Invariants of Frameshifted Variants

Abstract Frameshifts in protein coding sequences are widely perceived as resulting in either non-functional or even deleterious protein products. Indeed, frameshifts typically lead to markedly altered protein sequences and premature stop codons. By analyzing complete proteomes from all three domains of life, we demonstrate that, in contrast, several key physicochemical properties of protein sequences exhibit significant robustness against +1 and −1 frameshifts in their mRNA coding sequences. In particular, we show that hydrophobicity profiles of many protein sequences remain largely invariant upon frameshifting. For example, over 2900 human proteins exhibit a Pearson correlation coefficient between the hydrophobicity profiles of the original and the +1-frameshifted variants greater than 0.7, despite a median sequence identity between the two of only 6.5% in this group. We observe a similar effect for protein sequence profiles of affinity for certain nucleobases, their matching with the cognate mRNA nucleobase-density profiles as well as protein sequence profiles of intrinsic disorder. Finally, we show that frameshift invariance is directly embedded in the structure of the universal genetic code and may have contributed to shaping it. Our results suggest that frameshifting may be a powerful evolutionary mechanism for creating new proteins with vastly different sequences, yet similar physicochemical properties to the proteins they originate from. Significance Statement Genetic information stored in DNA is transcribed to messenger RNAs and then read in the process of translation to produce proteins. A frameshift in the reading frame at any stage of the process typically results in a significantly different protein sequence being produced and is generally assumed to be a source of detrimental errors that biological systems need to control. Here, we show that several essential properties of many protein sequences, such as their hydrophobicity profiles, remain largely unchanged upon frameshifts. This finding suggests that frameshifting could be an effective evolutionary strategy for generating novel protein sequences, which retain the functionally relevant physicochemical properties of the sequences they derive from.