Exploring the Mutational Robustness of Nucleic Acids by Searching Genotype Neighborhoods in Sequence Space
Exploring the Mutational Robustness of Nucleic Acids by Searching Genotype Neighborhoods in Sequence Space
复制标题
通过搜索序列空间中的基因型邻域探索核酸的突变鲁棒性
DOI：
10.1021/acs.jpclett.6b02769
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发表时间：
2017
影响因子：
5.7
通讯作者：
Liang Haojun
中科院分区：
文献类型：
--
作者：
Zhou Qingtong;Sun Xianbao;Xia Xiaole;Fan Zhou;Luo Zhaofeng;Zhao Suwen;Shakhnovich Eugene;Liang Haojun
为了评估核酸的突变稳健性，已经进行了许多基因组和蛋白质水平的研究，其中核酸被视为遗传信息的载体和转移者。然而，突变改变核酸的结构、动态和功能特性的分子机制却知之甚少。在这里，我们进行了一项SELEX in silo研究，以调查l-臂结合适配子基因邻域的适合度分布。分离出了两个新的功能基因社区，并通过实验验证了它们具有与野生型相似的适合度。实验适配子适应度图表明，突变的稳健性受到局部碱基环境和配体结合模式的强烈影响，而远离结合口袋的碱基提供了接近全局适应值最大值的潜在进化途径。我们的工作提供了SELEX在电子计算机中优化适配子的成功应用的一个例子，并证明了突变稳健性对遗传变异位置的强烈敏感性。
To assess the mutational robustness of nucleic acids, many genome- and protein-level studies have been performed, where nucleic acids are treated as genetic information carriers and transferrers. However, the molecular mechanisms through which mutations alter the structural, dynamic, and functional properties of nucleic acids are poorly understood. Here we performed a SELEX in silico study to investigate the fitness distribution of thel-Arm-binding aptamer genotype neighborhoods. Two novel functional genotype neighborhoods were isolated and experimentally verified to have comparable fitness as the wild-type. The experimental aptamer fitness landscape suggests the mutational robustness is strongly influenced by the local base environment and ligand-binding mode, whereas bases distant from the binding pocket provide potential evolutionary pathways to approach the global fitness maximum. Our work provides an example of successful application of SELEX in silico to optimize an aptamer and demonstrates the strong sensitivity of mutational robustness to the site of genetic variation.