WHY DO WE NEED TO ELIMINATE SCRAPIE?

Scrapie has been with the sheep industry for centuries and there is some resistance to the idea of the necessity for total eradication. I submit to you that Mad Cow disease should change that attitude among us immediately. Both Mad Cow disease (also called Bovine Spongiform Encephalopathy or BSE), and Scrapie are members of the group called: Transmissible Spongiform Encephalopathy or TSE diseases. Some shepherds claim that in all these centuries Scrapie has never been transmitted from sheep to man. This is completely true. However, how many years did the cattle industry go before a form of BSE was suddenly able to be transmitted to humans? Shouldn't we take a proactive stance and do everything possible to eliminate it in our flocks now? We are lucky in the sheep industry that science has provided us with a way to selectively breed animals that can not contract this disease, even if they are directly exposed to it. The cattle and goat industries have not been so fortunate to date.

UNDERSTANDING SCRAPIE - THE MOLECULAR BASICS:

There are long DNA strings found in the nucleus of every cell in the body which are faithfully copied every time a cell divides. Only very short segments of these strings, called genes, are used by the cell at any one time as a blueprint to make various proteins needed by the cell to live and perform its function. These DNA strings are made up of only four different nucleotides: Adenosine, Guanosine, Cytidine, and Thymidine (A,G, C, or T). Three of these nucleotides in a row form the code (or codon) for an amino acid. Chains of amino acids hooked together form a protein. For example: CGT, CGC, CGA, AGA, AGG, or CGG can all code for the single amino acid called Arginine. Whereas, only the two nucleotide triplets CAA or CAG can code for the amino acid Glutamine.

When a particular protein is needed by a cell, it will send a signal to the cellular machinery to translate the DNA code into its corresponding protein. When the cell no longer needs that protein (it could be minutes, hours, or days) that protein is then targeted to be destroyed by enzymes called proteases.

WHAT IS SCRAPIE? THE PROTEIN BASICS

A gene called PrP codes for a protein normally found in many tissues of the body. It is known to bind copper and protect neurologic synapses. In the case of an animal with Scrapie (or Mad Cow Disease in cattle), the protein encoded by the PrP gene is misfolded and can not be destroyed by cellular proteases when no longer needed by the cell. Scientists gave the name PrP to the gene because in the case of a Scrapie animal, it coded for a Protease Resistant Protein (PrP). Scientists found that not only could the cell not destroy the protein on its own, but it could not be destroyed in the laboratory even under high detergents and very high temperatures. This protein is almost totally resistant to sterilization, cooking heat, and ultraviolet light. The misfolded PrP protein can signal other normal PrP proteins to misfold as well. Worse, it takes very few molecules to start a cascade of misfolded proteins throughout the body which cannot be destroyed. When this protease resistant protein accumulates in the body, particularly the brain, the neurological symptoms of Scrapie appear followed eventually by death. It may take years to see actual symptoms. Since the protein in its normal conformation is found in the animal, it is not seen as an invader and the immune system is not triggered to fight it. As it is not a bacteria or virus, there are no possibilities of developing drugs against it.

IF IT IS JUST A PROTEIN, HOW IS IT SPREAD?

Abnormally folded PrP proteins have been found not only in the nervous system, but also in the spleen, lymph nodes, placenta, intestine, blood, pancreas, ovary, and liver of affected sheep. Scientists are unsure of all the possible mechanisms by which the misfolded protein is spread from animal to animal. One way is from ewe to lamb while in the uterus. Another way is from birth fluids contaminating fields or feed as there are high concentrations of PrP in the placenta. It is also possible for an animal to ingest the misfolded PrP protein from directly consuming parts of an affected animal. You say of course, that sheep do not eat other sheep - no they do not - unless it is fed to them! Though it is illegal for ruminant byproducts to be in sheep feed (or cattle feed) the farmer can only trust that every source of his food supplements are honest and legal. Remember that the heat used to process feeds is NOT enough to destroy these misfolded protease resistant proteins. The recent outbreaks of Mad Cow in Canada have reportedly been traced in all likelihood to an unethical feed supplier. Also, it is perfectly legal for lamb or beef products to be in dog food (Have you ever found your sheep with their heads in the livestock guard dog's feeder?).

Some scientific studies have found that Scapie can outbreak spontaneously in flocks where no originating source can be traced. Recent research is investigating geographic regions of low copper occurrence with a spontaneous appearance of a Scrapie-related disease in the deer family. Since the PrP protein binds copper, this area of research bears watching.

GENOTYPING FOR SCRAPIE RESISTANCE

By evaluating animals that did and did not get Scrapie from exposed flocks, scientists tracked down three single nucleotide changes in the genetic code of some sheep for the PrP gene which showed resistance to the misfolding of the protein, or that allowed the protein to misfold easier (i.e. made the animal more or less susceptible to contracting Scrapie). Scientists have numbered the codons of the PrP gene and it is at codons 136,154, and 171 where they found these changes. Shepherds can have their animals genotyped by a laboratory and then selectively breed for those animals that have a PrP gene which can NOT misfold even if the animal is directly exposed to Scrapie.

