Frameshifting preserves key physicochemical properties of proteins

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. frameshift | hydrophobicity | genetic code | evolution

Cas9-induced large deletions and small indels are controlled in a convergent fashion

“…Moreover, repair outcomes in a resection-deficient context are much more predictable and more likely to lead to frame-disrupting 1-2 bp deletions and insertion. However, we note that the frame-shifting phenotype caused by 1 bp lesions may also be more likely to be rescued by genetic compensation (54). A number of deficiencies in auxiliary repair genes had locusselective effects.…”

Dynamically evolving novel overlapping gene as a factor in the SARS-CoV-2 pandemic

“…One frequently overlooked source of novelty is the evolution of new overlapping genes (OLGs), wherein a single stretch of nucleotides encodes two distinct proteins in different reading frames. Such ‘genes within genes’ compress genomic information and allow genetic innovation via overprinting ( Keese and Gibbs, 1992 ), particularly as frameshifted sequences preserve certain physicochemical properties of proteins ( Bartonek et al, 2020 ). However, OLGs also entail the cost that a single mutation may alter two proteins, constraining evolution of the pre-existing open reading frame (ORF) and complicating sequence analysis.…”

Computational design of genes encoding completely overlapping protein domains: Influence of genetic code and taxonomic rank

“…Future research ought test the best candidates experimentally, and if the best candidates from the methods developed here are not successful, additional factors could be considered in comparing constructed sequences and their natural precursors. For instance, many protein characteristics can be assessed using servers or packages incorporating multiple bioinformatic tools such as PredictProtein, for various secondary structural elements [57], and many sequence properties, such as hydrophobicity profiles, can be computed using the VOLPES server [58], which has been applied to the related case of frame-shifted sequences compared to their mother genes [16]. Other properties required for functional protein sequences can be inferred from the evolutionary information contained in sequence alignments of protein families.…”

“…Genes within an antisense overlapping pair could also influence each other, for instance in a way similar to what has recently been termed a "noncontiguous operon", where genes in antisense to each other are nonetheless co-expressed as an operon [12]. Other proposed benefits of overlapping genes relate to templating structure based on the existing 'mother gene', namely, for genes directly in antisense ("-1 frame"), the creation of proteins with a complementary polarity structure to the gene on the antisense strand [13,14,15] or, in the case of sense overlaps, a similar hydrophobicity profile [16]. Overlapping open reading frames may play an important role in the origin of de novo genes, exploring new territory in the total space of sequences and functions [17,18,19,20].…”