Using conceptual biology and comparative genomics , we are systematically mapping the functional evolution of the three prion protein family genes (PrP; Doppel, Dpl; and Shadoo, Sho). For Sho – which we discovered by in silico methods in 2003 – we have identified an RGG-box motif in the disordered N-terminal region as having a potential RNA-binding function; a prediction now validated both by experiment and computational simulations. We expect that these protein-RNA interactions underlie Sho’s functions in neuronal development. We have also predicted and experimentally validated a mechanism for regulating co-ordinated transcription of the PrP and Dpl genes. This can explain how the relative levels of the two proteins are controlled, and can be perturbed under certain conditions to induce apoptosis and cell death in Alzheimers’ disease.