Selection maintains signaling function of a highly diverged intrinsically disordered region

Significance Intrinsically disordered regions (IDRs) are widespread, have diverse functions, and are involved in human disease. Because standard sequence analysis methods identify little sequence homology in IDRs, it is not currently understood whether (or how) the functions of these protein regions are preserved over evolution. Here we show that orthologous IDRs can preserve regulatory functions despite near-complete sequence divergence. This suggests that natural selection maintains aggregate molecular properties in IDRs, which we propose to be quantitative traits. Consistent with this, we find signatures of stabilizing selection on the electrostatic properties of IDRs. Thus, in analogy to the rapid evolution of noncoding DNA in eukaryotic enhancers, divergence in primary amino acid sequence does not imply functional divergence in IDRs.