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Chronic Wasting Disease Review
Written by Dr Debra Bourne, Wildlife Information Network, for SEAC

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182.  Data from studies on elk and white-tailed deer suggest that breeding for genetic resistance to CWD is not a practical option (Johnson et al., 2003).

Genetics in Cervus elaphus nelsoni

183.  Early coding of the PrP gene in Cervus elaphus canadensis (wapiti) found leucine (Leu) at codon 129 (Schätzl et al., 1997) (this is cervid codon 132 – see O'Rourke et al., 1999)). Later work showed that Rocky Mountain elk have a polymorphism (Met/Leu) at this codon (cervid codon 132) (O'Rourke et al., 1998a; O'Rourke et al., 1999).

184.  In a study looking at the genotypes of both free-ranging and captive Rocky Mountain elk with CWD, Met/Met homozygotes were over-represented among CWD-positive animals compared with control groups not affected by CWD, and no Leu/Leu animals were CWD-positive. However only a few Leu/Leu animals were tested so it could not be stated that this definitely showed resistance of the Leu/Leu genotype individuals. It was noted that the commonest CWD-positive genotype (Met/Met) was also the commonest genotype in the population (75.1 % of the wild population) while Leu/Leu homozygotes made up only 1.1% of the population (O'Rourke et al., 1999). A later study on 10,269 captive elk found that 96.7% of CWD-positive individuals were M/M homozygotes with one CWD-positive L/L homozygote and seven L/M heterozygotes (Spraker et al., 2004). When scrapie was inoculated intracerebrally into six elk, the last of the elk to develop spongiform encephalopathy was L/M heterozygous at codon 132; the other two individuals which became infected were both homozygous M/M (Hamir et al., 2004b). It has been suggested that experimental pathogenesis and oral challenge trials in elk of all three genotypes will be required to determine whether there are any differences in disease progression between the genotypes, such as a prolonged incubation period in heterozygotes (Spraker et al., 2004).

185.  Recent data suggests that genotype does affect incubation time in elk; incubation is shorter in individuals homozygous for methionine at codon 132 (Williams & Miller, 2004).

186.  An unexpressed pseudogene, as detected in the two Odocoileus spp. deer (see below), has not been detected in Cervus elaphus nelsoni (O'Rourke, 2004; Spraker et al., 2004).

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Genetics in Odocoileus hemionus

187.  Initial comparison of coding of the PrP gene in healthy Rocky Mountain elk (Cervus elaphus nelsoni) and mule deer (Odocoileus hemionus) revealed 99.6% similarity, with glutamine (gln, Q) at codon 226 in the mule deer whereas glutamic acid (glu, E) was found in this position in the elk; there was also a polymorphism at codon 138 in the mule deer, with either serine (Ser, S) or asparagine (Asn, N) at this position (Cervenáková et al., 1997). Raymond et al. (2000) confirmed the difference at codon 226 between Cervus elaphus nelsoni and Odocoileus spp. deer and also detected the polymorphism S/N at codon 138 in the deer. Work by O'Rourke et al showed three alleles, two alleles coding S and N respectively at codon 138 for alleles designated 138S2 and 138N1, with the third allele, designated 1238S1, differing from 138S2 by a silent mutation (O'Rourke et al., 1998a).

188.  Later studies (Brayton et al., 2004) on 145 samples found that 144 of the 145 were heterozygous at codon 138: serine [S] / asparagine [N] (agc change to aac) as well as non-coding polymorphisms at codon 139 (agg/aga) and codon 156 (aat/aac). Two to four PRNP alleles were detected per individual, with either one or two alleles encoding 138 S in every individual and one or two alleles always coding 138 N. It was determined that a gene duplication event had occurred: in addition to a full length functional gene there was a processed pseudogene, which is not translated. The single deer that typed homozygous for 138S was found to lack the pseudogene. Within the functional gene three alleles were detected; coding changes were found only at codon 20 (aspartic acid [D] or glycine [G] and at codon 225 serine [S] or phenylalanine [F]; all the functional gene alleles coded S at codon 138. There were also non-coding changes at codons 131, 146, 156, 202 and 206. The functional gene coded for S at codon 138 while the pseudogene coded for N at this location. Out of the six possible peptide combinations for the functional gene sequences, four combinations were found in the 47 CWD-positive mule deer tested: D20S225-D20S225, D20S225-D20F225, D20S225-G20S225 and G20S225-G20S225; 34 (72.3%) CWD-positive animals were homozygous for D20S225, one (2.1%) was homozygous for G20S225 while eight (17.0%) were heterozygous at codon 20 and four (8.5%) were heterozygous at codon 225. None of the 47 CWD-positive deer were found to be D20F225-D20F225 or D20F225- G20S225, but since the allele D20F225 was rare much larger sample sizes will be required to determine whether this allele affects susceptibility (Brayton et al., 2004).

