Negative purifying selection drives prion and doppel protein evolution.

Kyriakos Tsangaras,Serge Morand,Rainer G. Ulrich,Johan Michaux,Sergios-Orestis Kolokotronis,Alex D. Greenwood

doi:10.1007/s00239-014-9632-1

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 α-helices 1 and 2.

Highlights

The prion protein (PrP) when misfolded into the pathogenic conformer PrPSc is the major causative agent of several lethal transmissible spongiform encephalopathies in mammals
When we searched for episodic positive selection along the branches of the pressure on the prion gene (PRNP) gene tree, we found small, isolated bursts of diversifying selection acting on a limited number of codons on the internal branch before the Rodentia-Scadentia clade
No evidence of balancing selection or widespread positive selection could be identified in our study for either PRNP or PRND

Summary

Introduction

The prion protein (PrP) when misfolded into the pathogenic conformer PrPSc 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. 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. Accumulation of this misfolded conformer leads to severe neurodegeneration by an unknown mechanism (Kraus et al 2013)

Methods

Results

Conclusion