遗传密码的自动化原型设计
遗传密码的自动化原型设计
作者： 小柯机器人 发布时间：2026/8/27 22:00:47
本期文章：《自然》：Online/在线发表
美国哈佛医学院Felix Radford等科学家开发了自动化遗传tRNA扩展（AGENTEX）平台，实现了无细胞翻译系统中遗传密码的多重自动化原型设计。2026年8月26日出版的《自然》杂志发表了这项成果。
标准遗传密码使用64个密码子编码生命各域中的20种经典氨基酸。自然界中不存在的全新遗传密码能够实现新的化学、治疗方法和生态系统工程，但重新编码生物体的基因组极具挑战性。在此，研究人员描述了自动化遗传tRNA扩展（AGENTEX）方法，用于在无细胞翻译系统中对遗传密码进行多重自动化原型设计。核糖体大亚基中的两个Watson–Crick相互作用介导了对tRNA 3′ CCA末端的识别，阻止具有替代3′序列的tRNA在翻译过程中被接纳。基于这些相互作用，研究人员探究了非CCA-3′ tRNA（otRNA）被天然氨酰tRNA合成酶（aaRSs）氨酰化的程度，从而允许otRNA池通过具有改变的大亚基的核糖体来指定独特的遗传密码。他们开发了多重自动化方法来读取合成tRNA文库中的氨酰化。研究人员发现，tRNA的3′末端显示出对突变的显著灵活性，使得大多数otRNA能被所有大肠杆菌aaRSs氨酰化。基于这一发现，他们开发了无细胞翻译系统，实现了34个aaRSs对应34个密码子的压缩遗传密码。利用AGENTEX，研究人员评估了两种遗传密码以及标准遗传密码，实现了非标准氨基酸的掺入和最多三个密码子的重新分配。他们的发现对于设计全新的翻译系统、合成含有多个非标准单体的生物聚合物，以及理解可能的过去和未来遗传密码具有重要意义。
附：英文原文
Title: Automated prototyping of genetic codes
Author: Radford, Felix, Sapers, Nayan, Burgess, Hana M., Ort, Lucy, Budnik, Bogdan, Church, George M.
Issue&Volume: 2026-08-26
Abstract: The standard genetic code uses 64 codons to encode 20 canonical amino acids across domains of life. New-to-nature genetic codes enable new chemistries, therapeutics and ecosystem engineering, but recoding the genome of an organism is exceptionally challenging. Here we describe automated genetic tRNA expansion (AGENTEX) for multiplexed robotic prototyping of genetic codes in cell-free translation systems. Two Watson–Crick interactions in the ribosomal large subunit (LSU) mediate recognition of the 3′ CCA end of tRNAs, preventing tRNAs with alternative 3′ sequences from being accommodated during translation. Building on these interactions, we investigated the extent to which non-CCA-3′ tRNAs (otRNAs) would be aminoacylated by natural aminoacyl tRNA synthetases (aaRSs), allowing pools of otRNAs to specify unique genetic codes using ribosomes with altered LSU. We developed multiplexed and automated methods to read aminoacylation in libraries of synthetic tRNAs. We discovered that the tRNA 3′ end shows remarkable flexibility to mutation, allowing aminoacylation of most otRNAs by all Escherichia coli aaRSs. Building on our discovery, we developed cell-free translation systems enabling compressed genetic codes of 34 aaRSs for 34 codons. Using AGENTEX, we evaluated two genetic codes alongside the standard genetic code, with non-standard amino acid incorporation and reassignment of up to three codons. Our findings have implications for the design of radically new translation systems, the synthesis of biopolymers with several instances of non-standard monomers, and understanding of possible past and future genetic codes.
DOI: 10.1038/s41586-026-10949-y
Source: https://www.nature.com/articles/s41586-026-10949-y