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Polygenic variation involved in the resistance-susceptibility to scrapie , in a Romanov flock

INSTITUTO NACIONAL DE INVESTIGACIÓN Y TECNOLOGÍA AGRARIA Y ALIMENTARIA (INIA). MINISTERIO DE CIENCIA Y TECNOLOGIA. Polygenic variation involved in the resistance-susceptibility to scrapie , in a Romanov flock. C. Díaz 1 , R.  Rupp 2 , Z. Vitezica 2 , O. Andréoletti 3 J. M. Elsen 2

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Polygenic variation involved in the resistance-susceptibility to scrapie , in a Romanov flock

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  1. INSTITUTO NACIONAL DE INVESTIGACIÓN Y TECNOLOGÍA AGRARIA Y ALIMENTARIA (INIA) MINISTERIO DE CIENCIA Y TECNOLOGIA Polygenic variation involved in the resistance-susceptibility to scrapie, in a Romanov flock C. Díaz1, R.  Rupp2 , Z. Vitezica2, O. Andréoletti3 J. M. Elsen2 1Dpto de Mejora Genética Animal. INIA. Madrid. 2Station d'Amélioration Génétique des Animaux. INRA – Toulouse. France. 3Ecole Vétérinaire de Toulouse, Interactions Hotes-Agents Pathogènes, 31076 Toulouse, France.

  2. INTRODUCTION • Scrapie is one TSE affecting ovine and caprine. • Susceptibility to scrapie, determined by mortality rate and incubation period, is mainly controlled by polymorphisms at codons 136, 154 and 171 of the PrP gene. • In mouse, the incubation period of the diseases has been associated to the genotype of the PrP (Moore et al., 1998) and to the prion strain used (Bruce et al., 1991).However, the host genotype at PrP does not account for the total variation observed in the incubation period indicating the existence of other environmental and genetic factors involved in the control of the disease.

  3. Several studies have provided evidence of other genes influencing incubation period for scrapie: in inbred lines of mice (Stephenson et al., 2000; Lloyd et al., 2001; Manalakou et al., 2001; Moreno et al., 2003) and in sheep (Moreno et al., 2002) with defined PrP genotypes.

  4. OBJECTIVE To detect polygenic variation involved in the resistance - susceptibility to scrapie, in addition to the the PrP gene.

  5. DATA • Data from Langlade experimental INRA farm. This flock is naturally infected with scrapie. First outbreak in April 1993. First analysed by Elsen et al., 1999. • Data of 4049 Romanov animal alive between the 1st of April 1993 and the 4th of March of 2002. Animals were born between 1983 and 2002. • 447 died of scrapie. • Very prolific females with 1 to 7 lambs : Up to 2 lambs maternal and artificial milking.

  6. Survival Analysis (1) Failure time: the period between the first exposure to infection and the date they left the flock with scrapie signs confirmed afterwards with histology (TOEX): Beginning of infection was assumed in January, 1991. First exposure: • In 1991: born before. • Date of birth: born after . • Entry date: born outside.

  7. Survival Analysis (2) • Uncensored data: Clinical signs + Positive histology. • Censored data: - animal still alive on March, 2002 or - dead by other causes. • Computations were performed using the software package Survival Kit (Ducrocq and Sölkner, 1998).

  8. Sire-Dam frailty model PrP genotype : Baseline hazard function. Fj: the experimental group (j=1 to 4) AFEk: age (up to 2yrs, 3 yrs and older than 3 yrs). Sxl:sex of the ith animal. LEXn () : level of exposure that changes at time . rtddso: an interaction rearing type and dam’s disease status (4 levels). lsp: litter size in which the animal ithwas born (2 levels). sq and dr: sire and dam effect of the ith individual. If s and d are included in gMVN (0, A ),

  9. PrP Genotype information • Probability of genotypes: PrP_Prob_M. • =bm. represents the weighted average • effect of each genotype on the hazard of the ith animal. • Known genotypes: 1.0 at the position corresponding to its genotype • and 0.0 otherwise. • Unknown genotypes: corresponding probabilities of genotypes. Iterative Peeling (Fernando et al., 1993) • PrP genotypes as a class effect: PrP_Class_M 10 genotypes + unknown class

  10. Total genetic variation related to resistance_susceptibility to scrapie: G_T_M In both cases, genetic variation was as calculated as 4

  11. Mortality rate and Risk Associated to PrP genotypes relative to ARQ/VRQ

  12. Survivor function according to PrP genotypes

  13. Table 1. Mode and first three moments of the marginal posterior densities of under the three models (PrP_Prob_M, PrP_Class_M, and G_T). Ratios of the genetic variance for models with and without PrP information.

  14. Conclusion • Incubation period may be associated to PrP genotype: Elsen et al. (1999) fourand Díaz et al. (2003) eight out the ten genotypes. • Polygenic variance may approximately explain 16% of the total genetic variation involved in the resistance-susceptibility to scrapie. Heterogeneus variance. • New information may help to confirm these results.

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