Hsp90 shapes adaptation by controlling the fitness consequences of regulatory variation

The essential stress-responsive chaperone Hsp90 impacts development and adaptation from microbes to humans. Yet despite evidence of its role in evolution, pathogenesis, and oncogenic transformation, the molecular mechanisms by which Hsp90 alters the consequences of mutations remain vigorously debated. Here we exploit the power of nucleotide-resolution genetic mapping in Saccharomyces cerevisiae to uncover more than 1,000 natural variant-to-phenotype associations governed by this molecular chaperone. Strikingly, Hsp90 more frequently modified the phenotypic effects of cis-regulatory variation than variants that altered protein sequence. Moreover, these interactions made the largest contribution to Hsp90-dependent heredity. Nearly all interacting variants—both regulatory and protein-coding—fell within clients of Hsp90 or targets of its direct binding partners. Hsp90 activity affected mutations in evolutionarily young genes, segmental deletions, and heterozygotes, highlighting its influence on variation central to evolutionary novelty. Reconciling the diverse epistatic effects of this chaperone, synthetic transcriptional regulation and reconstructions of natural alleles by genome editing revealed a central role for Hsp90 in regulating the fundamental relationship between activity and phenotype. Our findings establish that non-coding variation is a core driver of Hsp90’s influence on heredity, offering a mechanistic explanation for the chaperone’s strong effects on evolution and development across species.核心应激响应分子伴侣热休克蛋白90（Hsp90）可影响从微生物到人类的发育与适应性过程。尽管已有证据表明其在进化、致病过程及致癌转化中发挥作用，但Hsp90改变突变后果的分子机制仍存在广泛争议。本研究借助酿酒酵母（Saccharomyces cerevisiae）中的核苷酸分辨率遗传定位技术，揭示了该分子伴侣调控的1000余条自然变异-表型关联。值得注意的是，相较于改变蛋白质序列的变异，Hsp90更频繁地修饰顺式调控变异的表型效应。此外，这类相互作用对依赖Hsp90的遗传效应贡献最大。几乎所有发生相互作用的变异——包括调控型变异与蛋白编码变异——均属于Hsp90的客户蛋白或其直接结合伴侣的靶标范围。Hsp90的活性可影响进化年轻基因、片段缺失及杂合子中的突变，凸显其对进化新性状相关变异的调控作用。为解析该分子伴侣多样的上位效应，本研究通过合成转录调控与基因组编辑构建天然等位基因的实验证实，Hsp90在调控活性与表型间的基础关系中发挥核心作用。本研究结果证实，非编码变异是Hsp90影响遗传性状的核心驱动因素，为该分子伴侣对跨物种进化与发育的显著调控效应提供了机制层面的解释。