Proteins with amino acid repeats constitute a rapidly evolvable and human-specific essentialome.

Protein products of essential genes, indispensable for organismal survival, are highly conserved and bring about fundamental functions. Interestingly, proteins that contain amino acid homorepeats that tend to evolve rapidly are enriched in eukaryotic essentialomes. Why are proteins with hypermutable homorepeats enriched in conserved and functionally vital essential proteins? We solve this functional versus evolutionary paradox by demonstrating that human essential proteins with homorepeats bring about crosstalk across biological processes through high interactability and have distinct regulatory functions affecting expansive global regulation. Importantly, essential proteins with homorepeats rapidly diverge with the amino acid substitutions frequently affecting functional sites, likely facilitating rapid adaptability. Strikingly, essential proteins with homorepeats influence human-specific embryonic and brain development, implying that the presence of homorepeats could contribute to the emergence of human-specific processes. Thus, we propose that homorepeat-containing essential proteins affecting species-specific traits can be potential intervention targets across pathologies, including cancers and neurological disorders.