A new rationale for TF paralog evolution, expression and function

Gene duplications are major drivers in the evolution of biological complexity, but the forces that shape paralog evolution remain incompletely understood. RUNX transcription factor paralogs are expressed in mutually exclusive cell types, sacrificing potential robustness conferred by gene duplications without obvious gain. To elucidate this issue, we explored two RUNX-dependent developmental branch points. In both settings, RUNX paralogs differed in their functional properties, providing a rationale for selective paralog expression, and allowing us to identify paralog-specific amino acids that modulate the strength of DNA binding and gene regulatory control. Remarkably, in both paradigms examined, the non-endogenously expressed paralog was biologically more potent than the endogenously expressed paralog, increasing the generation of specialized cell types regardless of environmental conditions. These findings suggest submaximal regulatory control as a driver for transcription factor paralog evolution, a conclusion supported by the evolutionary trajectory of RUNT domain residues, which indicates selection of sequences that moderate DNA binding and gene regulatory control.