The universal genetic code, protein coding genes and genomes of all species were optimized for frameshift tolerance

Frameshifted coding genes yield truncated and dysfunctional peptides. Frameshift protein sequences encoded by the alternative reading frames of a coding gene have been considered as meaningless. And frameshift mutations have been considered as utterly harmful and of little or no importance for the molecular evolution of proteins. However, previous studies showed that frameshift coding genes can be expressed, and frameshift proteins can be functional by themselves. By analyzing all coding genes in nine model organisms, here we show that protein coding genes have a quasi-constant shiftability of 0.5: the frameshift protein sequences encoded in the alternative frames remain nearly half conservative when compared with the protein sequence encoded in the main frame. The shiftability of protein coding genes was predetermined mainly by the genetic code. In the universal genetic code, amino acid pairs assigned to frameshift substitutions are more conservative than those to random substitutions, and the frameshift tolerability of the standard genetic code ranks among the top 6.3% of all compatible genetic codes. In addition, in the genomes of all species tested, high frameshift-tolerance codon pairs are overrepresented, and thus, sequence-level shiftability are achieved by biased usages of codons and codon pairs. We concluded that the genetic code, protein coding genes and genomes of all species were optimized to tolerate frameshift mutations.