Predicting the impact of selection for scrapie resistance on PRNP genotype frequencies in goats
Paola SacchiRoberto RaseroGiuseppe RuEleonora AiassaSilvia ColussiFrancesco IngravalleSimone PelettoMaria Gabriella PerrottaStefano SartoreDominga SogliaPier Luigi Acutis
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Abstract:
The European Union has implemented breeding programmes to increase scrapie resistance in sheep. A similar approach can be applied also in goats since the K222 allele provides a level of resistance equivalent to that of ARR in sheep. The European Food Safety Authority stated that breeding for resistance could be offered as an option for Member States to control classical scrapie in goats. We assessed the impact of different breeding strategies on PRNP genotype frequencies using a mathematical model that describes in detail the evolution of K222 in two goat breeds, Chamois Coloured and Saanen. Different patterns of age structure and replacement rate were modelled as factors affecting response to selection. Breeding for scrapie resistance can be implemented in goats, even though the initial K222 frequencies in these breeds are not particularly favourable and the rate at which the resistant animals increase, both breeding and slaughtered for meat production, is slow. If the goal is not to achieve the fixation of resistance allele, it is advisable to carry out selection only until a desired frequency of K222-carriers has been attained. Nucleus selection vs. selection on the overall populations is less expensive but takes longer to reach the desired output. The programme performed on the two goat breeds serves as a model of the response the selection could have in other breeds that show different initial frequencies and population structure. In this respect, the model has a general applicability.Keywords:
PRNP
Selective breeding
Numerous sheep with the prion gene (PRNP) that encodes for 171QQ develop scrapie, a neurodegenerative prion disease of sheep. Relatively few cases of scrapie-affected sheep with PRNP genetics that encode for 171RR, however, have been found. Using flow cytometric analysis, statistically fewer PrPc-positive microglia and monocytes were observed from sheep with 171RR PRNP genetics than from sheep with 171QQ PRNP genetics (P<0.05). One possibility for the lack of PrP(Sc) accumulation in brains and lymph nodes of scrapie-exposed sheep with 171RR PRNP genetics is because of fewer PrPc-positive myeloid-derived cells available for conversion of PrPc to PrP(Sc).
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Η scrapie αποτελεί λοιμώδες νευροεκφυλιστικό νόσημα των προβάτων και των αιγών. Η νόσος χαρακτηρίζεται από τη δομική τροποποίηση της φυσιολογικής PrPC πρωτεΐνης (προϊόν του prnp γονιδίου), που προκύπτει ως αποτέλεσμα της αλληλεπίδρασης της PrPC με μια πλούσια σε β-ελάσματα ισομορφή της (PrPSc). Η τελευταία πιστεύεται ότι αντιστοιχεί στον παθογόνο παράγοντα της scrapie. Πολυμορφισμοί του prnp γονιδίου αιγών έχουν συσχετιστεί με ορισμένο βαθμό προστασίας έναντι της scrapie. Ωστόσο, τα περιορισμένα διαθέσιμα δεδομένα σχετικά με τη γενετική ποικιλομορφία του prnp γονιδίου αιγών και των αλληλομόρφων του που σχετίζονται με ανθεκτικότητα έναντι της scrapie, δεν επέτρεψαν το σχεδιασμό και την εφαρμογή προγραμμάτων επιλεκτικών διασταυρώσεων που αποσκοπούν στην αύξηση των συχνοτήτων των προστατευτικών αλληλομόρφων σε πληθυσμούς αιγών, τόσο στην Ελλάδα όσο και σε άλλες χώρες. Στόχος της παρούσας διδακτορικής διατριβής ήταν: α) η ανίχνευση πολυμορφισμών στην κωδικοποιούσα περιοχή του prnp γονιδίου ελληνικών αιγών, με σκοπό την εκτίμηση της γενετικής ποικιλομορφίας του prnp γονιδίου και β) η μελέτη επιλεγμένων πολυμορφισμών σε κυτταρικό μοντέλο της scrapie, προκειμένου να διερευνηθεί η συσχέτισή τους με τη νόσο και να προσδιοριστούν πιθανοί μηχανισμοί που σχετίζονται με προστασία έναντι της scrapie. Για τη μελέτη της ποικιλομορφίας του prnp γονιδίου, εφαρμόστηκε αλληλούχιση κατά Sanger στο επιθυμητό τμήμα του prnp γονιδίου αιγών (436 δείγματα από εκτροφές της Βορείου Ελλάδος), σύγκριση των αποτελεσμάτων αλληλούχισης με την αντίστοιχη ακολουθία αναφοράς και προσδιορισμός της συχνότητας των πολυμορφισμών στο σύνολο του πληθυσμού που μελετήθηκε. Για την in vitro μελέτη επιλεγμένων πολυμορφισμών, ποικιλίες της PrP αιγών που έφεραν τους πολυμορφισμούς ενδιαφέροντος εκφράστηκαν σε μολυσμένα με το στέλεχος 22L της scrapie κύτταρα νευροβλαστώματος ποντικού (22L-scN2a) και εκτιμήθηκε το ποσοστό τροποποίησής τους προς PrPSc. Ποικιλίες