The AUG codon is a classical signal that tells the ribosome where protein synthesis (translation) should start. Despite in‐depth knowledge about translation initiation, the reason for the evolutionary assignment of this role to AUG is not clear. It was proposed that high metabolic costs of methionine synthesis, the amino acid coded by AUG, allow for the precise regulation of translation initiation.^[1^] Alternatively, this codon, together with an adenine occurring just after it, can easily generate the stop translation codon UGA in +1 frameshift, which can immediately terminate aberrant protein synthesis or adjust the ribosome to the appropriate frame.^[2^] However, that proposed mechanisms could have evolved later, when the AUG codon already existed, as a result of other selection pressures.

An interesting hypothesis, which provides a valuable insight into this subject, has been recently described by Demongeot and Seligmann in this issue.^[3^] Using simulation methods, the authors claim that short 22‐nucleotide‐long circular RNAs, termed “RNA rings,” can easily acquire AUG as the start codon if they adopt a stem‐loop hairpin structure and the number of coded amino acid is maximized when these RNA sequences are read in three frames. The first assumption is reasonable, because such a structure could protect the molecules against features of the prebiotic environment that damage macromolecules. The second stipulation also seems sensible, because the diversity of amino acids in primordial peptides was surely positively selected for enhanced functionality. Under these assumptions, 10 out of 25 generated RNA rings started with AUG, and all rings gained a stop codon at their ends.

This concept is especially noteworthy because it does not postulate mechanisms directly related to translation initiation. Interestingly, the RNA rings that are generated share properties with protein‐coding genes. The RNA sequences prefer 20 codons that are overrepresented in coding genes and enable detection of the ribosomal translation frame. The codon content is also biased toward codons encoding amino acids that are attached to appropriate tRNAs by aminoacyl‐tRNA synthetases of class II—considered to be ancient molecules. In this sense, the RNA rings are reminiscent of early stages in the origin and evolution of life. It should be emphasized that they may also be good candidates for proto‐tRNAs because they bear similarities to ancestral tRNA loops. Furthermore, the circular RNAs might also play a role in originating replication, because stem‐loop RNA structures possessing an anticodon resemble replication origin loops. If this feature were confirmed experimentally, it would suggest that these molecules were originally able to auto‐replicate and propagate, an essential property for their evolution.

The findings that the theoretical RNA rings could be both short protein‐coding sequences and primordial tRNAs find strong support in the form of modern RNA molecules called transfer‐messenger RNA (tmRNA). These are used as templates for continuation of translation when mRNA transcripts are broken. Additionally, the RNA ring structure is a well‐known motif in some mitochondrial tRNAs, whose sequences contain conserved stop codons between two stems and codon AUG, that is, between the hypervariable loop and a sidearm. The region encompassed by these codons seems capable of cyclization, and could code for a peptide, just like the RNA rings obtained by the authors.^[3^]

The presented hypothesis assumes that RNA molecules encoded potential peptides in three overlapping reading frames, which maximized information capacity in one stretch of RNA, as in present‐day viral genomes. This feature is well established in properties of the standard genetic code, which shows a tendency to minimize effects of frameshift mutations to a similar extent as point mutations.^[4^] It is conceivable that frameshift mutations were quite frequent at the early stages of life on Earth, but the mechanism of transformation from frameshifting to one‐frame translation is still unclear. The hypothesis does not explain whether precise frame reading would still support AUG as a start codon. It would be worth checking this. Moreover, the model claims that all 20 amino acids could be used in protein coding. However, only a small repertoire of amino acids produced by simple biochemical reactions was likely available at the origin of life, and other amino acids were incorporated into the genetic code with the evolution of more complex metabolic networks.^[5^] It would, therefore, be interesting to verify whether RNA rings with an AUG start codon and the afore‐mentioned properties are generated in a scenario where these rings encode smaller amino acid sets.

AUG密码子是一个经典信号，告诉核糖体应从何处开始蛋白质合成（翻译）。尽管对翻译启动有深入的了解，但尚不清楚将该角色逐步分配给AUG的原因。有人提出甲硫氨酸合成的高代谢成本（由AUG编码的氨基酸）可以精确调控翻译起始。^[ 1 ^]或者，此密码子与紧随其后的腺嘌呤一起可以轻松地在+1移码中生成终止翻译密码子UGA，这可以立即终止异常的蛋白质合成或将核糖体调节至合适的框架。^[ 2 ^] 但是，由于其他选择压力，当AUG密码子已经存在时，提出的机制可能会在以后发展。

Demongeot和Seligmann最近在本期中描述了一个有趣的假设，它提供了对该主题的宝贵见解。^[ 3 ^]使用模拟方法，作者声称，如果短的22个核苷酸长的环状RNA（称为“ RNA环”）采用茎环发夹结构，并且当编码氨基酸的数量达到最大时，它们很容易获得AUG作为起始密码子。这些RNA序列在三个框架中读取。第一个假设是合理的，因为这样的结构可以保护分子免受破坏大分子的益生元环境的影响。第二条规定似乎也是明智的，因为原始肽段中氨基酸的多样性肯定是为增强功能而积极选择的。在这些假设下，25个生成的RNA环中有10个以AUG开头，并且所有环在其末端均获得了终止密码子。

这个概念特别值得注意，因为它不假定与翻译起始直接相关的机制。有趣的是，生成的RNA环与蛋白质编码基因共享属性。RNA序列更喜欢20个在编码基因中过量表达的密码子，并能够检测核糖体翻译框架。密码子的含量也偏向于编码氨基酸的密码子，该密码子通过II类的氨酰基tRNA合成酶连接到适当的tRNA上，这被认为是古老的分子。从这个意义上讲，RNA环让人想起生命起源和进化的早期阶段。应该强调的是，它们也可能是原始tRNA的良好候选者，因为它们与祖先tRNA环具有相似性。此外，环状RNA也可能在起始复制中发挥作用，因为具有反密码子的茎环RNA结构类似于复制起点环。如果通过实验证实了此功能，则表明这些分子最初能够自动复制和繁殖，这是它们进化的基本特性。

研究发现，理论上的RNA环可能是短的蛋白质编码序列，而原始的tRNA则以称为转移信使RNA（tmRNA）的现代RNA分子的形式得到了强有力的支持。这些被用作当mRNA转录物被破坏时继续翻译的模板。此外，RNA环结构是某些线粒体tRNA中的一个众所周知的基序，其序列在两个茎和AUG密码子之间（即在高变环和侧臂之间）包含保守的终止密码子。这些密码子所包围的区域似乎能够环化，并且可以编码一种肽，就像作者获得的RNA环一样。^[ 3 ^]

提出的假设假设，RNA分子在三个重叠的阅读框中编码潜在的肽段，从而像当今病毒基因组一样，最大化了一段RNA的信息容量。此功能在标准遗传密码的属性中已得到充分确立，该属性显示出将移码突变的影响最小化到与点突变相似的程度的趋势。^[ 4 ^]可以想象，在地球生命的早期阶段，移码突变非常频繁，但是从移码到单帧翻译的转换机制仍然不清楚。该假设不能解释精确的读框是否仍将AUG作为起始密码子。值得检查一下。此外，该模型声称所有20个氨基酸均可用于蛋白质编码。然而，通过简单的生化反应产生的氨基酸中只有一小部分可能是在生命起源时获得的，其他氨基酸则随着更复杂的代谢网络的进化而被纳入了遗传密码。^[ 5 ^] 因此，验证带有AUG起始密码子的RNA环是否在上述环编码较小氨基酸组的情况下产生，并产生上述特性将是有趣的。