Protein tandem repeats that produce frameshifts can generate new structural states and functions

Abstract

The genetic code uses three‐nucleotide units to encode each amino acid in proteins. Insertions or deletions of nucleotides not divisible by three shift the reading frames, resulting in significantly different protein sequences. These events are disruptive but can also create variability important for evolution. Previous studies suggested that the genetic code and gene sequences evolve to minimize frameshift effects, maintaining similar physicochemical properties to their reference proteins. Here, we focused on tandem repeat sequences, known as frameshift hotspots. Using cutting‐edge bioinformatics tools, we compared reference and frameshifted protein sequences within tandem repeats across 50 prokaryotic and eukaryotic proteomes. We showed that, in contrast to the general tendency, frameshifts within these regions, especially with short repeats, lead to a significant increase in hydrophobicity and arginine content. Additionally, the frameshifts, particularly in short tandem repeats, rearrange transmembrane regions, potentially converting soluble proteins into membrane proteins and vice versa. Given their occurrence in rapidly evolving, essential proteins, such changes may promote rapid adaptability. Our large‐scale alphafold modeling suggested that frameshift events can generate novel structures and functions, enabling the synthesis of multiple protein variants within the same coding region. Overall, frameshifts cause more drastic changes in tandem repeat sequences compared to non‐repetitive sequences and therefore can be a primary cause of altered functions, cellular localization, and the development of various pathologies.