 This study proposes a new method called AQTL mapping, which uses prior knowledge about the in vitro DNA binding specificity of a transcription factor, TF, to identify the locky AQTLs whose inheritance modulates their protein-level regulatory activity. This method was applied to budding yeast and mouse data, and it was found to have greatly improved statistical power compared to existing methods, while being mechanism-based, computationally efficient, and generally applicable. This article was authored by Yungi Lee and Harman J. Busmaker.