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RNA Molecules Stimulate Prion Protein Conversion

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RNA Molecules Stimulate Prion Protein Conversion letters to nature between 0.2 and 1.0 in nestlings. As not all individuals were typed with the same set of pedigrees and (2) distinguishing full-sib pair members. Anim. Genet. 25, 37–44 (1994). microsatellite markers, we calculated standardized individual heterozygosity10 29. Pemberton, J. M., Coltman, D. W., Coulson, T. N. & Slate, J. in Microsatellites, Evolution and (proportion of heterozygous loci/mean heterozygosity of typed loci). This measure is used Applications (eds Goldstein, D. B. & Schlo¨tterer, C.) 151–164 (Oxford Univ. Press, Oxford, 1999). in all analyses and is referred to as ‘individual heterozygosity’ for simplicity. We also 30. Turelli, M. & Ginzburg, L. R. Should individual fitness increase with heterozygosity? Genetics 104, calculated two other, previously suggested measures of individual genetic diversity: 191–209 (1983). internal relatedness10 and mean d2-value29 where d 2 is the squared length difference between the alleles at a locus. Heterozygosity, standardized heterozygosity and internal Acknowledgements We thank D. Blomqvist, S. Griffith, D. Hasselquist, L. Keller, M. Milinski, relatedness were highly correlated (all r . 0.89, P , 0.0001) and all three measures led to A. Peters, B. Sheldon, C. Wedekind and D. Zeh for comments on the manuscript; K. Carter, similar conclusions (data not shown). Mean d 2-values were weakly correlated with the D. Kaulfuss, H. Kunc, K. Peer, A. Po¨sel and A. Tu¨rk for help with field and laboratory work; other measures (r ¼ 0.24–0.32, all P , 0.0001) and explained comparatively little S. Andersson for computing the colour variables; and H. Winkler (Konrad Lorenz Institute for variation in individual fitness. Comparative Ethology) and R.-T. Klumpp and A. Fojt (Institute of Silviculture, University of The assumption that heterozygosity measured at a limited number of loci reflects Agricultural Sciences, Vienna) for logistic support. genome-wide heterozygosity can be questioned30. Any relationship between average heterozygosity and fitness might be due to close linkage between a microsatellite locus and Competing interests statement The authors declare that they have no competing financial loci coding for fitness-related traits. To check whether the effect of overall heterozygosity interests. on fitness depended on one or a few of the microsatellite loci, we repeated all analyses for each locus separately (data not shown). Heterozygosity at six out of seven loci significantly Correspondence and requests for materials should be addressed to B.K. affected at least one fitness measure, and different fitness measures were predicted by ([email protected]). heterozygosity at different loci, so we only present data on overall heterozygosity. We calculated pairwise relatedness between partners using Relatedness 5.0 (http:// www.gsoftnet.us/GSoft.html). The average relatedness between adult males and females (expected r ¼ 0) in our study population was 20.0007 (s.e.m. calculated by ‘jack-knifing’ over loci ¼ 0.0009). In a random sample of 100 broods, the average relatedness among full siblings (expected r ¼ 0.5) was 0.47 (s.e.m. ¼ 0.02). The mean inbreeding coefficient of .............................................................. our population (F is), calculated from the microsatellite data using Fstat V2.9.3, equals 20.006. The observed level of inbreeding was 3.3%: two of 61 local recruits (with known RNA molecules stimulate prion parents) mated with close relatives (r ¼ 0.5 and 0.125). Received 21 March; accepted 25 July 2003; doi:10.1038/nature01969. protein conversion 1. Jennions, M. D. & Petrie, M. Why do females mate multiply? A review of the genetic benefits. Biol. Rev. 75, 21–64 (2000). Nathan R. Deleault, Ralf W. Lucassen & Surachai Supattapone 2. Tregenza, T. & Wedell, N. Genetic compatibility, mate choice and patterns of parentage: invited review. Mol. Ecol. 9, 1013–1027 (2000). Department of Biochemistry, 7200 Vail Building, Dartmouth Medical School, 3. Zeh, J. A. & Zeh, D. W. Reproductive mode and the genetic benefits of polyandry. Anim. Behav. 61, Hanover, New Hampshire 03755, USA 1051–1063 (2001). ............................................................................................................................................................................. 4. Brown, J. L. A theory of mate choice based on heterozygosity. Behav. Ecol. 8, 60–65 (1997). 