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Linkage disequilibrium across six prion gene regions spanning 20 kbp in U.S. sheep

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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. This report describes regions of linkage disequilibrium (LD) throughout the PRNP gene region in U.S. sheep and provides a genetic framework for identifying additional PRNP determinants associated with scrapie resistance. Four sequence tagged sites (i.e., STS or amplicons) totaling 3869 bp and spanning 20 kbp of genomic PRNP sequence were sequenced in a diverse panel of 90 sires representing ten popular U.S. breeds of sheep. Analysis of these sequences identified 36 previously unreported polymorphisms. In combination with two previously characterized STS, 62 polymorphisms were analyzed in a 20-kbp PRNP region in this panel of U.S. sheep. Two regions of strong LD and ten common haplotypes were identified. The haplotype encoding amino acid residues A, R, and Q at codons 136, 154, and 171, respectively, was observed on nine larger haplotypes spanning PRNP from the promoter region to the 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. The existence of multiple haplotypes encoding ARQ raises the question of whether sheep bearing these different haplotypes are equally susceptible to scrapie. The haplotype structure within the 20-kbp region of PRNP identified in this study is important for higher-resolution analysis of genetics contributions to scrapie susceptibility.

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References

  • Bandelt H-J, Forster P, Röhl A (1999) Median-joining networks for inferring intraspecific phylogenies. Mol Biol Evol 16, 37–48

    PubMed  CAS  Google Scholar 

  • Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265

    Article  PubMed  CAS  Google Scholar 

  • Baylis M, Goldmann W, Houston F, Cairns D, Chong A, et al. (2002) Scrapie epidemic in a fully PrP-genotyped sheep flock. J Gen Virol 83, 2907–2914

    PubMed  CAS  Google Scholar 

  • Baylis M, Goldmann W (2004) The genetics of scrapie in sheep and goats. Curr Mol Med 4, 385–396

    Article  PubMed  CAS  Google Scholar 

  • Baylis M, McIntyre KM (2004) Transmissible spongiform encephalopathies: scrapie control under new strain. Nature 432, 810–811

    Article  PubMed  CAS  Google Scholar 

  • Belt PB, Muileman IH, Schreuder BE, Bos-de Ruijter J, Gielkens AL, et al. (1995) Identification of five allelic variants of the sheep PrP gene and their association with natural scrapie. J Gen Virol 76, 509–517

    PubMed  CAS  Google Scholar 

  • Buschmann A, Luhken G, Schultz J, Erhardt G, Groschup MH (2004) Neuronal accumulation of abnormal prion protein in sheep carrying a scrapie-resistant genotype (PrPARR/ARR). J Gen Virol 85, 2727–2733

    Article  PubMed  CAS  Google Scholar 

  • Clawson ML, Heaton MP, Chitko-McKown CG, Fox JM, Smith TP, et al. (2004) Beta-2-microglobulin haplotypes in U.S. beef cattle and association with failure of passive transfer in newborn calves. Mamm Genome 15, 227–236

    Article  PubMed  CAS  Google Scholar 

  • Clouscard C, Beaudry P, Elsen JM, Milan D, Dussaucy M, et al. (1995) Different allelic effects of the codons 136 and 171 of the prion protein gene in sheep with natural scrapie. J Gen Virol 76, 2097–2101

    Article  PubMed  CAS  Google Scholar 

  • Elsen JM, Amigues Y, Schelcher F, Ducrocq V, Andreoletti O, et al. (1999) Genetic susceptibility and transmission factors in scrapie: detailed analysis of an epidemic in a closed flock of Romanov. Arch Virol 144, 431–445

    Article  PubMed  CAS  Google Scholar 

  • Ewing B, Green P (1998) Base-calling of automated sequencer traces using phred. II. Error probabilities. Genome Res 8, 186–194

    PubMed  CAS  Google Scholar 

  • Ewing B, Hillier L, Wendl MC, Green P (1998) Base-calling of automated sequencer traces using phred. I. Accuracy assessment. Genome Res 8, 175–185

    PubMed  CAS  Google Scholar 

  • Fallin D, Schork NJ (2000) Accuracy of haplotype frequency estimation for biallelic loci, via the expectation-maximization algorithm for unphased diploid genotype data. Am J Hum Genet 67, 947–959

    Article  PubMed  CAS  Google Scholar 

  • Freking BA, Murphy SK, Wylie AA, Rhodes SJ, Keele JW, et al. (2002) Identification of the single base change causing the callipyge muscle hypertrophy phenotype, the only known example of polar overdominance in mammals. Genome Res 12, 1496–1506

    Article  PubMed  CAS  Google Scholar 

  • Goldmann W, Baylis M, Chihota C, Stevenson E, Hunter N (2005) Frequencies of PrP gene haplotypes in British sheep flocks and the implications for breeding programmes. J Appl Microbiol 98, 1294–1302

    Article  PubMed  CAS  Google Scholar 

  • Heaton MP, Leymaster KA, Freking BA, Hawk DA, Smith TPL, et al. (2003) Prion gene sequence variation within diverse groups of U.S. sheep, beef cattle, and deer. Mamm Genome 14, 765–777

    Article  PubMed  CAS  Google Scholar 

  • Houston F, Goldmann W, Chong A, Jeffrey M, González L, et al. (2003) Prion diseases: BSE in sheep bred for resistance to infection. Nature 423, 498

    Article  PubMed  CAS  Google Scholar 

  • Hunter N, Goldmann W, Foster JD, Cairns D, Smith G (1997a) Natural scrapie and PrP genotype: case-control studies in British sheep. Vet Rec 14, 1137–1140

