Ensemble epistasis: thermodynamic origins of nonadditivity between mutations.
Ensemble epistasis: thermodynamic origins of nonadditivity between mutations.
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DOI：
10.1093/genetics/iyab105
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发表时间：
2021-08-26
期刊：
影响因子：
3.3
通讯作者：
Harms MJ
中科院分区：
文献类型：
--
作者：
Morrison AJ;Wonderlick DR;Harms MJ
当突变以非相加的方式联合收割机结合时，上位性是生物学的一个极其重要的方面。通常很难理解它的机械起源。在这里，我们表明，上位性可以产生的热力学合奏，或交换构象的蛋白质采用的集合。突变上位性的发生是因为突变可以对同一蛋白质的不同构象产生不同的影响，导致其平均可观察性质的非加性效应。使用一个简单的分析模型，我们发现，合奏上位性出现时，满足两个条件：（1）一个蛋白质人口至少有三个构象和（2）突变至少有两个构象的差异影响。为了探索整体上位性的相对大小，我们对变构信号蛋白S100A4进行了虚拟深度突变扫描。我们发现47%的突变对表现出总体上位性，其幅度相当于热波动的量级。我们观察到许多形式的上位性：量上位性、符号上位性和互符号上位性。同一突变对在不同的环境条件下甚至可以表现出不同形式的上位性。热力学系综在生物学中的普遍存在以及系综上位性在我们数据集中的普遍存在表明，它可能是蛋白质和其他大分子中上位性的常见机制。解决上位性的机制起源是理解基因型如何决定表型的关键。在这里，莫里森、旺德利克和哈姆斯研究了“总体上位论”的可解释性。大分子通常采用一组称为热力学系综的互换结构。突变可以改变每个结构的相对群体，改变未来突变的影响。有利于系综上位性的条件在大分子中是普遍的，作者得出结论，热力学系综是分子内上位性的关键来源
Epistasis—when mutations combine nonadditively—is a profoundly important aspect of biology. It is often difficult to understand its mechanistic origins. Here, we show that epistasis can arise from the thermodynamic ensemble, or the set of interchanging conformations a protein adopts. Ensemble epistasis occurs because mutations can have different effects on different conformations of the same protein, leading to nonadditive effects on its average, observable properties. Using a simple analytical model, we found that ensemble epistasis arises when two conditions are met: (1) a protein populates at least three conformations and (2) mutations have differential effects on at least two conformations. To explore the relative magnitude of ensemble epistasis, we performed a virtual deep-mutational scan of the allosteric signaling protein S100A4. We found that 47% of mutation pairs exhibited ensemble epistasis with a magnitude on the order of thermal fluctuations. We observed many forms of epistasis: magnitude, sign, and reciprocal sign epistasis. The same mutation pair could even exhibit different forms of epistasis under different environmental conditions. The ubiquity of thermodynamic ensembles in biology and the pervasiveness of ensemble epistasis in our dataset suggests that it may be a common mechanism of epistasis in proteins and other macromolecules. Addressing the mechanistic origins of epistasis is critical to understanding how genotype determines phenotype. Here, Morrison, Wonderlick, and Harms investigate the plausibility of “ensemble epistasis.” Macromolecules often adopt a set of interchanging structures called a thermodynamic ensemble. Mutations can change the relative population of each structure, altering the effects of future mutations. The conditions that favor ensemble epistasis are common in macromolecules and the authors conclude that thermodynamic ensembles are a key source of intramolecular epistasis
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