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 StatementGenetic 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.

Spotlight on alternative frame coding: Two long overlapping genes in Pseudomonas aeruginosa are translated and under purifying selection

“…The origin of a new gene within an existing gene is termed ''overprinting'' (Keese and Gibbs, 1992). Advantageous for same-strand overlaps is that the hydrophobicity profile of a frame-shifted sequence tends to be similar to that of the unshifted sequence (Bartonek et al, 2020), as may have contributed to the origin of an OLG in SARS-CoV-2 (Nelson et al, 2020a). Intriguingly, overlaps of the reference frame ''+1'' and antisense ''À1'' tend to have opposite hydrophobicities for their amino acids (Konecny et al, 1993).…”

The genetic robustness of RNA and protein from evolutionary, structural and functional perspectives

“…Furthermore, when point mutations change the amino acid, the new amino acid coded for is likely to have similar biochemical properties due to the code's organization (17) . Monte Carlo simulations have shown that the extant genetic code is significantly more robust to substitution and frameshift mutations than randomly generated genetic codes (18)(19)(20)(21)(22) . Premature stop codons and frameshift errors can be introduced by substitutions or indels (insertions and deletions).…”