Odocoileus virginianus PRNP sequencing reveals AF (Q95G96/H95G96) advantage over AC (Q95G96/Q95S96) against chronic wasting disease

Abstract Chronic wasting disease (CWD) is a highly transmissible spongiform encephalopathy impacting cervids. Variations in the prion protein gene ( PRNP ), encoding the prion protein (PrP), influence disease progression and susceptibility. Protein sequence is a key determinant of PrP strains and their capacity for interspecies transmission. Sequencing PRNP in white-tailed deer has revealed non-synonymous polymorphisms impacting disease—c.285A > C (Q95H) and c.286G > A (G96S). Previous PRNP amplification protocols misclassified homozygous and heterozygous deer due to allelic dropout by a widely used forward primer. We resequenced 586 deer previously classified as homozygous using a redesigned primer (designated Ov- PRNP -F2) and found 128 heterozygotes. Subsequently, we sequenced additional CWD-positive and CWD-negative deer using Ov- PRNP -F2 to correct for dropout and then estimated PrP variant susceptibility and CWD risk using 778 CWD-positive and 3,070 CWD-negative deer from 22 Illinois counties, the largest PRNP sequence dataset to date. Animals encoding PrP variant combination C (96S) and F (95H) were the least susceptible to CWD (OR = 0.03, p < 0.001) compared to deer encoding two copies of PrP variant A 95Q;96G. A novel finding is that deer encoding a single copy of PrP 95H were less susceptible to CWD compared to those with a single copy of PrP 96S (OR = 0.40, p < 0.001). The results support using genotyping methods to map susceptibility to CWD across the landscape, focusing on PrP variant frequencies to improve CWD epidemiological risk models.