Hsp90 shapes adaptation by controlling the fitness consequences of regulatory variation.
Hsp90 shapes adaptation by controlling the fitness consequences of regulatory variation.
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Hsp90 通过控制调节变异的适应性后果来塑造适应性。
DOI：
10.1101/2023.10.30.564848
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Jarosz,DanielF
中科院分区：
文献类型：
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作者：
Jakobson,ChristopherM;Aguilar-Rodríguez,José;Jarosz,DanielF
重要的应激反应伴侣蛋白Hsp90影响微生物对人类的发育和适应。然而，尽管有证据表明Hsp90在进化、发病机制和致癌转化中的作用，但Hsp90改变突变后果的分子机制仍存在激烈的争论。在这里，我们利用在酿酒酵母核苷酸分辨率遗传作图的力量，揭示了1000多种由这种分子伴侣控制的自然变异-表型关联。引人注目的是，Hsp90比改变蛋白质序列的变异更频繁地改变顺式调控变异的表型效应。此外，这些相互作用对hsp90依赖性遗传的贡献最大。几乎所有的相互作用变异——包括调控和蛋白质编码——都在Hsp90的客户或其直接结合伙伴的目标范围内。Hsp90活性影响进化年轻基因、片段缺失和杂合子的突变，突出了它对进化新颖性变异的影响。为了协调这种伴侣蛋白的多种上位性作用，通过基因组编辑对天然等位基因进行合成转录调控和重建，揭示了Hsp90在调节活性和表型之间的基本关系中的核心作用。我们的研究结果表明，非编码变异是Hsp90对遗传影响的核心驱动因素，为伴侣蛋白对物种进化和发育的强烈影响提供了机制解释。
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.