Abstract
Frameshifts in protein coding sequences are widely perceived as resulting in either nonfunctional 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 particular, we show that hydrophobicity profiles of many protein sequences remain largely invariant upon frameshifting. For example, over 2,900 human proteins exhibit a Pearson's correlation coefficient R between the hydrophobicity profiles of the original and the +1-frameshifted variants greater than 0.7, despite an average 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 as well as protein sequence profiles of intrinsic disorder. Finally, analysis of significance and optimality demonstrates that frameshift stability is 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 from which they originate.
Highlights
Frameshifts in protein coding sequences are widely perceived as resulting in either nonfunctional or even deleterious protein products
The average sequence identity between wild-type human proteins and proteins obtained by +1 frameshifting their messenger RNA (mRNA) is only 6.2% (SI Appendix, Fig. S1)
Importantly, frameshifted mRNAs frequently contain premature stop codons and in eukaryotes are rapidly degraded by the nonsense-mediated decay (NMD) machinery [8]
Summary
Frameshifts in protein coding sequences are widely perceived as resulting in either nonfunctional or even deleterious protein products. Frameshifts in the messenger RNA (mRNA) coding sequences of proteins are typically considered to be unproductive events, which, if unchecked, could result in nonfunctional and sometimes even deleterious protein products [1,2,3,4]. This notion is mainly based on the dramatic difference between the sequences of wild-type proteins and their frameshifted counterparts. We show that, several essential properties of many protein sequences, such as their hydrophobicity profiles, remain largely unchanged upon frameshifting 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 from which they derive
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