Selection Transforms the Landscape of Genetic Variation Interacting with Hsp90

Abstract

The protein-folding chaperone Hsp90 has been proposed to buffer the phenotypic effects of mutations. The potential for Hsp90 and other putative buffers to increase robustness to mutation has had major impact on disease models, quantitative genetics, and evolutionary theory. But Hsp90 sometimes contradicts expectations for a buffer by potentiating rapid phenotypic changes that would otherwise not occur. Here, we quantify Hsp90’s ability to buffer or potentiate (i.e., diminish or enhance) the effects of genetic variation on single-cell morphological features in budding yeast. We corroborate reports that Hsp90 tends to buffer the effects of standing genetic variation in natural populations. However, we demonstrate that Hsp90 tends to have the opposite effect on genetic variation that has experienced reduced selection pressure. Specifically, Hsp90 tends to enhance, rather than diminish, the effects of spontaneous mutations and recombinations. This result implies that Hsp90 does not make phenotypes more robust to the effects of genetic perturbation. Instead, natural selection preferentially allows buffered alleles to persist and thereby creates the false impression that Hsp90 confers greater robustness.

Modifiers of the Genotype–Phenotype Map: Hsp90 and Beyond

“…Given that the MA lines have not been exposed to selection and the isolates have, this result implies that Hsp90 predominantly acts as a potentiator and that selection has acted against Hsp90-potentiated phenotypic variation in nature. Consistent with this interpretation, cross progeny that carry new combinations of standing variants also show reduced heritable phenotypic variation upon Hsp90 perturbation [15]. This finding suggests that standing variants with Hsp90-potentiated effects are common in nature, but combinations of these variants that produce extreme phenotypes are selected against.…”

“…In this issue of PLOS Biology , Geiler-Samerotte, Siegal, and coauthors measure the degree to which Hsp90 buffers and potentiates the effects of new mutations [15]. To do this, the authors utilize a panel of yeast mutation accumulation (MA) lines, which accrued mutations during many generations of growth in the absence of selection.…”

“…Following Hsp90 impairment, heritable phenotypic variation is reduced in the MA lines but increased in the isolates [15]. Given that the MA lines have not been exposed to selection and the isolates have, this result implies that Hsp90 predominantly acts as a potentiator and that selection has acted against Hsp90-potentiated phenotypic variation in nature.…”

Control of Hsp90 chaperone and its clients by N-terminal acetylation and the N-end rule pathway

“…Because of its ability to modulate protein conformations, the Hsp90 system can either exacerbate or counteract the fitness-reducing effects of mutations in cellular proteins. This property of Hsp90 affects the standing genetic variation and thereby influences the impact of natural selection on rates and directions of evolution (13,14).The N-end rule pathways comprise a set of proteolytic systems whose unifying feature is their ability to recognize proteins containing N-terminal (Nt) degradation signals called N-degrons, thereby causing the degradation of these proteins by the proteasome or autophagy in eukaryotes and by the proteasome-like ClpAP protease in bacteria (Fig. 1) (15-26).…”

“…Because of its ability to modulate protein conformations, the Hsp90 system can either exacerbate or counteract the fitness-reducing effects of mutations in cellular proteins. This property of Hsp90 affects the standing genetic variation and thereby influences the impact of natural selection on rates and directions of evolution (13,14).…”