Location: Virus and Prion ResearchTitle: Disparate modes of evolution shaped modern prion (PRNP) and prion-related doppel (PRND) variation in domestic cattle Author
Submitted to: PLoS One
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/13/2016
Publication Date: 5/25/2016
Citation: Brunelle, B.W., Hannen, A.M., Nicholson, E.M., Seabury, C.M. 2016. Disparate modes of evolution shaped modern prion (PRNP) and prion-related doppel (PRND) variation in domestic cattle. PLoS One. 11(5):e0155924. doi: 10.1371/journal.pone.0155924. Interpretive Summary: The mammalian prion gene (PRNP) expresses a highly conserved protein termed the prion protein (PrP). PrP is best known as the causative agent of prion disease. Studies of PRNP knockout animals including both mice and cattle have failed to result in an overt change in animal behavior, health, or development. Some have used this to suggest that PrP is dispensable and that the high degree of sequence conservation is due to linkage to a nearby essential gene rather than due to high pressure to maintain the PrP sequence. In this work, we test the degree of sequence conservation in the nearest neighbor of PRNP, a gene known as PRND. We determine that in cattle, PRND, is not under any selective pressure and is not influencing PRNP nor is it being influenced in a manner similar to PRNP. This indicates an essential role for the protein PrP suggesting that the protein function is simply not manifesting in the controlled environmental conditions used to raise the knockout animals.
Technical Abstract: Previous investigations aimed at determining whether the mammalian prion protein actually facilitates tangible molecular aspects of either a discrete or pleiotropic functional niche have been debated, especially given the apparent absence of overt behavioral or physiological phenotypes associated with several mammalian prion gene (PRNP) knockout experiments. Moreover, a previous evaluation of PRNP knockout cattle concluded that they were normal, suggesting that the bovine prion protein is physiologically dispensable. Herein, we examined the distribution and frequency of nucleotide sequence variation within the coding regions of bovine PRNP and the nearby Doppel (PRND) gene, a proximal paralogue to PRNP on BTA13. Evaluation of PRND demonstrated that the gene is not under any selective pressure, and therefore would not influence PRNP. It appears that positive selection is indeed occurring directly on PRNP, which is indicative of an essential role for a protein; the lack of observed fitness effects may not manifest in the controlled environmental conditions used to raise the knockout animals.