    Google Scholar 

  • Hunter N, Moore L, Hosie BD, Dingwall WS, Greig A (1997b) Association between natural scrapie and PrP genotype in a flock of Suffolk sheep in Scotland. Vet Rec 140, 59–63

    CAS  Google Scholar 

  • Ikeda T, Horiuchi M, Ishiguro N, Muramatsu Y, Kai-Uwe GD, et al. (1995) Amino acid polymorphisms of PrP with reference to onset of scrapie in Suffolk and Corriedale sheep in Japan. J Gen Virol 76, 2577–2581

    PubMed  CAS  Google Scholar 

  • Jeffreys AJ, Kauppi L, Neumann R (2001) Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat Genet 29, 217–222

    Article  PubMed  CAS  Google Scholar 

  • Lee IY, Westaway D, Smit AFA, Wang K, Seto J, et al. (1998) Complete genomic sequence and analysis of the prion protein gene region from three mammalian species. Genome Res 8, 1022–1037

    PubMed  CAS  Google Scholar 

  • Leymaster KA (1991) Straightbred comparison of a composite population and the Suffolk breed for performance traits of sheep. J Anim Sci 69, 993–999

    PubMed  CAS  Google Scholar 

  • Mead S, Mahal SP, Beck J, Campbell T, Farrall M, et al. (2001) Sporadic—but not variant—Creutzfeldt-Jakob disease is associated with polymorphisms upstream of PRNP exon 1. Am J Hum Genet 69, 1225–1235

    Article  PubMed  CAS  Google Scholar 

  • Moum T, Olsaker I, Hopp P, Moldal T, Valheim M, et al. (2005) Polymorphisms at codons 141 and 154 in the ovine prion protein gene are associated with scrapie Nor98 cases. J Gen Virol 86, 231–235

    Article  PubMed  CAS  Google Scholar 

  • Nickerson DA, Tobe VO, Taylor SL (1997) PolyPhred: automating the detection and genotyping of single nucleotide substitutions using fluorescence-based resequencing. Nucleic Acids Res 25, 2745–2751

    Article  PubMed  CAS  Google Scholar 

  • O’Neill GT, Donnelly K, Marshall E, Cairns D, Goldmann W, et al. (2003) Characterization of ovine PRP gene promoter activity in N2a neuroblastoma and ovine foetal brain cell lines. J Anim Breed Genet 120, 114–123

    Article  CAS  Google Scholar 

  • Orge L, Galo A, Machado C, Lima C, Ochoa C, et al. (2004) Identification of putative atypical scrapie in sheep in Portugal. J Gen Virol 85, 3487–3491

    Article  PubMed  CAS  Google Scholar 

  • O’Rourke KI, Holyoak GR, Clark WW, Mickelson JR, Wang S, et al. (1997) PrP genotypes and experimental scrapie in orally inoculated Suffolk sheep in the United States. J Gen Virol 78, 975–978

    PubMed  CAS  Google Scholar 

  • Prusiner SB (1982) Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144

    Article  PubMed  CAS  Google Scholar 

  • Prusiner SB (1998) Prions. Proc Natl Acad Sci U S A 95, 13363–13383

    Article  PubMed  CAS  Google Scholar 

  • Prusiner SB (2004) Prion Biology and Diseases, 2nd ed. Cold Spring Harbor Monogr Ser (Cold Spring, NY: Cold Spring Harbor Laboratory Press)

  • Stephens JC, Schneider JA, Tanguay DA, Choi J, Acharya T, et al. (2001) Haplotype variation and linkage disequilibrium in 313 human genes. Science 293, 489–493

    Article  PubMed  CAS  Google Scholar 

  • Stephens M, Donnelly P (2003) A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73, 1162–1169

    Article  PubMed  CAS  Google Scholar 

  • Stumpf MP (2004) Haplotype diversity and SNP frequency dependence in the description of genetic variation. Eur J Hum Genet 12, 469–477

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Drs. G.P. Harhay, J.W. Keele, and S.N. White for help with data analysis, Drs. L.M. Durso, J.E. Keen, and M.R. Mousel for critical comments regarding the manuscript, R.A. Godtel, J.K. Carnahan, and T.A. Sorensen for technical assistance, and S.L. Kluver and J.K. Rosch for secretarial assistance. Names are necessary to accurately report the methods and results, and the use of names by USDA implies no approval of the product to the exclusion of others that may also be suitable. B.T. Green was partially supported by DARPA Project 5438-32000-023-01R.

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Authors and Affiliations

  1. U.S. Department of Agriculture, Agricultural Research Service, U.S. Meat Animal Research Center (USMARC), State Spur 18D, P.O. Box 166, Clay Center, Nebraska, 68933, USA

    Benedict T. Green, Michael P. Heaton, Michael L. Clawson & William W. Laegreid

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  1. Benedict T. Green
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  2. Michael P. Heaton
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  3. Michael L. Clawson
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  4. William W. Laegreid
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Correspondence to William W. Laegreid.

Additional information

Nucleotide sequence data reported are available in the DDBJ/EMBL/GenBank databases under the accession number DQ077504.

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Green, B.T., Heaton, M.P., Clawson, M.L. et al. Linkage disequilibrium across six prion gene regions spanning 20 kbp in U.S. sheep. Mamm Genome 17, 1121–1129 (2006). https://doi.org/10.1007/s00335-006-0042-6

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  • DOI: https://doi.org/10.1007/s00335-006-0042-6

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