PrP genotype frequencies of the scrapie‐infected sheep in various countries.
Prions are abnormal isoforms of the host‐encoded cellular prion proteins which are misfolding in its three‐dimensional structure acquire pathogenicity. Prions cause transmissible spongiform encephalopathy (TSEs) in humans and some animal species including sheep, goats, cattle, cat, deer and elk. TSEs, also called “prion diseases,” cause irreversible neurodegeneration in the central nervous system and are always fatal. Cellular prion proteins are encoded by prion protein gene (PRNP) in mammals; moreover, it is known that the variations in the PRNP gene have influence on the resistance and/or incubation period of the TSEs. It is well‐documented that after exposure to the pathogenic prions, development of some TSEs depend on the host PRNP genotype, for example, scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, Creutzfeldt‐Jakob disease (CJD) and kuru in humans, as well. In this chapter, genetic resistance to prion diseases will be reviewed.
- prion disease
- genetic resistance
It is known that conformational changes in prion protein cause Creutzfeldt‐Jakob disease (CJD) in humans, scrapie disease in sheep and goats [1, 2], bovine spongiform encephalopathy (BSE) in cattle, feline spongiform encephalopathy in cat, and wasting disease in deer and elk.
Polymorphisms inside the prion protein‐coding gene (
2. Resistance in humans
There exist various types of human prion disease such as Creutzfeldt‐Jakob disease (CJD), fatal familial insomnia (FFI), and Gerstmann Sträussler‐Scheinker syndrome (GSS). Related to the cause of the illness they exist in three main forms: Genetic, sporadic and acquired. Genetic form of the disease is caused by a mutation in prion protein‐coding gene (
The human prion‐coding gene consists of two exons and the second one contains the whole open reading frame. It is known that a valine amino acid at position 129 of the human prion protein provide resistancy to the Creutzfeldt‐Jakob disease. Both Valin129Valin and Methionine129Methionine genotypes are resistant to the disease, whereas Methionine129Methionine genotypes are susceptible [27, 28]. Another polymorphism at codon 219 was reported to be related with development of Creutzfeldt‐Jakob disease in Japanese population .
3. Resistance in small ruminants
Scrapie is a neurodegenerative disease of sheep and goats. As with other transmissible spongiform encephalopathies (TSE) which affect humans and animal species, scrapie is always fatal and characterized by long incubation periods ranging from months to years, vacuolation, neuronal loss and astrocytosis in the central nervous system (CNS) and has no inflammatory or immune responses . The earliest reports of the scrapie based on middle of 1700s in Britain. Various terms such as “scrapie,” “scratchie,” “rubbers,” “rickets” and “goggles” were used to indicate the disease .
It is thought that scrapie first occurred in the United Kingdom in the eighteenth century and following decades, particularly after World War II, the disease spread by importation of the infected animals. Scrapie has reported nearly all over the world, for example, Iceland (1878), Canada (1938), USA (1947), Australia (1952), Norway (1958), India (1961), Republic of South Africa (1966), Kenya (1970), Germany (1973), Brazil (1978), Yemen (1979), Sweden (1988), Cyprus (1989) and Japan (1990), reviewed in reference .
Scrapie has been known for over 250 years; therefore, it is regarded to be prototype of the TSEs . Earlier, researchers thought that it was a hereditary disease, but later, according to the results of the experimental transmission studies, they were considered that “Scrapie was a natural infection and gained from ground”. After seven years of working with several thousand breeding ewes within several hundred ewes were affected classical scrapie, H. B. Parry postulated some hypothesis that scrapie had a hereditary feature in a simple Mendelian autosomal recessive manner, development of the disease determined by genotype of the individuals, and it was not a natural infection. They observed that in high‐incidence flocks, many scrapie diseased individuals had affected parent or progeny [32, 33]. Later studies revealed the evidences that scrapie is a transmissible infection  which is caused by a kind of proteins called “prion” , and development and/or incubation period of the disease under genetic control [36–40].
3.1. Resistance in sheep
Sheep and goat prion protein‐coding gene (
Commonly encoded amino acids at three codons are as follows: alanine (A) or valine (V) at codon 136, arginine (R) or histidine (H) at codon 154 and glutamine (G), histidine (H) or arginine (R) at codon 171 and out of possible other combinations, common
|Risk groups||PrP Genotypes||Norway ||England ||England ||France ||France ||Ireland ||Italy ||The Netherlands ||Iceland ||Greece ||Japan ||Canada |
There is no report about direct transmission from sheep to human in natural condition, nevertheless, scrapie can be transmitted interspecies by experimentally [59–61], furthermore, the cattle prion disease, Bovine spongiform encephalopathy (BSE) which is transmitted to human and causes a variant of Creutzfeldt‐Jakob disease (vCJD) , originated from the usage of scrapie contaminated material in cattle nutrition . Even, in a more recent study, natural scrapie isolate was successfully transmitted to a primate (cynomolgus macaque) suggesting that scrapie has zoonotic potential to primates including human . Epidemiological connection with scrapie, BSE and vCJD emerged public health concerns and lead to establishing scrapie eradication programs, including increasing the genetic resistance to scrapie in scrapie epidemic countries.
