Genetic susceptibility to chronic wasting disease in free-ranging white-tailed deer: Complement component C1q and Prnp polymorphisms

Abstract

The genetic basis of susceptibility to chronic wasting disease (CWD) in free-ranging cervids is of great interest. Association studies of disease susceptibility in free-ranging populations, however, face considerable challenges including: the need for large sample sizes when disease is rare, animals of unknown pedigree create a risk of spurious results due to population admixture, and the inability to control disease exposure or dose. We used an innovative matched case-control design and conditional logistic regression to evaluate associations between polymorphisms of complement C1q and prion protein (Prnp) genes and CWD infection in white-tailed deer from the CWD endemic area in southcentral Wisconsin. To reduce problems due to admixture or disease-risk confounding, we used neutral genetic (microsatellite) data to identify closely related CWD-positive (n = 68) and CWD-negative (n = 91) female deer to serve as matched cases and controls. Cases and controls were also matched on factors (sex, location, age) previously demonstrated to affect CWD infection risk. For Prnp, deer with at least one Serine (S) at amino acid 96 were significantly less likely to be CWD-positive relative to deer homozygous for Glycine (G). This is the first characterization of genes associated with the complement system in white-tailed deer. No tests for association between any C1q polymorphism and CWD infection were significant at p < 0.05. After controlling for Prnp, we found weak support for an elevated risk of CWD infection in deer with at least one Glycine (G) at amino acid 56 of the C1qC gene. While we documented numerous amino acid polymorphisms in C1q genes none appear to be strongly associated with CWD susceptibility.

Influence of the geographic distribution of prion protein gene sequence variation on patterns of chronic wasting disease spread in white-tailed deer (Odocoileus virginianus)

“…Haplotypes rather than diplotypes were examined as previous studies found one copy of the protective mutations sufficient to cause a measurable effect[36]. Management of deer is typically coordinated by county; therefore, we grouped deer according to the county of harvest.…”

Prions are affected by evolution at two levels

“…Even with high levels of CWD exposure, the effects of selection on cervid PrP genotype frequencies could take decades [133], maybe even centuries [134] to manifest. Further, selection may not elicit a strong genotype shift in cervids because PrP genotypes do not confer complete resistance, but merely extend CWD incubation period [135], and susceptible animals would therefore have opportunities to reproduce before infection or during clinical progression [136]. As such, it has been suggested that partially resistant PrP genotypes could ultimately exacerbate CWD epidemics by prolonging the time period for dispersal-mediated spread or prion shedding into the environment [135].…”

Chronic Wasting Disease

“…Consequently it is clear that, to explain the observations in elk and deer reviewed here, we need to move beyond a tally of polymorphisms of the prion protein gene and examine other loci in conjunction with prnp allelic variations. Recently, Blanchong et al [85] have investigated polymorphisms in complement component C1q for association with CWD susceptibility and progression, and Ernest et al [86] have developed kinship analysis tools using microsatellite data and mitochondrial DNA sequence haplotypes that will allow finer analysis of factors influencing genetically linked transmission of CWD among white-tailed deer.…”