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Abstract

The genetic code defines the relationship between a protein and its coding DNA sequence. It was presumed that most frameshifts would yield non-functional, truncated or cytotoxic products. In this study, we report that in E. coli a frameshift β-lactamase (bla) gene is still functional if all of the inner stop codons were readthrough or replaced by a sense codon. By analyzing a large dataset including all available protein coding genes in major model organisms, it is demonstrated that in any species, and in any protein-coding genes, the three translational products from the three different reading frames, are always similar to each other and with constant ~50% similarities and ~100% coverages, and the similarities is predefined by the genetic code rather than the sequences themselves, suggesting that the genetic code was optimized for frameshift tolerating in the early evolution, which endows every protein coding gene a shiftability, an inherent and everlasting ability to tolerate frameshift mutations, and serves as an innate mechanism for cells to deal with the frameshift problem. In addition, it is likely that every protein-coding gene can be translated into three isoforms from the three different reading frames, we proposed a new gene expression paradigm, "one gene, three translations", which is an amendment to the "one gene, one/multiple peptides" hypotheses.