Hierarchy and extremes in selections from pools of randomized proteins
Hierarchy and extremes in selections from pools of randomized proteins
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DOI：
10.1073/pnas.1517813113
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发表时间：
2016-03-29
影响因子：
11.1
通讯作者：
Rivoire, Olivier
中科院分区：
文献类型：
--
作者：
Boyer, Sebastien;Biswas, Dipanwita;Rivoire, Olivier
变异和选择是达尔文进化论的核心原则，但将种群的多样性与其响应选择的能力定量联系起来具有挑战性。在这里，我们在选择用于与明确定义的靶标结合的部分随机蛋白质群体的背景下在分子水平上研究这个问题。我们建立了几个最小的蛋白质文库，通过噬菌体展示进行体外筛选，并通过高通量测序分析了它们对选择的反应。对结果的统计分析揭示了两个主要发现。首先，具有相同序列多样性但围绕不同“框架”构建的文库通常会产生截然不同的反应；其次，文库中最佳结合物的响应分布遵循简单的比例定律。我们展示了基于极值理论的基本概率模型如何合理化后一个发现。我们的结果对于设计合成蛋白质库、估计序列空间中功能生物分子的密度、表征自然群体的多样性以及通过实验研究进化性（即未来进化的潜力）具有重要意义。
Variation and selection are the core principles of Darwinian evolution, but quantitatively relating the diversity of a population to its capacity to respond to selection is challenging. Here, we examine this problem at a molecular level in the context of populations of partially randomized proteins selected for binding to well-defined targets. We built severalminimal protein libraries, screened themin vitro by phage display, and analyzed their response to selection by high-throughput sequencing. A statistical analysis of the results reveals two main findings. First, libraries with the same sequence diversity but built around different "frameworks" typically have vastly different responses; second, the distribution of responses of the best binders in a library follows a simple scaling law. We show how an elementary probabilistic model based on extreme value theory rationalizes the latter finding. Our results have implications for designing synthetic protein libraries, estimating the density of functional biomolecules in sequence space, characterizing diversity in natural populations, and experimentally investigating evolvability (i.e., the potential for future evolution).