Frameshifts and wild-type protein sequences are always highly similar because the genetic code and genomes were optimized for frameshift tolerance

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 frameshift homologs are widely existing. It was puzzling how a frameshift protein kept its structure and functionality while its amino-acid sequence changed substantially. Here we report that the similarities among frameshifts and wild-type protein sequences are higher than the random similarities, and are defined by both the genetic code and the genome. In the standard genetic code, amino acids assigned to frameshift codon substitutions are more conservative than those assigned to random substitutions. The frameshift tolerability of the standard genetic code ranks in the top 2.0-3.5% of all alternative genetic codes, showing that the natural genetic code was optimized for frameshift tolerance. Moreover, frameshift-tolerable codons and codon pairs appear more frequently in the genomes in higher species than in lower species, showing that the frameshift tolerability was further optimized by the usages of codons and codon pairs in these genomes. <br>S1a: Frame similarities aligned by <i>ClustalW</i> or <i>MSA</i>; S1b: Frame similarities aligned by <i>FrameAlign</i>; S2: FSSs of the natural genetic code; S3: FSSs of the alternative genetic codes; S4: FSSs of different codon usages; S5: FSSs of different usages of codon pairs.<br>