Researchers at CIC bioGUNE and collaborators have developed the most comprehensive phylogenetic tree to date of the PRNP gene, which encodes the prion protein, based on 1,146 sequences from 901 mammalian species. The work, which combines phylogenetic analyses and in vitro misfolding experiments using the PMSA technique, demonstrates that the tendency of a PrP variant to adopt a pathological conformation has not significantly influenced the evolution of this gene. The study also explores variants associated with susceptibility to prion diseases in humans, such as the M129V polymorphism, and detects a unique change in the human species compared to Neanderthals. These results provide new insight into the molecular evolution of the prion protein and its natural limits.