Prion protein gene (PRNP) variants and evidence for strong purifying selection in functionally important regions of bovine exon 3

Abstract

Amino acid replacements encoded by the prion protein gene (PRNP) have been associated with transmissible and hereditary spongiform encephalopathies in mammalian species. However, an association between bovine spongiform encephalopathy (BSE) and bovine PRNP exon 3 has not been detected. Moreover, little is currently known regarding the mechanisms of evolution influencing the bovine PRNP gene. Therefore, in this study we evaluated the patterns of nucleotide variation associated with PRNP exon 3 for 36 breeds of domestic cattle and representative samples for 10 additional species of Bovinae. The results of our study indicate that strong purifying selection has intensely constrained PRNP over the long-term evolutionary history of the subfamily Bovinae, especially in regions considered to be of functional, structural, and pathogenic importance in humans as well as other mammals. The driving force behind this intense level of purifying selection remains to be explained.T ransmissible spongiform encephalopathies, or prion diseases, are inevitably fatal neurodegenerative diseases that occur in humans as well as domestic and wild animals (1-3). Traditionally, human spongiform encephalopathies have been classified into Creutzfeldt-Jakob disease (CJD), GerstmannSträusler-Scheinker disease, and kuru, with more recent classification into variant CJD (1). Animal transmissible spongiform encephalopathies include transmissible mink encephalopathy, scrapie of sheep and goats, chronic wasting disease of deer and elk, feline spongiform encephalopathy, and bovine spongiform encephalopathy (BSE) (1). Central to the development of these diseases is the accumulation of an infectious protease-resistant isoform (PrP Sc ) of the host-encoded cellular prion protein (PrP C ) in tissues of the central nervous system (2-5).The prototypical transmissible spongiform encephalopathy, scrapie, has been observed in European sheep for Ͼ200 years, whereas BSE in domestic cattle (Bos taurus and Bos indicus; hereafter, cattle) dates to 1986, presumably resulting from scrapie-and͞or BSE-infected cattle feed (6-9). Thus, BSE seems to be a more recent phenomenon associated with modern agricultural practices. This idea is supported by several lines of evidence. First, at least 14 amino acid polymorphisms encoded by exon 3 of the ovine prion protein gene (PRNP) have been described (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), and those associated with codons 136 and 171 have been shown to influence expression of scrapie (8, 10). However, no amino acid polymorphisms associated with BSE have been identified in cattle, although an insertion-deletion (indel) polymorphism in the putative bovine PRNP promoter was shown to exhibit an association with BSE in a few German cattle breeds (21). Second, recorded patterns of variation within cattle PRNP exon 3 are markedly different from those observed in sheep, with variability in cattle primarily restricted to 11 synonymous nucleotide sites and two nonsynonymous sites where low-frequency variation has been observed (2...

Production of cattle lacking prion protein

“…This indicates that 'loss of function' of bovine PrP C itself does not cause BSE and that ablation of the normal cellular prion protein PrP C function does not adversely affect normal bovine development. It has been reported that evolution has exerted very intense purifying selection on exon 3 of bovine PRNP; the PRNP gene should have some indispensable function in bovine development because such strong purifying selection is usually seen only for proteins essential to eukaryotic life 21 . Therefore, our findings appear to be of particular interest in supporting a general hypothesis that PrP C function is dispensable for normal animal development.…”

Effects of PRNP polymorphisms on sperm quality traits in Chinese Holstein bulls

“…Generally, the bovine with the low PrP expression level has an advantage on resistance to BSE, and increasing the frequencies of 12-bp insertion and 23-bp insertion alleles will be improving the resistance to BSE (Sander et al 2005;Xue et al 2008). Furthermore, it was reported that an increased number of octapeptide repeats in bovine PRNP would enhance host susceptibility to BSE, and the general number of repeats was five or six in previous reports (Castilla et al 2005;Brun et al 2007), and the number of it had four and/or seven in a few cattle (Sander et al 2004;Seabury et al 2004). These advances on PRNP polymorphisms provided theory guidance for cattle genetics and breeding.…”

Negative Purifying Selection Drives Prion and Doppel Protein Evolution

“…The presence of some intermediate-frequency polymorphisms remains interesting and warrants a wider resequencing study and examination of the effect of the polymorphisms on protein structure and function. Another study (Seabury et al 2004) evaluated genetic variation in the exon 3 of PRNP in 36 breeds of domestic cattle and other bovine species and found negative selection against nonsynonymous changes and an excess of rare silent polymorphisms upstream the N-terminal cleavage site coding sequence.…”

“…Evolutionary analyses of PRNP have demonstrated conflicting results, with the prion gene being under balancing (Mead et al 2003), purifying (Seabury et al 2004), and positive selection (Premzl and Gamulin 2009) depending on the dataset. A recent study including representatives of multiple taxa suggested that positive selection was acting on PrP in various domains and intradomains (Premzl and Gamulin 2009).…”