In 2001, Great Britain has established the “National Scrapie Plan” (NSP) intending to increase the frequencies of resistance alleles by selective breeding and eventually eradicate scrapie from British sheep herds. According to disease‐associated alleles, five risk groups were designated from R1 to R5 where is R1 referring at the lowest risk and R5 at highest risk . NSP scrapie risk groups can be seen in Table 2.
|Risk groups||Genotype of individuals||Degree of resistance/susceptibility|
|R1||ARR/ARR||Sheep that are most resistant to scrapie|
|R2||ARR/AHQ||Sheep that are resistant to scrapie, but will need careful selection when used further breeding|
|R3||ARQ/ARH||Sheep that have little resistance and will need careful selection when used for further breeding|
|R4||ARR/VRQ||Sheep that are susceptible to scrapie and should not be used for breeding because of carrying VRQ allele|
|R5||AHQ/VRQ||Sheep that are highly susceptible to scrapie and should not be used for breeding|
Reported case per year and estimated of the case number per million sheep according to risk groups in the United Kingdom (UK) are given in Table 3.
|Risk groups||Case per year (||Percentage of sheep||Case per year per million (|
European Union (EU) Commission has issued a regulation in 2003 that required the establish of a selective breeding program for resistance to TSE in each sheep breed of member states ; therefore, European member states have been implementing breeding programs based on elimination of the most susceptible alleles while increasing resistant allele frequencies. For example, as a result of intensive genetic selection programs, particularly in high genetic merit flocks, ARR allele frequencies increased from 50 to 69% in the UK, 49 to 85% in France, 38 to 70% in the Netherlands and 47 to 70% in Italy .
Given the importance of the disease, a lot of genotyping studies on sheep
3.2. Resistance in goats
First natural scrapie case in goats was defined in 1942 . Although goat scrapie has rare incidence compared with sheep, a surveillance program between 2002 and 2009 was performed according to the EU commission direction and over 3000 scrapie cases were reported in goats . Scrapie cases occurring in natural condition in goats have been reported, particularly throughout Europe [76–78]. Transmission of the scrapie from naturally affected sheep to goats which rearing together has often been observed [77, 79–81], in addition, transmission from goat to goat has been known .
In contrast to sheep, limited data are available related to scrapie resistance and
|Codons||AA substitution||Association to disease||References|
|127||G‐S||Incubation period/resistance||[85, 86]|
|142||I‐M||Incubation period||[84, 86, 88, 89]|
|143||H‐R||Limited resistance||[80, 88]|
|146||N‐S or D||Resistance||[78, 90]|
|154||R‐H||Limited resistance||[78, 80, 83, 89]|
|211||R‐Q||Lower susceptibility||[84, 89]|
|222||Q‐K||Resistance||[83, 89, 90, 93]|
|240||S‐P||Resistance (connected with codon 142)||[88, 89]|
As provided in Table 4, some relationships between caprine
Apart from these polymorphisms, an allele of caprine
Influences of the remaining codons over scrapie resistance or susceptibility in goats are not known yet. Currently available data on genetic resistance to scrapie are considered insufficient to establish selective breeding programs in goats.
3.3. Atypical scrapie in sheep and goats
Norwegian researchers have recognized a novel type of scrapie case in 1998 which has unusual histopathological features comparing with classical scrapie. The geographical distribution of the disease indicated that it might be spontaneous scrapie, not a contagious disease. This atypical form of scrapie designated as Nor98 by the authors . Later studies conducted on archived tissue specimens revealed that atypical scrapie is not a new disease and has been existed at least from late 1980s in the UK herds [98, 99]. In the following years, many atypical scrapie cases were reported in sheep and/or goats from [100–103], North America  and New Zealand , as well.
Atypical cases have appeared to relate with the
|Risk groups for classical scrapie||Genotype of individuals|
Although there is very limited data about relationship atypical scrapie and
European selective breeding programs against to classical scrapie in sheep already eliminating the AHQ and AFRQ alleles which have demonstrated to relate with atypical scrapie susceptibility; however, the major problem about ARR (resistant to classical scrapie but susceptible to atypical scrapie) and VRQ (susceptible to classical scrapie but resistant to atypical scrapie) alleles remains to be solved.