189.  While no genotype is known to confer resistance to CWD infection, genotype does affect incubation times for CWD in this species; the incubation time is shorter for mule deer which are homozygous for serine at codon 225 compared to individuals heterozygous S/F at this codon (no data is yet available for incubation time in the rare F/F252 homozygote) (Williams & Miller, 2004).

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Genetics in Odocoileus virginianus

190.  The first polymorphisms detected in the PRPN of Odocoileus virginianus – white-tailed deer were at codon 96 glycine [G]/serine [S] and codon 138 serine [S]/asparagine [N]; in addition it was noted that, as with Odocoileus hemionus, this species differed from Cervus elaphus nelsoni by coding for Q rather than E at codon 226 (Raymond et al., 2000). Johnson et al. (2003) detected in addition a polymorphism at codon 95: glutamine [Q] to histadine [H]. The QGS allele (glutamine at codon 95, glycine at codon 96 and serine at 138) has been referred to as the "wild-type" allele (Raymond et al., 2000, Johnson et al., 2003). CWD-positive QGS/QGS, QGS/QGN and QGS/QSS deer were all detected in free-ranging white-tailed deer in Wisconsin. It was noted that, while no significant differences were found, trends indicated that the QSS allele was underrepresented within CWD-positive individuals (Johnson et al., 2003). This was not expected given that data from cell-free conversion studies had indicated little or no molecular barrier to conversion of the QSS allele to the PrP-res form (Raymond et al., 2000; Johnson et al. (2003). Note: this work was carried out before the presence of the PRPN pseudogene was recognised: see below, paragraph 191.

191.  More recent work, involving testing of 133 individuals from an enclosure in western Nebraska, USA, in which 50% of the deer were CWD-positive revealed a functional gene and a pseudogene (O'Rourke et al., 2004). Three polymorphisms encoding amino acid substitutions within the functional gene: glutamine [Q] or histadine [H] at codon 95, glycine [G] or serine [S] at codon 96 and alanine [A] or glycine [G] at 116; all alleles of the functional gene encoded serine [S] at codon 138. There were four functional alleles: QGAS, QSAS, QGGS and HGAS with allelic frequencies 0.50, 0.36, 0.13 and 0.011 respectively. In 26% of the deer a processed pseudogene was identified also, with two alleles, showing five or six copies of the octapeptide repeat and both of which encoded asparagine [N] at codon 138. The pseudogene was found in individuals of all the major PRNP genotypes and, as expected for a non-functional gene, did not correlate with CWD status.  Of the ten potential diploid genotypes (for the functional gene), nine were detected in the herd; no homozygotes of the rarest allele, HGAS, were present. All five of the commonest diploid genotypes in the herd were found in white-tailed deer with CWD. While no QGGS homozygotes or HGAS/QGAS individuals were found to be CWD-positive there were few deer with these genotypes within the herd (two of each), so conclusions cannot be drawn. Within the five major diploid genotypes the frequencies of CWD-positives differed (chi-squared 12.2, 4 df, p=0.016) and in particular deer haploid or diploid for QGAS were overrepresented within the CWD-affected animals, while those carrying one or two QSAS alleles were underrepresented among the CWD-positive animals. However there was no evidence of resistance to CWD in deer with any of the major alleles in this study (O'Rourke et al., 2004).

192.  No additional markers associated with resistance to CWD have been detected by microsatellite analysis of DNA samples from a herd of white-tailed deer which is heavily infected with the disease (O'Rourke, 2004).

193.  Differences in the PRPN gene between species, and polymorphisms within species for the known natural hosts of CWD are provided in Table 2. See Table 3 for a comparison of PRNP sequences from various North American and European cervid species.

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Age specific susceptibility?

194.  It is probable, based on age-class specific prevalence data from wild cervids and epidemiological evidence from captive cervids in affected research centres, that both adults and fawns may become infected with CWD (Miller, Wild & Williams, 1998; Miller et al., 2000).

195.  Most cases in the research facilities in Colorado and Wyoming where the disease was first investigated occurred in animals of three to four years of age (Williams & Young, 1992). Early-stage disease with PrPCWD found only in the lymphoid system, not in the CNS, has been identified in adult white-tailed deer of estimated age five years or older, suggesting either infection as adults or extremely prolonged incubation (O'Rourke et al., 2004).

