The aim of this study was to apply a back-calculation model to Great Britain (GB) classical scrapie surveillance data, and use this model to estimate how many more cases might be expected, and over what time frame these cases might occur. A back-calculation model was applied to scrapie surveillance data between 2005 and 2019 to estimate the annual rate of decline of classical scrapie. This rate was then extrapolated to predict the number of future cases each year going forward. The model shows that there may be yet further cases of classical scrapie in GB. These will most likely occur in the fallen stock scheme, with approximately a 25% probability of at least 1 further scrapie positive, with a very low probability (~0.2%) of having up to three additional scrapie positives. This highlights the difficulty of completely eliminating all further cases, even in the presence of very effective control measures.

The results of the study reported here are part of an ongoing integrated research programme aimed at producing additional, robust, evidence on the genetic resistance to classical scrapie in goats, with particular reference to codon 146. The study targeted animals aged ⩾6 years, which were born and raised in infected herds and were being culled for management reasons. A total of 556 animals were tested, and all positive animals (n = 117) were of the susceptible NN genotype. A total of 246 goats heterozygous or homozygous for putatively resistant alleles (S146 and D146) were screened with no positive results. The outcome of this study supports the hypothesis that the D146 and S146 alleles could be used as the basis for a nationwide strategy for breeding for resistance in the Cypriot goat population.

Multiple cases of atypical scrapie in the same holding and co-existence with classical scrapie have been reported in Great Britain. A two-stage simulation tool was developed by combining a sampling algorithm and a hierarchical Bayesian model to simulate the number of positive cases of atypical scrapie from: (i) random sampling and (ii) using the actual sampled population in Great Britain, being the output probability of detection of flocks with one and more cases. Cluster analysis was conducted to assess the level of geographical over- and under-sampling over the years. The probability of detecting at least two cases of atypical scrapie in the same holding is much lower in simulated random data than in simulated actual data for all scenarios. Sampling bias in the selection of sheep for testing led to multiple sampling from fewer but larger holdings, Scotland, and areas of Wales were under-sampled and the South-West and East of England oversampled. The pattern of atypical scrapie cases observed is unlikely to be explained by a multi-case event epidemiologically linked. The co-existence of classical and atypical scrapie is a rare event with 19 holdings detected in GB and does not suggest an epidemiological link between the two types of disease.

Previous studies have shown the association between the polymorphisms serine (S) or aspartic acid (D) at codon 146 of the PRNP gene and resistance to scrapie. All goats aged >12 months (a total of 1075 animals) from four herds with the highest prevalence of scrapie in the country were culled and tested, of which 234 (21·7%) were positive by either the rapid test or immunohistochemistry (IHC) for any of the tissues tested. The odds of scrapie infection occurring in NN146 goats was 101 [95% credible interval (CrI) 19–2938] times higher than for non-NN146 or unknown genotypes. IHC applied to lymphoreticular tissue produced the highest sensitivity (94%, 95% CrI 90–97). The presence of putatively resistant non-NN146 alleles in the Cypriot goat population, severely affected by scrapie, provides a potential tool to reduce/eradicate scrapie provided that coordinated nationwide breeding programmes are implemented and maintained over time.

