Synonymous genes explore different evolutionary landscapes.
Synonymous genes explore different evolutionary landscapes.
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DOI：
10.1371/journal.pgen.1000256
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发表时间：
2008-11
期刊：
影响因子：
4.5
通讯作者：
Mazel, Didier
中科院分区：
文献类型：
--
作者：
Cambray, Guillaume;Mazel, Didier
基因的进化潜力不仅受其产物的氨基酸序列的制约，而且还受其DNA序列的制约。遗传密码的拓扑结构是这样的：一半的氨基酸显示出同义密码子，这些密码子可以通过单一突变相互到达不同的氨基酸子集。因此，同义DNA序列应该通过有限数量的突变进入蛋白质序列空间的不同区域，这可能会深刻影响天然蛋白质的进化。在这里，我们证明了这个特征对于控制蛋白质的进化性是有价值的。我们设计了一种算法，从输入基因开始，构建一个同义序列，系统地包括具有最不同进化观点的密码子，即最大限度地获得以前通过点突变无法从模板中获得的氨基酸的密码子。计算并合成了细菌抗生素耐药基因的同义版本。当同时提交相同的定向进化方案时，野生型和重新编码的序列都导致分离出特定的、有利的表型变体。基于仅从合成基因库中分离的突变进行模拟，以评估亚功能选择性限制，如密码子的使用，对自然适应的影响。我们的数据表明，同义合成基因的合理设计是对任何定向进化协议的负担得起的改进。我们表明，使用两个同义DNA序列通过增加产生的突变的多样性来提高该过程的总体产率。这些结果提供了确凿的证据，证明同义编码序列确实经历了相应蛋白质适应景观的不同区域，并且序列的密码子使用有效地限制了编码蛋白质的进化。进化过程在很大程度上依赖于多样性的产生。遗传稳健性，通过允许在种群内积累中性多样性，一直与进化潜力(进化性)的增加有关。在这项工作中，我们建议使用众所周知的健壮性来源，遗传密码的冗余，来改变任何蛋白质的进化性。该代码的拓扑结构允许同义密码子采样不同的突变邻域。利用这一性质，我们开发了一种算法来设计相对于输入序列具有最大发散进化潜力的同义序列。在种群水平上，这些序列中的每一个都扩大了编码蛋白质可以探索的进化图景的范围，并最终增加了发现适应性突变的几率。我们应用这一原理进化出新的抗生素耐药表型变种。从根本上说，我们的结果提供了中性多样性如何有利于进化性的一个例子。此外，鉴于核酸合成的快速发展，合理设计的同义基因的使用为任何定向进化过程提供了有益的增强。
The evolutionary potential of a gene is constrained not only by the amino acid sequence of its product, but by its DNA sequence as well. The topology of the genetic code is such that half of the amino acids exhibit synonymous codons that can reach different subsets of amino acids from each other through single mutation. Thus, synonymous DNA sequences should access different regions of the protein sequence space through a limited number of mutations, and this may deeply influence the evolution of natural proteins. Here, we demonstrate that this feature can be of value for manipulating protein evolvability. We designed an algorithm that, starting from an input gene, constructs a synonymous sequence that systematically includes the codons with the most different evolutionary perspectives; i.e., codons that maximize accessibility to amino acids previously unreachable from the template by point mutation. A synonymous version of a bacterial antibiotic resistance gene was computed and synthesized. When concurrently submitted to identical directed evolution protocols, both the wild type and the recoded sequence led to the isolation of specific, advantageous phenotypic variants. Simulations based on a mutation isolated only from the synthetic gene libraries were conducted to assess the impact of sub-functional selective constraints, such as codon usage, on natural adaptation. Our data demonstrate that rational design of synonymous synthetic genes stands as an affordable improvement to any directed evolution protocol. We show that using two synonymous DNA sequences improves the overall yield of the procedure by increasing the diversity of mutants generated. These results provide conclusive evidence that synonymous coding sequences do experience different areas of the corresponding protein adaptive landscape, and that a sequence's codon usage effectively constrains the evolution of the encoded protein. Evolutionary processes largely rely on the production of diversity. Genetic robustness, by allowing the accumulation of neutral diversity within a population, has been associated with increase in evolutionary potential (evolvability). In this work, we propose to use a well-known source of robustness, the redundancy of the genetic code, to alter the evolvability of any protein. The topology of the code allows synonymous codons to sample different mutational neighborhoods. Using this property, we developed an algorithm to design synonymous sequences with maximally divergent evolutionary potentials relative to the input sequences. At the population level, each of these sequences expands the scope of the evolutionary landscape that can be explored by the encoded protein, and ultimately increase the odds of uncovering adaptive mutants. We applied this principle to evolve new antibiotic resistance phenotype variants. Fundamentally, our results provide an example of how neutral diversity may favor evolvability. Moreover, in light of the rapid development in nucleic acid synthesis, the use of rationally designed synonymous genes offers a profitable enhancement to any directed evolution procedure.
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影响因子：
4.5
作者：
Hoede C;Denamur E;Tenaillon O
通讯作者：
Tenaillon O
影响因子：
7.7
作者：
Maurice, Frederique;Broutin, Isabelle;Dardel, Frederic
通讯作者：
Dardel, Frederic
影响因子：
3.9
作者：
Lawrence, JG;Ochman, H
通讯作者：
Ochman, H
DOI：
10.1016/s0006-291x(02)00226-7
发表时间：
2002-04-26
影响因子：
3.1
作者：
Cortazzo, P;Cerve単ansky, C;Deana, A
通讯作者：
Deana, A
影响因子：
2.1
作者：
Archetti, M
通讯作者：
Archetti, M