196.  In Rocky Mountain elk, clinically affected individuals have been diagnosed from about 17 months old to 15 years old while infection has been diagnosed by immunohistochemistry (IHC) in individuals from one year old upwards. Within free-living elk submitted from northcentral Colorado, March 1981- June 1995 due to suspicious clinical signs and diagnosed with CWD the youngest affected animal was 1.8 years old and the oldest 15 years old (Spraker et al., 1997). In 4/23 female elk (17%) from a cohort hand-reared at a wildlife research facility in Colorado in 1986 the age at onset of clinical signs was about 2.9 to 8.1 years (Miller, Wild & Williams, 1998). Within farmed elk, in a herd presumed to be recently infected one individual was older than 15 years (Williams, Kirkwood & Miller, 2001).  The earliest age of diagnosis in an elk from a privately owned game farm in South Dakota was 17 months, while other affected animals from that herd were at least two years old (O'Rourke et al., 1999). In 46 clinically normal elk on an infected elk farm in Saskatchewan, Canada, shown to be CWD-positive by IHC, the age range was one to 13 years (Balachandran et al., 2002). In another captive herd, the presence of PrPres in the brain was confirmed in ten of 17 animals, including four animals only two years old and four animals of three years old. Clinical signs were present in two animals three and five years old, with histological lesions consistent with CWD in one of the two-year-old animals and mild lesions suggestive of CWD in another three-year-old animal (Peters et al., 2000). Testing of 10 269 elk from farmed elk herds in the USA and Canada in which at least one animals had been found to be CWD-positive detected CWD-positive animals of all ages from about 18 months to more than 12 years old (Spraker et al., 2004).

197.  In mule deer, deer diagnosed with CWD in captive research facilities in Colorado and Wyoming were all adults of 2.8 to 4.0 years old (Williams & Young, 1982). In free-living individuals from northcentral Colorado diagnosed with CWD between March 1981 and June 1995, the estimated age range was 2.5 to7.5 years old (Spraker et al., 1997). A study of naturally-infected individuals, based on immunohistochemical  staining and histological lesions, suggested that the progression of disease may be more rapid for individuals infected early in life (Spraker et al., 2002b).

198.  In Odocoileus virginianus – white tailed deer, out of 179 white-tailed deer which had become enclosed by an elk farm fence, in Sioux County, northwestern Nebraska, four fawns only eight months old were among the 50% of CWD-positive animals; these fawns were not showing any clinical signs of CWD (Davidson, 2002). In a study of 500 deer of one year old or older in southern Wisconsin in 2002, within an area radius approximately 18 km, from 476 useable samples there was a trend towards an increase in prevalence with age; only 32 samples were from animals more than five years old, which reduced the study's ability to confirm whether there was a statistically significant increase in prevalence with age (Joly et al., 2003).

199.  A functioning immune system appears to be required for transmission of the TSE agent from peripheral sites (Dickinson & Outram, 1979; Mabbott & Bruce, 2001). It has been suggested that young animals, with a more active immune system, may be more susceptible to peripheral infection with TSEs than older animals; experimental verification would require a crossover design with young and older animals inoculated peripherally and intracerebrally (Heisey & Joly, 2004).

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Effect of sex on susceptibility?

200.  Male, female and castrated animals have all been affected (Williams et al., 1990). A study of free-living mule deer, elk and white-tailed deer in Colorado and Wyoming indicated no obvious sex-related difference in prevalence (Miller et al., 2000). However in mule deer in Colorado and Wyoming data to the end of 2003 showed a higher prevalence in males than females in the age class three years and older (T. R. Kreeger, pers. comm.). Increased prevalence in males over females has also been noted in white-tailed deer in Wisconsin (Langenberg, 2004). Field observations in Canada indicate that within elk, males and females are equally susceptible (Kahn et al., 2004).

201.  In a study of 500 white-tailed deer of one year old or older in southern Wisconsin in 2002, within an area radius approximately 18 km, from 476 useable samples, prevalence was not found to vary with sex: 3.4% of 87 males (95% CI 0.1% - 9.7%) and 3.1% of 386 females (95% CI 1.6% - 5.3%) were CWD-positive (Joly et al., 2003). Further studies in Wisconsin deer have found prevalence in adult males to be higher than prevalence in adult females. It was considered that males might have a higher exposure than females to infection due to larger home ranges increasing their likelihood of contacting CWD, females passing disease to males during the mating season (when males visit many females), or due to the formation of bachelor groups of males in which the males have closer physical contact with one another, which may make spread of disease easier (Wisconsin Department of Natural Resources, 2004a).

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