Scrapie, a transmissible spongiform encephalopathy (TSE) or prion disease, is a fatal, neurodegenerative disease in sheep and goats. This disease has been known in Europe for more than 250 years. Susceptibility to scrapie is associated with polymorphisms in the sheep prion protein gene (PrP) gene. In sheep, polymorphism in the PrP gene has been identified at a number of codons, and polymorphisms at codons 136, 154 and 171 have reported linkage with susceptibility to scrapie. Polymorphisms at the PrP locus were studied in 413 animals representing three native sheep breeds (Imroz, Chios and Kıvırcık) in Turkey. Genomic DNA was obtained from blood, and genotypes were screened using PCR and direct DNA sequencing. We report 17 genotypes derived from seven different alleles. The most frequent genotype in the Kıvırcık sheep is ARQ/ARQ, whereas the ARR/ARQ genotype is predominant in the Chios and Imroz breeds. In general, the ARQ haplotype was the predominant haplotype. ARQ haplotype was also predominant in the Kıvırcık and Chios sheep breeds, whereas the Imroz sheep predominantly had the ARR haplotype. The susceptibility-associated VRQ haplotype was found in 2.38%, 0.35% and 0.81% of the Imroz, Kıvırcık and Chios sheep, respectively. Moreover, seven additional polymorphisms have been detected at codons G127S, G127V, H143R, G145S, Y172D, N174Y and Q189L. Among these polymorphisms, the N174Y allele is a novel polymorphism, and the G145S allele is a novel allele for a known polymorphic locus.

The Ram Genotyping Scheme was launched in Great Britain in 2001 as part of the National Scrapie Plan and was devised to reduce and eventually eradicate classical scrapie susceptible genotypes from the national pedigree flock. Anecdotal claims from breeders suggest that sheep with more resistant PrP genotypes may have inferior phenotypes. In this study, we test this possibility for lamb production traits in three breeds of lowland sheep: Charollais (22 752 lambs), Poll Dorset (22 589 lambs) and Texel (23 492 lambs). Data were received from 50 breeders and comprised weights at birth, 8 weeks and scanning (from which average daily weight gain was derived), and ultrasonic muscle and fat depths. Animal (direct) genetic effects and up to three maternal effects were fitted in linear mixed models for each trait. Fitting either PrP genotype or number of copies of individual alleles carried as fixed effects allowed potential associations with the PrP gene to be assessed. There were no significant associations seen in the Poll Dorset breed; however, significant associations were found with the number of allele copies carried in the other two breeds included in this study. Charollais lambs carrying one copy of the VRQ allele had significantly (P < 0.01) greater ultrasonic muscle depth (0.58 mm) and fat depth (0.2 mm) than non-carriers. In the Texel breed, lambs with one ARR allele were significantly heavier than those with two or zero ARR alleles; heterozygous ARR lambs were 0.07 kg heavier at birth (P < 0.05), 0.42 kg heavier at 8 weeks (P < 0.01) and 0.17 kg heavier at scan weight (P < 0.01), than non-carriers. After Bonferroni corrections to adjust significance thresholds to account for the large number of independent comparisons made, all significant results remained so at P < 0.05 or greater, except for the ARR allele effect on birth weight in the Texel breed, which was no longer significant. These results compare favourably with others from studies on many continental breeds of sheep, published in recent years, and add credence to the conclusion that selection on PrP genotype is unlikely to have any noticeable impact on the measured growth and carcass traits in sheep.

The risk of classical scrapie in sheep is associated with polymorphisms in the prion protein (PrP) gene. In recent years, large-scale selective breeding programmes for sheep at lower risk of disease have been undertaken across the European Union. We analysed large-scale datasets on scrapie and sheep demography to investigate additional effects of sheep breed on scrapie risk. There was evidence for variation between certain breeds in the scrapie risk of some PrP genotypes, which could be caused by innate breed differences or distinct scrapie strains circulating within them. While the PrP genotypes of cases are generally consistent across breeds, some exceptions provide evidence that scrapie strain may influence affected PrP genotypes to a greater extent than innate breed differences. There was a significant association between the breed-level incidence of scrapie and the frequency of susceptible PrP genotypes in breeds. Our results lend support to selective breeding programmes which aim to reduce the frequency of high-risk PrP genotypes with measures not varying by sheep breed.