με μικρότερο βαθμό τροποποίησης σε σχέση με την αγρίου τύπου PrP αιγών συσχετίστηκαν με ορισμένο βαθμό προστασίας έναντι της scrapie. Η παρούσα διδακτορική διατριβή συνέβαλλε σημαντικά στην ενίσχυση της υπάρχουσας γνώσης που αφορά την ποικιλομορφία του prnp γονιδίου στις Ελληνικές αίγες, μέσω της ανίχνευσης νέων πολυμορφικών θέσεων και του προσδιορισμού των συχνοτήτων προστατευτικών έναντι της scrapie αλληλομόρφων, σε αντιπροσωπευτικό δείγμα Ελληνικών αιγών. Τα αποτελέσματα που προέκυψαν από την έρευνα αυτή συνηγορούν υπέρ της επιλογής των αλληλομόρφων S146, Κ222 και Q211 του prnp γονιδίου αιγών για το σχεδιασμό και την εφαρμογή προγραμμάτων επιλεκτικών διασταυρώσεων με σκοπό την αντιμετώπιση της scrapie στις Ελληνικές αίγες, εφόσον επιβεβαιωθεί η προστατευτική τους δράση στις Ελληνικές αίγες μέσω μεγάλης κλίμακας μελετών και εκτιμηθεί η συσχέτισή τους με παραγωγικά χαρακτηριστικά των ζώων. Επιπρόσθετα, η μελέτη ορισμένων από τους φυσικά απαντώμενους πολυμορφισμούς του prnp γονιδίου αιγών που μελετήθηκαν στα πλαίσια της παρούσας διδακτορικής διατριβής σε κυτταρικό μοντέλο της νόσου, επιβεβαίωσε την προστατευτική δράση του αλληλομόρφου S146 και παράλληλα επέτρεψε τη μελέτη χαρακτηριστικών της βιοσύνθεσης του, που πιθανόν να συμβάλλουν στην κατανόηση της προστατευτικής του δράσης.
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Natural scrapie in sheep occurs through a complex interplay between host genetic elements and various strains of the infectious scrapie agent. Scrapie‐related polymorphisms in the coding region of the prion protein (PrP) gene, Prnp, have been studied in a number of breeds. The disease‐promoting V 136 allele, and the susceptibility‐reducing R 171 allele, have proved to be most important. However, variation in the coding region of Prnp cannot alone explain the diverse patterns of scrapie susceptibility in various breeds. For instance, in many breeds plagued with scrapie, the V 136 allele appears to be a rarity. The R 171 allele greatly reduces scrapie susceptibility. This lays the molecular foundation for marker‐assisted breeding for reduced scrapie susceptibility now underway in many countries. Although potentially important, and still under investigation, variable expression level and pattern of the ovine Prnp appears to be of little importance for the occurrence of natural scrapie. Studies of scrapie in mice also indicate that genetic elements other than Prnp may have a strong influence on scrapie incubation time, and hence susceptibility. Narrowing down the search to focus on these elements and identification of candidate genes are important tasks for future research in sheep scrapie.
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Transmissible spongiform encephalopathies (TSEs) are infectious, fatal neurodegenerative diseases characterized by aggregates of modified forms of the prion protein (PrP) in the central nervous system. Well known examples include variant Creutzfeldt-Jakob Disease (vCJD) in humans, BSE in cattle, chronic wasting disease in deer and scrapie in sheep and goats. In humans, sheep and deer, disease susceptibility is determined by host genotype at the prion protein gene ( PRNP ). Here I examine the molecular evolution of PRNP in ruminants and show that variation in sheep appears to have been maintained by balancing selection, a profoundly different process from that seen in other ruminants. Scrapie eradication programs such as those recently implemented in the UK, USA and elsewhere are based on the assumption that PRNP is under positive selection in response to scrapie. If, as these data suggest, that assumption is wrong, eradication programs will disrupt this balancing selection, and may have a negative impact on the fitness or scrapie resistance of national flocks.
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Scrapie is a fatal disease of small ruminants that is not transmitted to humans. The disease became the focus of research and policy when it was shown that sheep infected with BSE develop symptoms indistinguishable from scrapie, and it could not be ruled out that humans could be infected via this route. Among other measures, breeding programs were established to improve resistance to scrapie infection. These were based on selection for a single genotype (PRNP). Here we investigate the effects of the breeding program on PRNP allele frequencies and the impact of the selection for resistance in Bavarian herdbook sheep. We show that selection was successful and no severe side effects occurred.