4. Resistance in cattle
Bovine spongiform encephalopathy (BSE), the cattle prion disease, belongs to animal TSE's which has been characterized histopathological changes in the CNS as with scrapie. It is newly diagnosed prion disease, which has been never known until 1986 . BSE became epidemic during the 1980s in the UK as a result of the changing rendering process and allowing to enter the prion contaminated product to cattle nutrition, and it is estimated that the exposure began in the early 1980s . Having transmitted to human and causing a new variant of Creutzfeldt‐Jakob disease (CJD)  which is a human prion disease acquired from consumption of the meat products of the BSE diseased cattle , BSE has been regarded by the World Health Organization  as zoonotic. Unlike CJD, vCJD has diagnosed in younger people in the UK , latter in France . Up to 2003, 135 vCJD cases have reported from the UK and 6 cases from France (reviewed in reference ).
BSE could transmit to sheep and goats by experimental routes  and development of the disease seemed to be affected by the
Because of the zoonotic potential and the ability to spread between species of the BSE, it has raised the public health concerns and enforced to governments to take control and preventive measures; moreover, researchers have intensified to reveal the genetic background of the disease.
Early studies on association between
In the following years, hundreds of nucleotide changes and insertions/deletions (indel) were identified in bovine
|23 bp indel genotypes|
|Healthy cattle||BSE‐affected cattle|
|Pooled German breeds||48||0.210||0.440||0.350||43||0.050||0.440||0.510|||
|Pooled German and Switzerland breeds||574||0.160||0.470||0.370||670||0.090||0.470||0.450|||
|Pooled Japanese breeds||464||0.071||0.440||0.489||6||0.000||0.333||0.467|||
|Pooled Czech breeds||81||0.235||0.543||0.222||26||0.077||0.538||0.385|||
|12 bp indel genotypes|
|Healthy cattle||BSE‐affected cattle|
|Pooled German breeds||48||0.210||0.560||0.230||43||0.090||0.470||0.440|||
|Pooled German and Switzerland breeds||574||0.230||0.460||0.310||670||0.170||0.490||0.340|||
|Pooled Japanese breeds||476||0.095||0.468||0.437||6||0.000||0.333||0.467|||
|Pooled Czech breeds||81||0.358||0.444||0.198||26||0.231||0.462||0.308|||
Although the clear association has been shown between
Apart from classical BSE, two more types of the disease have been diagnosed by histopathological examinations; H‐type and L‐type, both of two types classified as atypical BSE and have been observing sporadically. While H‐type BSE characterized with higher molecular mass , L‐type BSE which is also named as bovine amyloidotic spongiform encephalopathy (BASE), characterized with lower molecular mass and has diverse glycopattern of pathogenic prion proteins .
It is reported that
5. Resistance in water buffaloes
During the BSE epidemic in 1980s, it can be assumed that BSE and/or scrapie contaminated by‐products most likely have entered in to water buffalo (Bubalus bubalis) nutrition systems, as well. EU member states have approximately 409 thousand of buffaloes, where 90% of those have been reared in Italy . Between 2001 and 2005, 128 BSE cases in cattle have been reported from Italy . Along with cattle, bison, sheep, goats and some exotic ruminants, water buffaloes have been considered as TSE‐related risk factors ; nevertheless, no BSE or any other TSE has ever been reported in water buffaloes  neither in Italy nor the rest of the world.
Only few studies on indel polymorphisms of the water buffalo
|23 bp indel alleles||12 bp indel alleles||References|
|Country||Breed||In %||Del %||In %||Del %|
|Nili Ravi Buffalo||122||94||6||87||13|
As seen in Table 7, almost all buffalo breeds, except Thai river buffalo, are carrying mostly insertion alleles either at 23 or 12 bp indel loci. This may be an explanation for why buffaloes putatively resistant to BSE.
The SPRN gene, which belongs to the prion protein gene family, encodes the shadow protein. Shadow protein shares characteristic features with cellular prion protein, suggesting the existence of a functional relation with prion proteins . A comparative study revealed that the SPRN gene has species‐specific indel polymorphisms in cattle and buffaloes and causes different promoter activity and expression levels . Furthermore, according to the results of more recent study, molecular structure of buffalo cellular prion protein is different from cattle, but similar to those of rabbits, dog and horse which are considered low susceptible to TSEs . These molecular and structural differences may be another explanation with regard to TSEs resistance in buffaloes.
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