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Title: LINKAGE DISEQUILIBRIUM ACROSS SIX PRION GENE REGIONS SPANNING 20 KBP IN U.S. SHEEP

Author
item Green, Benedict - Ben
item Heaton, Michael - Mike
item Clawson, Michael - Mike
item Laegreid, William

Submitted to: Mammalian Genome
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/6/2006
Publication Date: 11/17/2006
Citation: Green, B.T., Heaton, M.P., Clawson, M.L., Laegreid, W.W. 2006. Linkage disequilibrium across six prion gene regions spanning 20 kbp in U.S. sheep. Mammalian Genome. 17(11):1121.1129.

Interpretive Summary: Scrapie is a fatal neurological disorder of sheep characterized by the accumulation of a mis-folded form of the prion protein. There are five common amino acid variants of the sheep prion protein (ARQ, ARR, ARH, AHQ, and VRQ). Sheep with the ARQ and VRQ variants of the prion protein are commonly considered susceptible to scrapie, while sheep with the ARR variant are considered resistant. Although the ARQ variant of the prion protein has been associated with scrapie susceptibility, many susceptible animals do not develop clinical signs of the disease. In this study, 36 previously unknown DNA markers were identified. In combination with previously characterized DNA markers, a total of 61 markers were analyzed in the sheep prion gene. The specific pattern of inheritance for a group of 12 common DNA markers was characterized and ten common patterns identified. The ARQ and VRQ amino acid variants were present on the background of many of the ten common patterns of inheritance. These ten patterns of inheritance represent the genetic variation across the sheep prion gene and provide a mechanism to define scrapie-resistant or susceptible subgroups of animals possessing the ARQ or VRQ prion protein variants. This will allow for the refinement of genetics-based scrapie eradication programs.

Technical Abstract: Single nucleotide polymorphisms (SNPs) and haplotype alleles within the prion gene (PRNP) coding sequence of domestic sheep (Ovis aries) are associated with genetic predisposition to scrapie, a transmissible spongiform encephalopathy disease of sheep. Our goal was to characterize regions of linkage disequilibrium (LD) throughout the PRNP gene region in U.S. sheep and provide a genetic framework for identifying additional PRNP determinants associated with scrapie resistance. Four sequence tagged sites (STS/amplicons) totaling 3869 bp which span 20 kbp of genomic PRNP sequence were sequenced in a diverse panel of 90 sires representing nine U.S. breeds of sheep. Thirty six previously unknown polymorphisms were identified. In combination with two previously characterized STS, 61 polymorphisms were analyzed in the PRNP region in this panel of U.S. sheep. Two regions of strong LD and ten haplotypes were identified. The haplotype encoding ARQ at codons 136, 154, and 171, respectively, was observed on nine larger haplotypes spanning PRNP from the promoter region to 3’ untranslated region. The haplotype encoding VRQ was observed on two larger haplotypes, whereas, ARR, ARH, and AHQ were each present on a single haplotype. Identifying haplotypes spanning the 20 kbp region of PRNP is important for higher resolution genetic studies of variation in scrapie susceptibility.