Extensive surveillance for classical scrapie has been carried out in Great Britain since 1993, the results of which can be used for monitoring the effect of control measures introduced since 2001. A back-calculation approach was used to estimate the prevalence of sheep infected with classical scrapie, which integrates data on reported clinical cases (1993–2007) and the results of fallen stock and abattoir surveys (2002–2007). The prevalence of classical scrapie in GB was fairly constant until 2003, although the estimates depended on assumptions made about the performance of diagnostic tests used in the surveys. If infected animals could be detected in the final quarter of the incubation period, the estimated prevalence was 0·6–0·7%, while if they could be detected in the final half of the incubation period, it was 0·3–0·4%. Between 2003 and 2007 the prevalence declined by around 40%, and the magnitude of the reduction was independent of assumptions made about the diagnostic tests.

The National Scrapie Plan (NSP) was launched in Great Britain in 2001, with the aim of eventually eradicating scrapie, a small ruminant transmissible spongiform encephalopathy, from the national sheep flock. Specifically, a selective breeding programme, the Ram Genotyping Scheme, was devised enabling pedigree ram breeders to reduce the number of scrapie-susceptible genotypes from their flocks. The effect of large-scale manipulation of PrP genotypes on commercially important traits within the sheep industry is, however, unknown. We have therefore examined production traits in a total of 43 968 lambs from 32 pedigree breeders across three British hill breeds, comprising 8163 North Country Cheviot (Hill), 21 366 Scottish Blackface and 14 439 Welsh Mountain lambs. Traits examined included: weights at birth, 8 and 20 weeks; ultrasonic fat and muscle depth, and average daily weight gain from 8 to 20 weeks. Linear mixed models were fitted for each trait, including animal (direct) genetic effects and up to three maternal effects. Potential associations with the PrP gene were assessed by fitting either PrP genotype or number of copies of individual alleles as fixed effects. A number of breed-specific significant associations between production traits and the PrP gene were found, but no consistent significant effects were detected across the three breeds. Breed-specific effects were as follows: (i) 0.37 kg higher birth weights (BWTs) in AHQ homozygous North Country Cheviot (Hill) lambs (P < 0.01); (ii) 0.16 kg higher BWTs in ARR homozygous Scottish Blackface lambs (P < 0.05); (iii) 0.5 kg higher 8-week weights in VRQ heterozygous Scottish Blackface lambs (P < 0.01); (iv) a 0.72 kg decrease in scan weight associated with homozygous ARR Welsh Mountain lambs (P < 0.01); (v) 0.51 mm higher ultrasonic muscle depths in AHQ homozygous Welsh Mountain lambs (P < 0.01); (vi) 0.48 mm lower ultrasonic muscle depths in Welsh Mountain lambs carrying one or more copies of the ARR allele (P < 0.05) and (vii) 0.2 mm higher ultrasonic fat depths in heterozygous VRQ Welsh Mountain lambs (P < 0.05). The use of a Bonferroni correction to define appropriate significance thresholds across the three datasets, which account for the large number of independent comparisons made, resulted in breed-specific comparisons, with P < 0.01 becoming significant at P∼0.05, and the remaining breed-specific comparisons no longer being significant. The absence of a common effect across the three breeds suggests that any true association found may be due to breed-specific alleles of neighbouring genes in linkage disequilibrium with the PrP locus.

The UK national scrapie plan (NSP) for sheep is based on selection for the resistant ARR/ARR genotype and elimination of susceptible types of the ovine prion protein (PrP) gene. The aim of this study was to estimate the possible association of the PrP genotype and performance traits by using data from the CAMDA Welsh Mountain flock. Four alleles (ARH, ARQ, ARR and VRQ) and 10 genotypes covering all five NSP risk groups were present in the CAMDA flock. Overall, the most common allele was ARR (35.2%), and VRQ was the least common (5.4%). The commonest genotypes were ARR/ARQ (23.7%) and ARR/AHQ (23.1%). The most resistant genotype, ARR/ARR, and the most susceptible genotype, VRQ/VRQ, were found in 10.2% and 0.3%, respectively, of the population tested. The associations of PrP genotypes with weight and ultrasonically scanned traits were investigated in three analyses, the first using genotypes, the second using risk categories and the third using number of alleles. These associations were evaluated by univariate analysis of each trait using an animal model with maternal effects where appropriate, and PrP was included as a fixed effect. Selection for scrapie resistance will not adversely affect progress in the traits considered and is consistent with improvements in muscle depth.

Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders of humans and animals associated with an accumulation of abnormal isoforms of prion protein (PrP) in nerve cells. The pathogenesis of TSEs involves conformational conversions of normal cellular PrP (PrPc) to abnormal isoforms of PrP (PrPSc). While the protein-only hypothesis has been widely accepted as a causal mechanism of prion diseases, evidence from more recent research suggests a possible involvement of other cellular component(s) or as yet undefined infectious agent(s) in PrP pathogenesis. Although the underlying mechanisms of PrP strain variation and the determinants of interspecies transmissibility have not been fully elucidated, biochemical and molecular findings indicate that bovine spongiform encephalopathy in cattle and new-variant Creutzfeldt–Jakob disease in humans are caused by indistinguishable etiological agent(s). Cumulative evidence suggests that there may be risks of humans acquiring TSEs via a variety of exposures to infected material. The development of highly precise ligands is warranted to detect and differentiate strains, allelic variants and infectious isoforms of these PrPs. This article describes the general features of TSEs and PrP, the current understanding of their pathogenesis, recent advances in prion disease diagnostics, and PrP inactivation.

Gene banks are usually used for storing general genetic variability of endangered living populations but can be also used for storing alleles of a particular locus that are being eradicated through artificial selection programmes. In such scenarios gene banks would allow future re-introduction of one or more of the alleles being eradicated (and the associated diversity) into living populations. Frequencies within the bank for the locus of interest should have pre-determined target values. In this study, an algorithm is derived to obtain the optimal contributions of all candidate donors to achieve the target frequencies of the removed alleles in the bank while maintaining at the same time genetic variability in other loci unlinked to those targeted in the eradication programme. The efficiency of the algorithm is tested using the case of gene banks storing prion protein alleles currently disfavoured in scrapie eradication programmes (i.e., the AHQ, ARH, ARQ and VRQ alleles). Results showed that the algorithm was able to find the combinations of candidate contributions fulfilling different objectives regarding target frequencies and restrictions on coancestry. The most important factors influencing the optimal contributions were the allelic frequencies and the levels of diversity (coancestry) of the living population. Heterozygotes were favoured over homozygous individuals as, for a given number of animals contributing to the bank, the use of heterozygotes leads to lower levels of coancestry. Notwithstanding, almost all donors were sampled when restrictions on the global genetic diversity to be stored were severe.

Polymorphisms at codons 136, 154 and 171 of the gene encoding the prion protein (PrP) are associated with susceptibility to classical scrapie in sheep. Genetic selection for scrapie resistance based on PrP genotypes is central to the scrapie eradication programme in Great Britain but there are concerns about how this may affect other economically important traits. The objective of this study was to evaluate associations of PrP genotypes with live weight and slaughter traits in a hill sheep breed in Great Britain. Data used were from an experimental flock of Swaledale sheep in which the alleles ARR, ARQ, AHQ and VRQ were present. About 1450 genotyped lambs with birth, marking and weaning weights, and 620 with slaughter records were used for the study. Mixed models with various fixed effects and random direct genetic and maternal effects were tested to determine the appropriate model to use for each trait. None of the differences in lamb performance between PrP genotypes consistently reached significance. Therefore, this study does not support existence of significant relationships between PrP genotype and lamb performance traits in this breed.

