The G6S Gene A Genetic Defect and its Management By Dagny Vidinish All animals, including dairy goats, have numerous genetic defects of varying severity. We are all familiar with the occasional multiple teats, for instance, and with such defects as undershot and overshot jaws. Other defects are rapidly fatal, and it often is unclear whether the death of a kid should be attributed to genetics or to misfortune. The exact inheritance of many of these defects is often obscure; for instance, although most people believe that multiple teats show up when both parents carry a gene for this trait there is evidence that in some cases they are actually caused by environmental factors. In order to manage these undesirable genes breeders usually have to fall back on the "don't repeat that breeding" strategy, which is very crude and unsatisfactory. This article will describe a recently discovered genetic defect which is easily managed and eliminated because its mode of transmission is straightforward and, more important, because a foolproof DNA test is available to identify carriers of the gene. This defect's full names are mucopolysaccharidosis IIID, or G-6-Sulfase deficiency, and it is usually referred to as G-6-S. It was first identified in 1987 at Michigan State University, and subsequently the researchers tested nearly one thousand goats in Michigan and concluded that about 25% of Nubians carry this gene. All cases are the result of a single mutation, and appear to be confined to Nubians and their crosses; other breeds were tested initially and they do not have this particular defect. The affected goats lack an enzyme (G-6-S) and this results in a variety of symptoms of varying severity. The main symptom exhibited by affected goats is failure to grow. Sometimes the kid is smaller than normal at birth, and grows slowly. Some breeders have reported kids which grew normally for the first three months and then stopped growing. Other affected goats grow to what appears to be normal size but is in fact small for the particular bloodlines. They lack muscle mass, appear "slab-sided", sometimes with blocky heads. Immune function appears to be compromised, and sometimes they become deaf or blind. The longest-lived goat known to be G-6-S affected died at just under four years of age, and death is usually due to heart failure. Unfortunately affected animals can and do grow up to breed, although they often experience reproductive problems. The same symptoms can have many other causes, so that affected animals are seldom recognized as having a genetic defect. Often they grow normally for the first few months and may be sold before any problems become apparent. In that case the breeder may blame the new owner for the goat's failure to thrive and early demise. Every animal has two genes for every trait, one inherited from the dam and one from the sire. In turn, that animal will pass only one of those genes to each offspring, and which one it will be is a matter of chance, like the flip of a coin. On the average, half the offspring will inherit one gene and half the other. If the two genes are different, then there is a question as to which of them will determine how the animal actually looks or functions. The defective G-6-S mutation is a simple recessive gene, which means that a goat which has only one copy of it will appear perfectly normal and will not show any of the symptoms described above. Such a goat is referred to as a "carrier". A goat which inherits the defective gene from both parents shows symptoms and is referred to as "affected". A "normal" goat, in this context, is one who has two copies of the normal gene. If a normal goat is bred to a carrier, then all offspring will inherit a normal gene from the normal parent. The carrier parent will pass a normal gene to half the offspring, and a defective gene to the other half. Thus such a mating will, on the average, produce half normal kids and half carriers, and no affected ones. If two carriers are bred to each other, then one quarter of the kids will be normal, one half will be carriers, and one quarter will be affected. If an affected goat is bred to a normal goat, all offspring will be carriers. An affected goat bred to a carrier will produce half carriers and half affected. As stated above, research shows that 25% of Nubians carry the defective G-6-S gene. Almost all of these are carriers, since most of the affected animals which are born would be culled, and the rest die early. Most people find it surprising that something which is in one quarter of the population can have escaped notice for so long. However, random matings in such a population would result in only one out of sixteen being carrier to carrier, and only one quarter