The Shiftability of Protein Coding Genes: The Genetic Code was Optimized for Frameshift Tolerating

It has been presumed that most frame-shifted protein coding genes yield truncated, non-functional, and potentially cytotoxic products, and the robustness of the genetic code to frameshift errors is achieved by increasing the probability that a stop codon is encountered upon a frameshifting. Here we report that in E coli a frame-shifted gene is still functional and the reading frame is restored gradually, suggesting that the hidden stop codons signal translational readthrough and reading frame restoration. Moreover, by analyzing all available coding genes in major model organisms, it is revealed that in any species, and in any gene, the three translation products from three different reading frames are always highly similar to each other, with a constant ~50% similarity and a ~100% coverage. Therefore, most frame-shifted coding genes are potentially functional, since in a frameshift isoform not only the protein sequence is conserved, but also the active sites can be regenerated. It is suggested that in early evolution the genetic code was optimized for frameshift tolerating, endows every coding gene a constant shiftability, and therefore, every protein has three frameshift isoforms and every life has an inherent and everlasting ability to tolerate frameshift mutations.