Research Article: Implications of Conflicting Associations of the Prion Protein (PrP) Gene with Scrapie Susceptibility and Fitness on the Persistence of Scrapie

Date Published: November 24, 2009

Publisher: Public Library of Science

Author(s): Andrea Doeschl-Wilson, Rami Sawalha, Simon Gubbins, Beatriz Villanueva, Matthew Baylis.

Abstract: Existing mathematical models for scrapie dynamics in sheep populations assume that the PrP gene is only associated with scrapie susceptibility and with no other fitness related traits. This assumption contrasts recent findings of PrP gene associations with post-natal lamb survival in scrapie free Scottish Blackface populations. Lambs with scrapie resistant genotypes were found to have significantly lower survival rates than those with susceptible genotypes. The present study aimed to investigate how these conflicting PrP gene associations may affect the dynamic patterns of PrP haplotype frequencies and disease prevalence.

Partial Text: Incidences of scrapie, a fatal transmissible spongiform encephalopathy (TSE) of sheep and goats, have been reported in European countries for several centuries [1], but progress on the control of this disease was long inhibited by the restricted understanding of the causes of infection and modes of transmission. The discovery that polymorphisms at codons 136, 154 and 171 of the prion protein (PrP) gene determine susceptibility to classical scrapie [2]–[4], constituted a major break-through for scrapie control. Since then national breeding programmes aimed to reduce and eventually eradicate small ruminant TSEs have been established in several European countries.

Assuming first that the PrP genotype is only associated with scrapie susceptibility (i.e. εi = 0 for all i), so that changes in PrP haplotype frequencies are exclusively caused by scrapie related mortality, our model predicts that scrapie eventually disappears from the population within a few decades or centuries (Figures 1a, 1c). The frequency of the susceptible haplotype declines towards a non-zero steady state value (Figure 1d). This behaviour was observed for all parameter combinations within the admissible range shown in Table 1. Inclusion of unfavourable associations between the scrapie resistant PrP haplotype and non-scrapie lamb mortality (i.e. ε3>0) does not drastically alter this behaviour for the majority of model parameter values. The lower average life expectancy and prolificacy of scrapie susceptible genotypes remain the main drivers for frequency changes throughout the epidemic phase of the infection, and lead to the gradual decrease of susceptible genotypes until the disease can no longer be sustained. The additional boost in the replenishment of susceptible genotypes due to their lower mortality rates is too weak to prevent scrapie from gradually dying out.

In this study a model was developed to determine the influence of conflicting associations of the PrP genotype with scrapie susceptibility and lamb mortality on PrP haplotype frequencies and scrapie prevalence patterns. The potential impact of such associations on scrapie epidemiology and PrP haplotype frequencies had been drawn to attention in previous studies [9], [14], but was dismissed due to lack of empirical evidence. Recent findings of a positive association of the scrapie susceptible ARQ haplotype with post-natal lamb survival rate in scrapie free Scottish Blackface flocks [10] however suggest that the earlier speculations merit further consideration. Based on a quantitative genetics approach, the conflicting PrP genotype associations with respect to scrapie susceptibility and fitness imply that the scrapie susceptible haplotype will forever prevail in the population at high frequency (approx. 0.9, see Figure S1 in the supplementary material). These results may warrant speculations that scrapie is also likely to persist in the population without human intervention [10]. Quantitative predictions on the long-term persistence of scrapie require however also the consideration of epidemiological disease characteristics.



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