Selection Transforms the Landscape of Genetic Variation Interacting with Hsp90.
Selection Transforms the Landscape of Genetic Variation Interacting with Hsp90.
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DOI：
10.1371/journal.pbio.2000465
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发表时间：
2016-10
期刊：
影响因子：
9.8
通讯作者：
Siegal ML
中科院分区：
文献类型：
--
作者：
Geiler-Samerotte KA;Zhu YO;Goulet BE;Hall DW;Siegal ML
蛋白质折叠分子伴侣Hsp90已被提出来缓冲突变的表型效应。Hsp90和其他推定缓冲剂增强突变鲁棒性的潜力对疾病模型、数量遗传学和进化理论产生了重大影响。但是，热休克蛋白90有时会通过增强原本不会发生的快速表型变化而与人们对缓冲剂的期望相矛盾。在这里，我们量化了Hsp90缓冲或增强的能力（即，减少或增强）遗传变异对芽殖酵母中单细胞形态特征的影响。我们证实报告，热休克蛋白90往往缓冲的影响，常设的遗传变异在自然种群。然而，我们表明，热休克蛋白90往往有相反的影响，经历了减少选择压力的遗传变异。具体来说，热休克蛋白90往往会增强，而不是减少，自发突变和重组的影响。这一结果表明，热休克蛋白90并没有使表型更强大的遗传扰动的影响。相反，自然选择优先允许缓冲的等位基因持续存在，从而造成Hsp90赋予更大鲁棒性的错误印象。大多数生物学家都认为自然选择会过滤掉新的突变（例如，通过消除有害的），这样自然界中的遗传变异是有偏见的。选择也会扭曲自然界中存在的遗传相互作用的类型，这一观点不太受欢迎。例如，对不同物种的研究表明，有助于其他蛋白质正确折叠的Hsp90蛋白往往会减少遗传变异的可观察影响。这一观察结果导致了这样的假设，即Hsp90也缓冲了新突变的影响。这一未经检验的假设已经成为癌症治疗策略的基本原理，并塑造了我们对复杂性状变异的理解。我们测量了新突变对单个酵母细胞形状和大小的影响，发现Hsp90并不倾向于缓冲这些影响。相反，Hsp90以不同的方式与新的突变相互作用，有时缓冲，但更经常地增强对细胞形状和大小的突变效应。我们的结论是，选择优先允许缓冲突变在自然群体中持续存在。这一结果改变了人们对为什么神秘（即，缓冲的）遗传变异的存在，并对旨在靶向突变效应的假定缓冲区的癌症治疗策略产生怀疑。
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. Most biologists appreciate that natural selection filters new mutations (e.g., by eliminating deleterious ones), such that genetic variation in nature is biased. The idea that selection also skews the types of genetic interactions that exist in nature is less appreciated. For example, studies spanning diverse species have shown that the protein Hsp90, which helps other proteins to fold properly, tends to diminish the observable effects of genetic variation. This observation has led to the assumption that Hsp90 also buffers the effects of new mutations. This untested assumption has served as a rationale for cancer-treatment strategies and shaped our understanding of variation in complex traits. We measured the effects of new mutations on the shapes and sizes of individual yeast cells and found that Hsp90 does not tend to buffer these effects. Instead, Hsp90 interacts with new mutations in diverse ways, sometimes buffering, but more often enhancing mutational effects on cell shape and size. We conclude that selection preferentially allows buffered mutations to persist in natural populations. This result alters common perceptions about why cryptic (i.e., buffered) genetic variation exists and casts doubt on cancer-treatment strategies aiming to target presumed buffers of mutational effects.
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影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
影响因子：
3.3
作者：
Masel, J
通讯作者：
Masel, J
影响因子：
16
作者：
Hsieh, Yu-Ying;Hung, Po-Hsiang;Leu, Jun-Yi
通讯作者：
Leu, Jun-Yi
影响因子：
7
作者：
Elyashiv, Eyal;Bullaughey, Kevin;Sella, Guy
通讯作者：
Sella, Guy
DOI：
10.1126/science.1166426
发表时间：
2009-01-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gerke J;Lorenz K;Cohen B
通讯作者：
Cohen B