Frameshift protein sequences encoded by alternative reading frames of coding genes have been considered meaningless, and frameshift mutations have been considered of little importance for the molecular evolution of coding genes and proteins. However, functional frameshifts have been found widely existing. It was puzzling how a frameshift protein kept its structure and functionality while its amino-acid sequence was changed substantially. Here we show that frame similarities between frameshifts and wild types are higher than random similarities and are defined at the genetic code, gene, and genome levels. In the standard genetic code, frameshift codon substitutions are more conservative than random substitutions. The frameshift tolerability of the standard genetic code ranks in the top 2.0-3.5% of alternative genetic codes, showing that the genetic code is nearly optimal for frameshift tolerance. Furthermore, frameshift-resistant codons (codon pairs) appear more frequently than expected in many genes and certain genomes, showing that the frameshift optimality is reflected not only in the genetic code but more importantly, in its allowance of further optimizing the frameshift tolerance of a particular gene or genome, which shed light on the role of frameshift mutations in molecular and genomic evolution.

中文翻译：

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移码和野生型蛋白高度相似，因为遗传密码和基因组针对移码耐受性进行了优化

由编码基因的替代阅读框编码的移码蛋白质序列被认为是没有意义的，并且移码突变被认为对于编码基因和蛋白质的分子进化没有多大意义。但是，已经发现功能性移码已广泛存在。令人困惑的是，移码蛋白如何在氨基酸序列发生实质性变化的同时保持其结构和功能。在这里，我们表明移码和野生型之间的框架相似性高于随机相似性，并且在遗传密码，基因和基因组水平上定义。在标准遗传密码中，移码密码子替换比随机替换更保守。标准遗传密码的移码耐受性在其他遗传密码中排在前2.0-3.5％，表明遗传密码对于移码耐受性几乎是最佳的。此外，抗移码密码子（密码子对）在许多基因和某些基因组中的出现频率比预期的要高，这表明移码的最优性不仅反映在遗传密码中，而且更重要的是，其允许进一步优化α的移码耐受性。特定的基因或基因组，阐明了移码突变在分子和基因组进化中的作用。