loading . . . A comprehensive phylogeny of mammalian PRNP gene reveals no influence of prion misfolding propensity on the evolution of this gene Author summary Prion diseases are rare and complex neurodegenerative disorders that affect humans, and other mammals, such as cattle or sheep. They are caused by a poorly understood conformational or structural change of normal, physiological prion protein. This abnormally structured form, known as prion, acquires the capacity to induce the same transformation to surrounding physiological prion proteins, leading to disease. Although this protein is very similar in all mammals, prion diseases have only been described in some species. For this reason, we decided to look at as many mammal prion protein sequences as possible and analyze the evolution of this protein in this group of species, to compare it with the tendency of these species’ prion proteins to adopt a toxic conformation. Our results indicate that prion diseases have not shaped the evolution of the prion protein in mammals. Our study provides an insight into the molecular evolution of prion proteins. For example, it has allowed us to look at the evolution of the human prion protein and compare it to older humans and Neanderthals, which has identified a change that is unique to the human species. Thus, although some evolutionary differences could be related to the differential susceptibility of the prion protein variant to misfold, our results indicate that prion diseases have not significantly influenced the evolution of the gene that encodes the prion protein. https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1013257