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Scrapie is a fatal neurodegenerative disease of sheep resulting from the accumulation of a misfolded form of the prion protein (PrP Sc ). Polymorphisms in the host prion protein gene ( PRNP) can affect susceptibility to the scrapie agent. Lysine (K) at codon 171 of PRNP is an inadequately characterized, naturally occurring polymorphism in sheep. We inoculated Barbado sheep with PRNP genotypes QQ171, QK171, or KK171 by either the intracranial (IC, n = 2–7 per genotype) or oronasal (ON, n = 5 per genotype) routes with a scrapie isolate to investigate the effect of lysine at codon 171 on susceptibility. When neurologic signs were observed or at the end of the experiment (70 months postinoculation [MPI]), sheep were necropsied and tissue collected for histopathologic, immunohistochemical, enzyme immunoassay and Western blot examination for PrP Sc . All genotypes of sheep developed scrapie after IC inoculation. After ON inoculation, sheep with the QK171 genotype had prolonged incubation periods compared to the QQ genotype. During the experiment, 2 of 5 of the ON-inoculated QK genotype sheep developed neurologic signs and had PrP Sc in the brain. The other 3 of 5 sheep were asymptomatic at 70 MPI but had detectable PrP Sc in peripheral tissues. None of the ON-inoculated sheep of the KK171 genotype developed signs or had detectable PrP Sc . Our experiments demonstrate that sheep with the KK171 genotype are resistant to scrapie via oronasal exposure and that sheep with the QK171 genotype have prolonged incubation relative to QQ171 sheep. The K171 prion protein allele may be useful to enhance scrapie resistance in certain breeds of sheep.
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The prion protein gene (Prnp) is highly influential in determining risk and susceptibility of sheep exposed to classical scrapie. Sheep homozygous for alanine at codon 136 and arginine at codons 154 and 171 (ARR/ARR) of the Prnp gene are historically considered to be highly resistant to classical scrapie, although they form a significant fraction of cases of atypical scrapie. To date, experimental transmission of prions to ARR/ARR sheep has only been achieved with the BSE agent and mostly by the intracerebral route. We summarise here the results of six separate studies, in which 95 sheep of the ARR/ARR genotype were naturally exposed to (n = 18) or experimentally challenged with (n = 77) natural or experimental sources of classical scrapie by the oral, intra-intestinal, subcutaneous or intracerebral routes and allowed to survive for periods of up to 94 months post-infection. Only the intracerebral route resulted in disease and/or amplification of disease associated PrP (PrPd), and only in two of 19 sheep that survived for longer than 36 months. Discriminatory immunohistochemistry and Western blot confirmed the scrapie, non-BSE signature of PrPd in those two sheep. However, the neuropathological phenotype was different from any other scrapie (classical or atypical) or BSE source previously reported in sheep of any Prnp genotype. These studies confirm the widely held view that ARR/ARR sheep are highly resistant to classical scrapie infection, at least within their commercial lifespan. Moreover, within the constraints of the present studies (only two infected sheep), these results do not support the suggestion that atypical scrapie or BSE are generated by adaptation or mutation of classical scrapie in sheep of resistant ARR/ARR genotype.
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Abstract Prion diseases are progressive and fatal, neurodegenerative disorders described in humans and animals. According to the “protein-only” hypothesis, the normal host-encoded prion protein (PrP C ) is converted into a pathological and infectious form (PrP Sc ) in these diseases. Transgenic knockout models have shown that PrP C is a prerequisite for the development of prion disease. In Norwegian dairy goats, a mutation (Ter) in the prion protein gene ( PRNP ) effectively blocks PrP C synthesis. We inoculated 12 goats (4 PRNP +/+ , 4 PRNP +/Ter , and 4 PRNP Ter/Ter ) intracerebrally with goat scrapie prions. The mean incubation time until clinical signs of prion disease was 601 days post-inoculation (dpi) in PRNP +/+ goats and 773 dpi in PRNP +/Ter goats. PrP Sc and vacuolation were similarly distributed in the central nervous system (CNS) of both groups and observed in all brain regions and segments of the spinal cord. Generally, accumulation of PrP Sc was limited in peripheral organs, but all PRNP +/+ goats and 1 of 4 PRNP +/Ter goats were positive in head lymph nodes. The four PRNP Ter/Ter goats remained healthy, without clinical signs of prion disease, and were euthanized 1260 dpi. As expected, no accumulation of PrP Sc was observed in the CNS or peripheral tissues of this group, as assessed by immunohistochemistry, enzyme immunoassay, and real-time quaking-induced conversion. Our study shows for the first time that animals devoid of PrP C due to a natural mutation do not propagate prions and are resistant to scrapie. Clinical onset of disease is delayed in heterozygous goats expressing about 50% of PrP C levels.
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Transmissible spongiform encephalopathy
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Chronic wasting disease
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Prion protein (PrP) is a pathogeny identified in recent years, which infects both mankind and other mammals.It has been proved that PrP is a sole protein able to duplicate and propagate with itself.PrP can express in many tissues and has important physiological functions in many species of animals.The conformation change of PrP is the origin of transmissible spongiform encephalopathies (TSEs).It has been proved that the sheep genetic diversity of prion protein gene (PRNP) is significantly associated with the resistance to scrapie.In this review, the evidence of association between polymorphisms of PRNP and resistance or susceptibility to scrapie and its effects on reproduction and performance traits were focused.The aim is to provide theory guidance for sheep breeding resistant to disease.
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