Codon 136 codes for either the amino acid Valine (V) or Alanine (A). With Valine allowing the protein to misfold easier and thus makes the animal more susceptible to Scrapie. Alanine (A) is the desired amino acid at codon 136.
Codon 154 codes for either Histidine (H) or Arginine (R). It is less important in breeding for Scrapie resistant animals in the U.S. as it appears to be involved more in fast onset (R) or slower onset (H) of symptoms. However, research is ongoing on this codon especially in breeds which have no RR 171 animals in their populations. It has been found to be important for resistance to some of the Scrapie types found in Europe, and may become important in sheep exporting.
Codon 171 codes for Glutamine (Q), Arginine (R), Histidine (H), or Lysine (K). Arginine (R) at codon 171 makes it nearly impossible for the PrP protein to be misfolded and result in Scrapie. H or Q at 171 are considered very susceptible to Scrapie. The K at 171 has been found recently in the Barbados breed and its effect on Scrapie resistance has not yet been studied. Arginine (R) is the desired amino acid at codon 171.

UNDERSTANDING YOUR SHEEP'S GENOTYPE

Things get just a little more complicated when you consider that both the ram's sperm and the ewe's egg contribute to the genetic code of their offspring. If both the Ram and the Ewe contribute an Arginine (R) to the lamb at codon 171, the lamb is termed homozygous RR at codon 171. If both parents contribute a Glutamine (Q) code at 171 the lamb is termed homozygous QQ at codon 171. However if one parent contributes an Arginine and one a Glutamine the lamb is called heterozygous QR at codon 171. The good news is that though the homozygous RR 171 animal is considered fully resistant to Scrapie, even the heterozygous QR animal is very highly resistant to Scrapie if the animal has AA at codon 136 (rather than the susceptible V 136 genotype). Following is a table giving the general Scrapie risk for each known genotype at 136/154/171. It should be noted that the categories below may vary slightly depending on the breed, particular outbreak studied, or country. The simple message from all the combined science is: to get rid of the highly susceptible V136, Q 171 genotypes and reduce your A 136 Q 171 genotypes in favor of the fully resistant A 136, R 171 genotype.

ON GENOTYPING EWES AND BREEDING FOR RESISTANCE:

Please Note: To reduce confusion in the discussion below, an "H" at codon 171 is treated as a "Q" at that codon. The H polymorphism is like the Q at 171 in that it does not confer any resistance to Scrapie.

Many current Scrapie educational efforts are emphasizing the genotyping of rams only and breeding only RR 171 rams. This meets the USDA goal of ensuring that all of that animal's offspring will be at least QR at codon 171. This is an important first step toward the eradication of Scrapie. However, it should be pointed out that if these QR offspring happen to be VA at codon 136 (by that RR ram having been bred to a VV or VA codon 136 ewe), they are still Scrapie susceptible (see chart above).

Another area of concern, is that there is a scarcity of RR 171 rams which also display all of the breed characteristics and production goals that many ranchers and breeder's organizations have been working to achieve. We do not want to have a Scrapie free U.S. but destroy the wonderful attributes of many of our breeds in the process! It IS possible to breed QR or even QQ 171 rams and still move your flock (albeit slower) to a more resistant genotype. To do this, the producer must be armed with the genotype information of both the ewe and the ram, at both codons: 136 and 171, and knowledge of basic genetic inheritance patterns provided below. If you are going to use a QQ or QR 171 ram you should always ensure that he has the resistant AA at codon 136 to reduce the number of the most highly susceptible genotype animals in your flock.

The following is breeding information necessary to utilize that exceptional QQ or QR 171 ram, by breeding with the appropriate genotype ewes. It should be noted that these are statistical probabilities of inheritance only. If it is said that 50% of the offspring of a cross will be genotype "X" and 50% will be genotype "Y" this does not mean that you can genotype one twin and get an X and then assume that the other will automatically be a Y. It does mean that if you bred this particular cross repeatedly and produced 20 lambs about 10 would be "X" and 10 would be "Y".

Genotype breeding crosses listed below are in descending order with cross number one being the most preferred to ensure animals resistant to Scrapie, and cross number six being the least preferred cross.

#1) RR 171 by RR 171 cross: This cross will always produce a fully Scrapie resistant RR 171 lamb.

#2) QR 171 by RR 171 cross: 50% of the lambs will be QR at 171 and 50% will be RR at 171.

#3) QQ 171 by RR 171 cross: All of the lambs from this cross will be QR at 171.

#4) QR 171 by QR 171 cross: 25% of the lambs will be QQ at 171, 50% will be QR at 171, and 25% will be RR at 171.

#5) QQ 171 by QR 171 cross: 50% of the lambs will be QQ 171 and 50% will be QR 171.

#6) QQ 171 by QQ 171 cross: This cross will always produce a QQ 171 Scrapie susceptible lamb. If either parent has a V at codon 136 the lamb could be very highly susceptible.

IN SUMMARY:

By checking the chart above (understanding your genotype section) you can see that you would want to genotype any lambs from the above crosses and if at all possible eliminate from your flock QQ 171 lambs which also have a susceptible VA or VV at codon 136. These animals will never help you reach the goal of a Scrapie resistant flock and are themselves the most highly susceptible.

The QR 171 which is VA at codon 136 should be bred with caution (preferably to an RR 171) as a small percentage of offspring from any crosses other than to the RR 171, may be back down in the most susceptible category of QQ 171 with a VA or VV at 136.

The QR 171 lambs (or even the QQ 171 lambs) that are AA at codon 136 however, can be bred by using the above information to slowly reduce the overall percentage of susceptible QQ's in your flock without losing the other characteristics for which you breeding.