5. Zeh, J. A. & Zeh, D. W. The evolution of polyandry I: intragenomic conflict and genetic Much evidence supports the hypothesis that the infectious agents incompatibility. Proc. R. Soc. Lond. B 263, 1711–1717 (1996). of prion diseases are devoid of nucleic acid, and instead are 6. Tregenza, T. & Wedell, N. Polyandrous females avoid costs of inbreeding. Nature 415, 71–73 (2002). composed of a specific infectious protein1. This protein, PrPSc, 7. Thornhill, N. W. The Natural History of Inbreeding and Outbreeding: Theoretical and Empirical Perspectives (Univ. Chicago Press, Chicago, 1993). seems to be generated by template-induced conformational C 8. Kempenaers, B., Adriaensen, F., van Noordwijk, A. J. & Dhondt, A. A. Genetic similarity, inbreeding change of a normally expressed glycoprotein, PrP (ref. 2). and hatching failure in blue tits: are unhatched eggs infertile? Proc. R. Soc. Lond. B 263, 179–185 (1996). Although numerous studies have established the conversion of 9. Coltman, D. W., Bowen, W. D. & Wright, J. M. Birth weight and neonatal survival of harbour seal pups PrPC to PrPSc as the central pathogenic event of prion disease, it is are positively correlated with genetic variation measured by microsatellites. Proc. R. Soc. Lond. B 265, C 803–809 (1998). unknown whether cellular factors other than PrP might be Sc 10. Amos, W. et al. The influence of parental relatedness on reproductive success. Proc. R. Soc. Lond. B 268, required to stimulate efficient PrP production. We investigated 2021–2027 (2001). the biochemical amplification of protease-resistant PrPSc-like 11. Hansson, B., Bensch, S., Hasselquist, D. & Akesson, M. Microsatellite diversity predicts recruitment of 3 sibling great reed warblers. Proc. R. Soc. Lond. B 268, 1287–1291 (2001). protein (PrPres) using a modified version of the protein-mis- 4 12. Ho¨glund, J. et al. Inbreeding depression and male fitness in black grouse. Proc. R. Soc. Lond. B 269, folding cyclic amplification method .Herewereportthat C 711–715 (2002). stoichiometric transformation of PrP to PrPres in vitro requires 13. Hansson, B. & Westerberg, L. On the correlation between heterozygosity and fitness in natural specific RNA molecules. Notably, whereas mammalian RNA populations. Mol. Ecol. 11, 2467–2474 (2002). 14. Pusey, A. & Wolf, M. Inbreeding avoidance in animals. Trends Ecol. Evol. 11, 201–206 (1996). preparations stimulate in vitro amplification of PrPres, RNA 15. Petrie, M. & Kempenaers, B. Extra-pair paternity in birds: explaining variation between species and preparations from invertebrate species do not. Our findings populations. Trends Ecol. Evol. 13, 52–58 (1998). suggest that host-encoded stimulatory RNA molecules may 16. Blomqvist, D. et al. Genetic similarity between mates and extra-pair parentage in three species of have a role in the pathogenesis of prion disease. They also provide shorebirds. Nature 419, 613–615 (2002). 17. Kempenaers, B. et al. Extra-pair paternity results from female preference for high-quality males in the a practical approach to improve the sensitivity of diagnostic blue tit. Nature 357, 494–496 (1992). techniques based on PrPres amplification. 18. Kempenaers, B., Verheyen, G. R. & Dhondt, A. A. Extrapair paternity in the blue tit (Parus caeruleus): We previously showed that PrPres amplification in vitro shares female choice, male characteristics, and offspring performance. Behav. Ecol. 8, 481–492 (1997). 19. Aparicio, J. M., Cordero, P. J. & Veiga, J. P. A test of the hypothesis of mate choice based on many specific features with the pathogenic process of prion propa- 3 heterozygosity in the spotless starling. Anim. Behav. 62, 1001–1006 (2001). gation in vivo, including strain and species specificity . In a typical 20. Andersson, S., O¨ rnborg, J. & Andersson, M. Ultraviolet sexual dimorphism and assortative mating in amplification reaction, diluted prion-infected brain homogenate blue tits. Proc. R. Soc. Lond. B 265, 445–450 (1998). (0.1% w/v) is mixed with either 5% (w/v) normal brain homogenate 21. Hunt, S., Cuthill, I. C., Bennett, A. T. D. & Griffiths, R. Preferences for ultraviolet partners in the blue tit. Anim. Behav. 58, 809–815 (1999). or buffer control and incubated overnight at 37 8C. Hamster Sc237 22. Sheldon, B., Andersson, S., Griffith, S. C., O¨ rnborg, J. & Sendecka, J. Ultraviolet colour variation PrPres is amplified about sixfold under these conditions (Fig. 1a, influences blue tit sex ratios. Nature 402, 874–877 (1999). compare M with Sc). While characterizing the biochemical require- 23. Mitton, J. B., Schuster, W. S. F., Cothran, E. G. & De Fries, J. C. Correlation between the individual ments of PrPres amplification reactions, we were surprised heterozygosity of parents and their offspring. Heredity 71, 59–63 (1993). 24. Stockley, P., Searle, J. B., MacDonald, D. W. & Jones, C. S. Female multiple mating behaviour in the to discover that treatment of such reactions with DNase-free, common shrew as a strategy to reduce inbreeding. Proc. R. Soc. Lond. B 254, 173–179 (1993). heterogeneous pancreatic RNase abolished PrPres amplification in 25. Dawson, D. A., Hanotte, O., Greig, C., Stewart, I. R. K. & Burke, T. Polymorphic microsatellites
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