Swappable and non-swappable homorepeats in orthologous proteins reflect distinct patterns of evolutionary flexibility

Abstract

Abstract Proteins frequently contain runs of a single repeated amino acid, known as homorepeats or polyX regions. While their presence across orthologous proteins is an indicator of their functional importance, less is understood about whether different types of homorepeats can occupy the same position in related proteins: a concept we term “swappability”. Here we study homorepeat overlaps in orthologs from 695 species, tracking swappable and non-swappable cases to analyze their evolution and functional implications. We obtained 17,415,904 orthologous protein pairs from OrthoMCL, analyzed their homorepeats and aligned each orthologous pair to detect overlaps between these regions. Among more than 8.7 million orthologous pairs, we detected 99,386 non-swappable (same amino acid type) and 5,018 swappable (different amino acid type) overlapping homorepeats. Swappable cases tended to be longer and enriched in acidic residues, whereas non-swappable showed lineage-specific variation. Based on their prevalence in our data, we focused on D/E and A/S overlapping homorepeat pairs. PolyD and polyE were frequently found as swappable, maintaining their functional roles primarily linked to ribosomal biogenesis. PolyA and polyS, by contrast, show divergent enrichment patterns in their non-swappable forms, pointing to distinct functional specializations. This work illustrates the balance between positional conservation and sequence flexibility in homorepeat evolution.