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Title: PRION PROTEIN GENE (PRNP) VARIANTS AND EVIDENCE FOR STRONG PURIFYING SELECTION IN FUNCTIONALLY IMPORTANT REGIONS OF BOVINE EXON 3

Author
item SEABURY, CHRISTOPHER - TEXAS A&M UNIVERSITY
item HONEYCUTT, RODNEY - TEXAS A&M UNIVERSITY
item Rooney, Alejandro - Alex
item HALBERT, NATALIE - TEXAS A&M UNIVERSITY
item DERR, JAMES - TEXAS A&M UNIVERSITY

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/16/2004
Publication Date: 10/19/2004
Citation: Seabury, C.M., Honeycutt, R.L., Rooney, A.P., Halbert, N.D., Derr, J.N. 2004. Prion protein gene (PRNP) variants and evidence for strong purifying selection in functionally important regions of bovine exon 3. Proceedings of the National Academy of Sciences. 101(42):15142-15147.

Interpretive Summary: Prions are proteins that cause fatal neurodegenerative disorders known as spongiform encephalopathies, such as bovine spongiform encephalopathy (BSE), or "mad cow" disease. Cattle that are infected with BSE pose a significant health risk to humans, because consumption of meat from an infected cow can lead to the onset of the disease in humans. In this study, we described for the first time, and subsequently characterized, a large number of prion alleles (gene variants) in domestic cattle and compared these alleles to those from other bovine species. As a result, we also characterized regions of the domestic cattle prion gene that appear to be of unique evolutionary and biomedical importance. As such, this study provides important new information for biomedical researchers studying both the causes and means to prevent mad cow disease.

Technical Abstract: Amino acid replacements encoded by single nucleotide polymorphisms (SNPs) within the prion protein gene (PRNP) have been associated with transmissible and hereditary spongiform encephalopathies in mammalian species. However, a definitive relationship between bovine spongiform encephalopathy (BSE) and bovine PRNP exon 3 has not been demonstrated. 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, including a large reference sample of American bison (Bison bison). 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 mammalian species. The driving force behind this intense level of purifying selection remains to be explained.