Baking Bread: The Red Hen Approach to Genetic Disease Originally published in Double Helix Network News, Vol. X No. 2, Spring 2002. by C.A. Sharp Remember the story of the Little Red Hen? She grew grain, harvested it, ground it to flour, and used the flour to make bread. At each step she asked the other barnyard animals if they would help. No one would. When the bread came out of the oven wafting its wonderful aroma, everyone wanted some. The hen, refusing to share with a bunch of freeloaders, told them to cluck-off. The original purpose of this old fable was to teach children that if they want a share of life's good things, they have a responsibility to contribute to the process of producing them. While it might not seem so on the surface, this lesson can be applied to dog breeders and canine genetic disease. For breeders the "bread" is the results of hereditary disease research. If we don’t participate in the process—not just in ones and twos, but in dozens and hundreds—our dogs will only get crumbs. Of the nearly 400 identified hereditary diseases in dogs, nearly half have been identified in a single breed only. If that breed is yours and you aren’t doing anything about it, dogs will continue to suffer. Even if a disease occurs in multiple breeds, we cannot assume that research on another breeds will help our own. Determining incidence, mode of inheritance and developing screening tests are vital to the effective control of genetic disease. Breeders hold the key to accomplishing these goals: Data. None of these goals will be reached without effort on the part of those who should be the most interested in the preservation and improvement of the breed. Listings of diseases reported in various breeds are nothing new, but they can provide an inaccurate picture of what is going on. Lists of peer-reviewed journal articles give no indication of how frequent any particular disease is in a given breed, though some of the specific articles in such a listing might do so. A published journal article indicates that someone had the interest or (very important) funding to conduct research on that problem or to write up a case study on one or a few affected dogs. Such articles may describe signs, prognosis and treatment or investigate what goes wrong and brings about disease, but they often do not include any detailed discussion of disease frequency in a population. Very rare conditions can find their way onto such lists and frequently encountered problems may not appear at all. If no one has researched and published an article, the only ones who will know about it are the breeders and the veterinarians who treat their dogs. The author frequently encountered a frustrating “this does not happen in your breed” attitude when she first started investigating Collie Eye Anomaly in Australian Shepherds in the mid 1980s. Except for breeders who had affected dogs or knew those who did and veterinary ophthalmologists experienced with the breed, no one knew it was there. It wasn’t in the veterinary literature or textbooks so it effectively did not exist. Sadly, dogs might be judged clear when they were not, because vets did not know CEA occurred in Aussies and breeders didn’t realize the necessity of checking all puppies at an early age. In 1991 a peer-reviewed article was published on CEA in Aussies and the presence of the disease became an established fact. Every so often, the author still hears of a vet who has told an owner that CEA "doesn’t exist" in Aussies. When this occurs, she gladly sends that vet a copy of the journal article. Disease registries give a better indication of disease incidence, but they also have their limitations. Unless all results of all examinations are submitted, the results may be skewed. For example, many breeders will have Orthopedic Foundation of Animals (OFA) hip x-rays done to screen for hip dysplasia. But those who discover that the hips are bad may opt not to send them on to OFA, thereby skewing the registry’s database toward unaffected dogs and giving a rosier picture of disease incidence than is actually the case. How much rosier will depend on what portion of negative reports is withheld. Even in the case of a database which collects results of all exams, like Penn-Hip and the Canine Eye Research Foundation (CERF), disease incidence will only apply to the reporting population. If a breed is rare and few breeders screen their dogs, the registry’s data will have little meaning. In small-population breeds everyone needs to cooperate to see that most dogs get screened. Even in populous breeds, statistics may or may not be indicative of the whole picture. As a group, show breeders are the ones most likely to utilize screening programs, though that utilization certainly isn’t universal. Working and performance breeders, depending on the breed and the disease, may or may not participate. Those who breed dogs primarily to make money selling puppies, whether on a large or small scale, rarely if ever bother with screening tests. Those who have no intention of breeding are unlikely to screen unless the health of their dog or one of its near relatives makes the test seem necessary. In all of these situations, the resultant registry statistics apply only to the sub-population of the breed that is being tested. If most show-bred dogs are screened and reported, you will have a good idea of how frequent something is in show dogs but you will know nothing about the pet population if those dogs come largely from non-show breeders. For many inherited diseases there is no standard, accepted