In this study the potential association of PrP genotypes with meat traits has been investigated. The data included young rams from individual testing stations of three breeds: Ile de France, Préalpes du Sud and Blanc du Massif Central. These breeds were chosen due to their large number of available animals (with performance records and PrP genotypes) and their differential ARR haplotype frequency. Two analyses differing in the PrP genotype classes considered were carried out. Firstly, animals were categorized into three classes: ARR homozygous, ARR heterozygous, and animals without the ARR haplotype. The data for this analysis included 725, 534 and 832 animals for Ile de France, Préalpes du Sud and Blanc du Massif Central breeds, respectively. Secondly, as the two predominant haplotypes in these breeds are ARR and AR- (and AR- includes ARQ and ARH haplotypes), the effect of substituting 1 or 2 ARR haplotypes for AR- haplotypes was studied. These comparisons involved three genotype classes: ARR homozygous, ARR/AR-, and AR-homozygous. The data for this analysis included 532, 509 and 620 animals of Ile de France, Préalpes du Sud and Blanc du Massif Central breeds, respectively. Meat traits were analysed using an animal model (where the PrP genotype was included as a fixed effect) and they included growth rate, ultrasonic fat depth, and ultrasonic muscle depth. The results of this study indicate no evidence of association between PrP genotypes and the meat traits studied in these sheep breeds.

The objective of this study was to analyse the associations between ovine prion protein (PrP) genotypes and reproduction traits in three German meat sheep breeds. Reproduction traits were age at first early lambing, age at first late lambing, first lambing interval, second lambing interval and total number of lambs born. The data set included 595 genotyped German Texel sheep among 5225 recorded sheep, 351 genotyped German Black-Headed Mutton among 10 177 sheep and 282 genotyped Suffolk sheep among 2849 sheep. Linear animal models were employed for the analysis of the PrP-genotype effect. The PrP-genotype effect was analysed by comparing the most frequent PrP genotypes ARR/ARR, ARR/ARQ, and ARQ/ARQ. In a more general analysis three PrP genotype classes of animals with two, one or no copy of the ARR allele were compared.

In most cases, no significant associations were found between the PrP genotypes and the reproduction traits investigated. Only for the traits age at first early lambing in German Texel and second lambing interval in German Black-Headed Mutton and Suffolk could a significant association with the PrP genotype be observed.

The Dutch scrapie eradication programme aims at the exclusive use of homozygous ARR/ARR breeding rams by the end of 2004. As a consequence, breeds with a small population size and a low frequency of the ARR allele may suffer unacceptable losses of genetic diversity and high inbreeding levels. We simulated three breeding strategies to assess their efficacy in eliminating scrapie sensitive alleles and their effect on inbreeding levels. Under mild selection, both homozygous and heterozygous ARR rams were used indiscriminately. Under moderate selection, homozygous ARR rams were used preferably but they were supplemented with heterozygous rams when necessary. Under severe selection, only homozygous rams were used. Severe selection mimics then the proposed eradication programme. Simulations were carried out with allelic frequencies and population parameters of existent rare breeds in The Netherlands. With severe selection all simulated breeds showed unacceptably high inbreeding rates (> 0·5% per year). For some breeds, moderate selection resulted in acceptable inbreeding rates, while for other breeds only mild selection resulted in acceptable rates. The frequency of the ARR allele after 5 years of selection was only slightly lower with moderate selection than with severe selection (0·8% lower on average), but it was clearly lower with mild selection. Based on these simulations, we propose a selection programme where with low frequencies of the ARR allele, mild selection is used initially. Once the ARR frequencies rise to a particular value, the switch can be made to moderate selection. The population size (e.g. below 750, 750 to 3750 and above 3750 ewes) determines the frequency of the ARR allele at which the switch can be made (33%, 25% and 10%, respectively). With even higher ARR frequencies (above 70%, 50% and 33%, respectively) the regime can be changed to severe selection.

The transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative diseases that are also transmissible. The PrP protein is central to the disease process and has been hypothesised to be the infectious agent. Polymorphisms in the PrP gene have been linked to the incubation time of TSE disease, and mutations in the human PrP gene have been suggested to result in genetic TSE disease. Several PrP transgenic models have been developed. These models express PrP from different species, with and without PrP mutations, and at different levels of gene expression. This article discusses the contribution of these transgenic models to our present understanding of the TSE diseases.