belong to two major chaperone families: Hsp70s and Hsp90s. Our analyses show that protein chaperones, by virtue of their ability to buffer destabilizing mutations and their role in modulating protein genotype-phenotype maps, have a considerable accelerating effect on protein evolution.

Keywords: d N/dS; molecular chaperones; mutational robustness; protein evolution.

Fig. 1.

—Rates of evolution of yeast chaperone clients and non-clients. Outliers (those above the 90th and below the 10th percentiles) are not shown. Significance levels: *P < 0.05, **P < 0.001, and ***P < 10⁻⁵.

Fig. 2.

—Comparison of the rate of evolution of clients and non-clients with different numbers of protein-protein interactions. Clients are represented in gray and non-clients in white. Outliers (those above the 90th and below the 10th percentiles) are not shown.

Fig. 3.

—Principal component regression on (A) d_N/d_S, (B) d_N, and (C) d_S calculated using divergence data between Saccharomyces cerevisiae and S. paradoxus for 5,532 yeast genes. For each principal component, the height of the bar represents the percent of variance in the rate of evolution explained by the component. The relative contribution of each variable to a principal component is represented with different colors. Table 3 contains the numerical data used to draw this figure.

Fig. 4.

—ANCOVA. Chaperone clients (gray points, continuous line) evolve 23% above the genome average rate (light points, dashed line) when considering divergence data between Saccharomyces cerevisiae and S. paradoxus.

Fig. 5.

—Principal component regression on (A) d_N/d_S, (B) d_N, and (C) d_S calculated using divergence data between Saccharomyces cerevisiae and S. paradoxus for 5,532 yeast genes. For each principal component, the height of the bar represents the percent of variance in the rate of evolution explained by the component. The relative contribution of each variable to a principal component is represented with different colors. Table 8 contains the numerical data used to draw this figure.

Fig. 6.

—Principal component regression on d_N/d_S calculated using genetic variants segregating in Saccharomyces cerevisiae for 6,132 yeast genes. For each principal component, the height of the bar represents the percent of variance in the rate of evolution explained by the component. The relative contribution of each variable to a principal component is represented with different colors. Table 13 contains the numerical data used to draw this figure.

Fig. 7.

—ANCOVA. Chaperone clients (gray points, continuous line) evolve 19.2% above the genome average rate (light points, dashed line) when considering genetic variants segregating in Saccharomyces cerevisiae.