Introduction: The chaperone Hsp90 decreases variation in quantitative traits by buffering the effects of polymorphisms found in nature. This result prompts a question: does Hsp90 increase an organism’s robustness to genetic perturbation? The potential for Hsp90 and several other putative buffers to increase robustness to mutation has had a major impact on disease models, quantitative genetics and evolutionary theory. But perhaps Hsp90-buffered mutations are rare, yet appear prevalent in nature because stabilizing selection cannot act efficiently on such mutations. This may allow buffered mutations to persist, while other mutations that have immediate effects on phenotype are purged.
Methods: We measure how Hsp90 inhibition affects phenotypic variation among 174 yeast strains that experienced reduced selection as well as 96 yeast strains that experienced natural or artificial selection. We measure 29 orthogonal quantitative traits related to cell morphology for two million yeast cells in control or Hsp90-inhibited conditions. Ours is the first study to rigorously quantify how Hsp90 influences variance in quantitative traits by using statistics that partition multiple contributions to variance.
Results: Hsp90 tends to decrease quantitative trait variation among populations that have been exposed to selection. In contrast, Hsp90 predominantly increases quantitative trait variation between yeast strains possessing spontaneous mutations that accumulated under reduced selection.
Conclusions: Hsp90 does not make phenotypes more robust to mutations’ effects. Stabilizing selection preferentially allows buffered alleles to persist, transforming the pool of Hsp90-interacting genetic variation found in natural populations to leave the false impression of robustness.
Other selective regimes: Adaptive evolution may enrich for different types of Hsp90-interacting genetic variation. We very recently tested how Hsp90 influences fitness of 82 yeast lineages that each contain on average a single adaptive mutation in one of eleven genes involved in glucose metabolism. Preliminary results show that the presence and direction of Hsp90-induced changes in fitness depend upon which gene contains the mutation. Understanding how hub proteins, like Hsp90, influence the relationship between genetic variation and quantitative traits, and how selection’s sieve enriches for certain relationships, will contribute unique knowledge to the larger goal of mapping genotype to phenotype.