Disordered but Different: Functional and Evolutionary Divergence of Transcription Factor Intrinsically Disordered Regions

Intrinsically disordered regions (IDRs) of proteins play key roles in multivalent interactions and the formation of biomolecular condensates. IDRs are widespread across the human proteome but are significantly enriched in transcription factor (TF) activation domains. However, it remains unclear why TF activation domains are enriched for IDRs and whether these regions are fundamentally distinct from IDRs in other proteins. Here, we comprehensively identify and analyze human IDRs and discover widespread functional, phenotypic, and evolutionary differences between TF and non-TF IDRs. Notably, in contrast to the broader proteome, TFs have evolved to become more disordered over time. Correspondingly, highly disordered TFs are more likely to regulate developmental processes, govern larger regulatory networks, and be subject to stronger regulatory constraints. TF IDRs are also enriched for pathogenic mutations relative to non-TF IDRs, and disorder content significantly predicts the mode of disease inheritance. Our results provide novel insights into how the evolution of gene regulation has uniquely shaped the molecular function and disease burden of TF IDRs.