Genetic Resistance Research

The project's overall mission is to develop a strain of North American elk genetically immune to Chronic Wasting Disease (CWD) while retaining superior fitness.

Throughout history when different species have been challenged with disease situations such as CWD their survival has depended upon some of the population having resistance to the disease. In the case of CWD, scientists have identified a genetic strain of elk that shows strong resistance to CWD. Unfortunately, this genotype exists in a very small portion of wild elk populations.

Our approach is to first breed more of the resistant genotype then to evaluate it for fitness. If the viability of the resistant strain can be demonstrated, applications can be studied. The knowledge gained involving elk could be helpful in finding similar solutions regarding deer, as well as any other species, including livestock/food chain animals, domestic pets and other wildlife should CWD cross to them.

ERI's goal is to provide this knowledge and make it available to others to use at their discretion. It has been suggested that knowing that a viable resistant genotype exists could significantly impact culling policies. Where culling is deemed the best option, it may be better to identify resistant animals and leave them to rebuild the population. Random culling removes animals that may be resistant.

In some situations the release of resistant animals may be necessary to provide genetic variation or to supplement numbers of animals to bring a depleted population back on a timely basis. Releasing resistant animals may have application in CWD-free populations where it is beneficial to develop a greater percentage of animals that will not contract CWD when it migrates into that population. It is prudent to use resistant animals in any introduction program.

Dr. Dorian Garrick, a CSU researcher in the animal breeding and genetics department, has had significant involvement in the strategy and evaluation of the ERI breeding program. Dr. Garrick writes,"TSE diseases are particularly novel because they are caused by a protein (known as a prion or PrP) and not due to a DNA- or RNA-containing organism, such as a virus, bacterium or fungus that are the usual causes of infectious disease.  Even more intriguing is the fact that prions are naturally occurring cellular proteins that are found in many tissues including the brain and other nerve tissues.  The functions of prions are not well understood.  However, they can take on a normal shape or an abnormal shape.  Exposure to abnormal prions can somehow convert normal prions which then aggregate and cause disease.

 Cattle have been shown to contract BSE from consuming feed containing abnormal BSE prions.  Humans are believed to contract CJD from the introduction of abnormal prions from infected instruments during eye surgery, from eating brains during cannibalism or from eating certain tissues from BSE-infected beef.  It is not known how CWD is transmitted among deer or elk.  However, unaffected animals can contract the disease without direct animal contact when living in environments in which infected animals have previously resided.  Some form of environmental contamination must therefore be capable of spreading CWD. 

PrP polymorphisms

Proteins such as PrP consist of a chain of amino acids.  The sequence of amino acids in the chain is determined by the sequence of base pairs in the coding region of the host DNA.  As with almost all other proteins, mutations can occur that can change the DNA sequence and therefore the makeup of the protein.  When more than one sequence exists in a population, these variants are known as polymorphisms.  Polymorphisms in the PrP gene are known to influence the susceptibility of sheep to scrapie and the susceptibility of humans to CJD.  All the humans who contracted the so-called new variant CJD from consuming BSE-contaminated beef had a particular polymorphism in the 129 codon of their PrP gene.  This codon determines the amino acid that occurs in the 129^th position of the protein. In elk, there are two common polymorphisms in the PrP gene.  The most abundant form contains the amino acid Methionine (M) in the 132^nd position of the protein.  The alternate, less common variant contains Leucine (L).  Population genetics of PrPThe genetic code or DNA is stored on structures known as chromosomes.  Different species of animals have different numbers of pairs of chromosomes.  Animals (including humans) inherit one member of each pair from their father and the other member from their mother.  They thus have two copies of the PrP gene.  When the two copies are the same, the animal is said to be homozygous because all the gametes (sperm or eggs) the animal can produce will contain the same form of the gene.  About two-thirds of elk are believed to be homozygous MM.  Most of the rest of the elk are heterozygous LM – they carry both polymorphisms.  A very rare fraction of elk are homozygous LL. Elk that have been shown to have CWD do not exhibit the same proportion of MM, LM and LL genotypes as does the population at large.  This indicates an association between the susceptibility of contracting CWD and the PrP genotype.  Elk that are MM are more likely to contract CWD then LM or LL elk.  There is also some evidence that the rate of disease progression is more rapid in MM than LM or LL elk. All other things affecting natural fitness being equal, prolonged exposure of a population of elk to CWD would therefore be expected to increase the frequency of the resistant L polymorphism at the expense of the common M variant.  From a population genetics viewpoint it is of interest to know whether MM, LM and LL animals have equal fitness with respect to growth, reproduction, antler production, longevity and resistance to other diseases. Although deer have been shown to exhibit polymorphism of their PrP gene, to date there has been no evidence of associations between these polymorphisms and susceptibility.  Recent evidence suggests that some deer may have a duplication of the PrP gene onto a second chromosomal region.  The polymorphisms that specifically exist on each of these two regions have yet to be detailed. 

Breeding Objective for PrP polymorphisms

Before embarking on a project to artificially select and change the frequency of the L PrP polymorphism, it is critical to determine the relative performance of MM, LM and LL animals.  Presently it is very difficult to compare this performance because the L allele is not particularly common and LL animals are very rare.  All animals vary in genetic merit for a wide range of attributes and a random selection of one or a few LL animals could well exhibit above- or below-average performance simply as a result of chance sampling.  A preferred method to determine gene effects is to mate together heterozygous LM animals.  One or more LM bulls mated to LM cows can generate MM, LM and LL offspring in an expected ratio of 1:2:1.  Comparing the performance of these three groups of offspring will give a much more reliable assessment of PrP effects than will comparison of randomly selected animals from the three genotypes. The primary ERI research objective is to compare the performance of the three genotypes (MM, LM and LL) for a range of performance attributes in both intensive and extensive CWD-free production systems.  In order to achieve this objective, two complementary mating strategies are required.  All available heterozygous LM bulls are mated to heterozygous LM cows.  At the same time, to try and increase the number of heterozygotes, all MM cows are being mated to LL bulls. The matings among LM animals should produce one quarter LL offspring. The highest performing of those LL males will be used for breeding to increase the frequency of the L polymorphism, provided that variant does not adversely affect attributes of fitness other than CWD resistance.