Negative Purifying Selection Drives Prion and Doppel Protein Evolution

Abstract

The prion protein (PrP) when misfolded into the pathogenic conformer PrP Sc is the major causative agent of several lethal transmissible spongiform encephalopathies in mammals. Studies of evolutionary pressure on the corresponding gene using different datasets have yielded conflicting results. In addition, putative PrP or PrP interacting partners with strong similarity to PrP such as the doppel protein have not been examined to determine if the same evolutionary mechanisms apply to prion paralogs or if there are coselected sites that might indicate how and where the proteins interact. We examined several taxonomic groups that contain model organisms of prion diseases focusing on primates, bovids, and an expanded dataset of rodents for selection pressure on the prion gene (PRNP) and doppel gene (PRND) individually and for coevolving sites within. Overall, the results clearly indicate that both proteins are under strong selective constraints with relaxed selection on amino acid residues connecting a-helices 1 and 2.

Evaluation of Resistance and Susceptibility to Prion Diseases in Pelibuey Sheep from Mexico

“…In addition, it is to be expected that individuals with phenotypes corresponding to traits related to better production are being selected. Purifying selection has been reported for this same gene and its paralogous genes in some studies: the first was a sequence analysis in 26 mammalian species (37); the second was an evaluation of the PRNP gene in bovines and the results indicate that a strong purifying selection acted on this gene (38) and the third consisted in the exploration of the PRND gene that is paralogous to the PRNP gene and whose evolution has been by virtue of purifying selection among mammalian taxa (39). Sezgin et al reported that a complex selection favoring excessive replacement changes together with weak purifying selection possibly driven by frequency-dependent selection is driving PRNP sequence evolution (40).…”

Disparate Modes of Evolution Shaped Modern Prion (PRNP) and Prion-Related Doppel (PRND) Variation in Domestic Cattle

“…ZMYND11 encodes a transcriptional regulator protein that binds to adenovirus E1A proteins [ 12 ] while PRND encodes the doppel protein (Dpl), an evolutionarily related paralogue of PRNP believed to be involved in sperm maturation and capacitation [ 13 ]. Given the physical proximity between PRNP and PRND [ 14 ], as well as phylogenetic evidence that the two genes have been evolutionarily co-selected [ 15 ], we tested the hypothesis that strong selection within bovine PRND may be explanatory for selective signals previously detected in bovine PRNP [ 9 ]. Collectively, our analyses provide statistical support for intense purifying selection operating on bovine PRNP , with bovine PRND variation exhibiting no evidence for deviation from a strictly neutral model.…”