of the kids from these breedings would be affected. Thus only one kid in sixty-four (1.6%) would be affected. Given the variable and obscure symptoms of G-6-S affected kids, it really is understandable that most Nubian breeders believe that they have never encountered affected kids. However, many Nubians are line-bred, and this practice will concentrate certain genes in some lines while eliminating them from others. It has been observed that the G-6-S mutation is very prevalent in the same lines which are known for high milk production. Thus breeders who have been selecting for milk may have inadvertently also been selecting for the G-6-S defect. Fortunately it appears that the two traits are actually independent, that you can cull the G-6-S carriers without at the same time culling the high producers. Usually it is difficult to eliminate a genetic defect without losing all the good genetics for which a line is known. For instance, if a buck throws double teats, then there is no way of knowing which of his offspring will do the same and which will not. You can cull him, but that seems rather heavy-handed since the bad gene will undoubtedly live on in some of his relatives. With G-6-S we are very fortunate to have a foolproof DNA test available which will tell us whether a goat is normal, or a carrier, or affected. This test makes it possible to save the good genetics and eliminate the defective gene if that is our wish. If a superior animal is a carrier, then we can test the kids and manage them in such a way as to avoid the birth of any affected individuals. What is a good management strategy? What is the most efficient way to save the good and get rid of the bad? The usual recommendation for such testable defects is to cull carrier males, but not the females. Remember that if a normal buck breeds a carrier doe, then only half the kids will be carriers, and none will be affected. Thus if there are some carrier females in the herd, then using only normal bucks will reduce the incidence of carriers in the next generation by one half. The average herd would start with 25% carrier females, and if only normal bucks were used the next generation of females would be down to 12.5% carriers, and the next generation to 6.25%, etc. This is in sharp contrast to what a carrier buck would do in the same herd: if used to breed all the does, his daughters would be 50% carriers and 6.25% affected. Clearly there is much to be gained by testing buck kids and retaining only normal ones for breeding. While it is relatively easy to cull a buck kid, one might hesitate to do the same with a proven sire. In particular, there are some very popular bucks whose semen commands a high price and who are carriers for the defective G-6-S gene. A reasonable strategy here would be to use these bucks only on normal does, thus avoiding affected kids. Then one would test the kids and cull carrier bucks. Although the DNA tests are expensive, if testing one's bucks prevents the birth of even one affected kid then it is cost effective. Unlike tests for diseases, a genetic test does not need to ever be repeated. Also, the DNA tests are completely accurate, there are none of the gray areas which can be so frustrating. There is no need to test the kids if both parents are known to be normal. One can work back from one's foundation animals and if there really is no problem in the herd then it may be possible to establish that at reasonable cost. Normally whole blood is used for the test, but semen can also be used. If an AI buck is a carrier, that can be established by finding a carrier offspring out of a normal doe, but no number of normal offspring will prove that a buck is nomal. A number of breeders have expressed the opinion that the G-6-S defect is no more of a problem than many other genetic defects, and therefore does not merit any particular attention. They evidently miss the point that it is the availability of a DNA test which makes this defect special. One can use goats from bloodlines which are known to have a high concentration of the G-6-S defect completely safely by just testing the particular individuals and either rejecting carriers or using them with proper precautions. There is nothing to be gained by trying to sweep G-6-S under a rug, and much to be gained by sharing information about it. One may wonder why a DNA test has been developed for such an obscure defect, and no help is available for, say, multiple teats. The answer is simple - humans don't have a problem with multiple teats, they do with G-6-S. The same genetic defect, when found in humans, is called Sanfilippo IIID; the affected child appears normal at birth but soon stops growing, looses muscle mass, has neurological deterioration and dies. When the same genetic defect was discovered in goats researchers used them as models for treatment, and goat breeders in turn benefited from their discoveries. ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ G-6-S testing: All samples must be accompanied by a submission form<http://tvmdlweb.tamu.edu/forms/interactive%20Cash%20Sale.pdf>( http://tvmdlweb.tamu.edu/forms/interactive Cash Sale.pdf) and payment. Current pricing for G-6-S testing is $30/in state or $35/out of state. (please check website <http://tvmdlweb.tamu.edu/> for updated info) You need 1-2 ml EDTA blood (whole blood in a purple top tube) or 2 straws of semen to do this test. When shipping from Canada, it is advisable to first obtain a copy of TVMDL's import permit for blood samples. Make sure you check out their shipping regulations on their website, too! ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ More Information: The TVMDL website http://tvmdlweb.tamu.edu/ (Choose "Testing" from the menu at the top of the screen, then Molecular Diagnostics under Fee Schedule to the left. It is listed as G6S mutation, Caprine <http://tvmdlweb.tamu.edu/testinf.php?unit=907>.) Direct link to TVMDL contact information<http://tvmdlweb.tamu.edu/gen.php?page=contact>page to get more info. >>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>> The full name for G-6-S is: Glucosamine-6-Sulfatase Deficiency *or* Caprine Mucopolysaccharidosis-IIID It was first discovered in Nubians by Michigan State University in the 1980's. This is a simple recessive gene (meaning goats with only one copy appear normal) that can be breed out in a few generations. There are *Affected* (has two copies of the defective gene & has symptoms), *Carriers* (has one copy of the defective and one copy of the normal gene & no symptoms), and then we have the *Normal* (has two copies of the normal gene) goats. Symptoms of Affected animals can include: * Small Stature * Lack of Muscling * Immune System Problems * Heart Problems * Reproductive Problems * Death by 3 to 4 years of age Here's an example of how this works: Let's say the affected gene is an "X" and a normal gene's a "Y". *Affected* goats would have two X's (XX) *Carriers* goats would have an "X" & a "Y" (XY) *Normal* goats have two Y's (YY) Parents give one of their two genes to their kids. SO....... An *Affected* (XX) bred to an *Affected* (XX) will produce: 100% *Affected* (XX) An *Affected* (XX) bred to a *Carriers* (XY) will produce: 50% *Affected* (XX) -- 50% *Carriers* (XY) A *Carriers* (XY) bred to a *Carriers* (XY) will produce: 25% *Affected* (XX) -- 50% *Carriers* (XY) -- 25% *Normal* (YY) A *Carriers* (XY) bred to a *Normal* (YY) will produce: 50% *Carriers* (XY) -- 50% *Normal* (YY) A *Normal* (YY) bred to a *Normal* (YY) will produce: 100% *Normal* (YY) The "ideal" breeding system is to only use Normal bucks & Normal does. But since the cost of the test ($35 per test) can be expensive for most farms ... I would recommend at least getting your bucks tested. Then only use Normal bucks. If you do have a Carrier buck that you want to use. You will need to test does that you want to breed him to and only use Normal does with him. Then test kids (or at least intact bucks) from breedings that the dam or sire is a Carrier. This is what I have done. I've had my buck tested and he tested Normal, so I will only use Normal bucks and test any intact buckling I plan on selling and only sell ones that test Normal. Then when I have enough money to test my does, too, and know their status I'll be able to test less because you can't get Carriers or Affected from Normal parents. ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ G-6-S testing: All samples must be accompanied by a submission form<http://tvmdlweb.tamu.edu/forms/interactive%20Cash%20Sale.pdf>( http://tvmdlweb.tamu.edu/forms/interactive Cash Sale.pdf) and payment. Current pricing for G-6-S testing is $30/in state or $35/out of state. (please check website <http://tvmdlweb.tamu.edu/> for updated info) You need 1-2 ml EDTA blood (whole blood in a purple top tube) or 2 straws of semen to do this test. When shipping from Canada, it is advisable to first obtain a copy of TVMDL's import permit for blood samples. Make sure you check out their shipping regulations on their website, too! ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ More Information: The TVMDL website http://tvmdlweb.tamu.edu/ (Choose "Testing" from the menu at the top of the screen, then Molecular Diagnostics under Fee Schedule to the left. It is listed as G6S mutation, Caprine <http://tvmdlweb.tamu.edu/testinf.php?unit=907>.) Direct link to TVMDL contact information<http://tvmdlweb.tamu.edu/gen.php?page=contact>page to get more info.