Caribou Prnp polymorphism distribution in Canada and its impact on CWD pathogenesis
Bibliographic record
Abstract
Wild reindeer in Norway were recently diagnosed withchronic wasting disease (CWD) [1]. Prions from CWD-infected deer were also transmissible to other reindeer inexperimental settings [2,3]. Although CWD has not yetbeen reported in wild reindeer (caribou) in Canada, thesestudies show that they are at risk of infection. The wild-typereindeer, homozygous for serine at prion protein (PrP)residue 138 (138SS), developed clinical disease upon oralinoculation. Animals carrying at least one asparagine allele(138SN, 138NN) accumulated prions only in the periphery.However, both genotypes were susceptible to intracerebralprion inoculation [2,3]. Fallow deer are wild-type 138NNand are resistant to peripheral but not intracerebral prioninfection [4]. Thus, we hypothesize that the138N allele,present in caribou herds in Alberta [5], alters CWD patho-genesis by limiting prion transport from the periphery tothe CNS. Our aim is to elucidate the mechanisms involvedin this process.We extracted DNA from ±800 caribou, sequenced thePrnpopen reading frame and determined the 138N alleleprevalence in Canadian caribou populations. Resultsshow that the 138N allele was highly prevalent in theChinchaga woodland caribou population in BC (64%). Itwas also higher in barren-ground (37%) than in otherwoodland caribou populations (26%). To analyse howthe 138N allele affects CWD pathogenesis, we generatedknock-in (KI) mice where the mouse PrP is replaced bywild-type 138SS or 138NN cervid PrP. The KIs wereobtained by injecting CRISPR/Cas9-edited C57BL6embryonic stem cells (Bruce4) into wild-type blastocysts,generating chimeras, and breeding progeny to homozyg-osity in a C57BL6 background. PrP expression was deter-mined using western blotting and qPCR. Correct PrPpost-translational modifications were confirmed byPNGase-F and Endo-H digestion. We will inoculate ourKIs with CWD-positive material from the correspondingreindeer genotypes [1,2]. The CWD-infected reindeermaterial was characterized by real-time quaking-inducedconversion (RT-QuIC) and its transmissibility to trans-genic mice overexpressing elk PrP (TgElk). Attack rate inthe TgElks were almost 100%, except for those inoculatedwith 138SN lymph node material. Western blotting con-firmed the presence of proteinase-K resistant PrP in allterminally ill mice. Our goal is to analyse the susceptibilityof KIs carrying the 138N allele to intracerebral and per-ipheral prion infection. We will also assess the efficiencyof prion transport from the periphery to the CNS in intraperitoneally inoculated KIs. Prion strain propagationwithin a host is highly dependent on its PrP genotype.This study will provide insight into how the 138N PrPspecifically influences CWD propagation in caribou.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.002 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".