screening test. Epilepsy is a common inherited problem in a number of breeds for which there is not yet any screening test. Therefore, there can be no registry to record data on affected dogs. Health surveys conducted by breed clubs can be a constructive way to gather disease incidence data. Every breed should conduct them at intervals, but their usefulness can be limited by design, participation and politics. Those who develop the survey must have a good idea of what is going on in the breed genetically and have the will to tackle all pertinent issues. If the question isn’t asked, there will be no answer. Response needs to be statistically significant. Not everyone must respond, but if only a tiny percentage do or only one segment does so (e.g. pet owners vs. breeders,) the results may not give a true picture of disease incidence. Some parent clubs have rather small membership even though the breed is populous. In such cases, if only members are polled even full response may provide inaccurate data on the breed as a whole. And then there is politics. Having been intimately involved with a breed health survey herself, the author has had occasion to discuss the process with a number others who have been involved in such surveys. Several individuals in various breeds voiced frustration at survey results that were edited before presentation or even suppressed at the demand of those with the political power and, one presumes, personal motivation to do so. If sufficient breeders and owners have cooperated with the data-gathering process, good disease incidence statistics may be available. If the mode of inheritance is known, it may be possible to determine the frequency of the gene in the breed population. Steps can then be taken to reduce that frequency. Unfortunately, the mode of inheritance often is not known. Many inherited diseases—and recent research indicates this "most" might be more accurate—do not have simple single-gene modes of inheritance. Even if they do, genealogy data (pedigrees plus diagnostic information) must be gathered on numerous affected dogs and their kin before the mode of inheritance can be discerned. CEA was presumed to be recessive in Collies, but when the disease first was noted in Aussies we could not be sure it was the same in our breed. The author gathered pedigrees and CERF reports provided by a number of people who owned or produced affected dogs. These indicated that recessive inheritance in Aussies was a strong probability. When a breeder donated two affected puppies, those dogs were bred together. All the puppies from that litter were affected, thereby proving the recessive inheritance in the breed. None of this could have been accomplished without the willing participation of those who provided data to build the genealogies and the breeder who made the puppies available. [Note: Recent research is Collies indicated that inheritance did not show a strictly single-gene recessive pattern. Given the variable presentation of the disease it is probably polygenic. Some researchers believe that there is a single recessive gene of major effect, one for which a dog must be homozygous to have the disease at all. The Collie research may indicate that some combinations of the other genes may result in an unaffected dog. Whether this holds true for other CEA breeds remains to be discovered and warrants further research.] Genealogies and biological samples are necessary to develop DNA screening tests. Genealogies can be built from pedigrees and diagnostic paperwork alone, but samples, usually in the form of blood draws or cheek swabs, must come from several members of a family, those with the disease and some of their healthy kin. Breeders are the ones who are most likely to have access to multiple members of an affected family. The author is presently attempting to assist VetGen, a commercial laboratory, to gather data on Australian Shepherd families affected with epilepsy, a common breed problem. In spite of the fact that there are numerous affected Aussies (so numerous that one vet has told her that Aussies "always" come up in discussions of epilepsy among her colleagues), VetGen has been unable to get sufficient data over the course of several years. While owners of sick dogs are usually willing to provide whatever they can if it might help, those who own the parents or siblings of the affected dog frequently are not. Without a screening test those uncooperative individuals will be able to continue hiding behind a curtain of deniability while the breed health crisis continues to get worse. Progressive Retinal Atrophy (PRA), caused by a recessive gene, occurs in numerous breeds of dog, including the Irish Setter. A DNA test was developed for PRA in Irish Setters a few years ago that allows breeders to know ahead of time if a dog will develop the disease as well as whether it carries a single PRA gene and might produce affected offspring. But different genes cause PRA in different breeds, so the Irish Setter test will not work for others. Each breed needs its very own loaf of PRA-test bread. The "recipe" (research and technology) for the Irish Setter test might be used to develop a test for another breed but the "ingredients," in the form of data, can come only from people in that breed. When the disease occurs in closely related breeds, as with CEA in Australian Shepherds, Border Collies, Collies and Shetland Sheepdogs, the genetic cause may be the same. But genes can be difficult to pin-point and sometimes the best that can be achieved is a marker test. The markers are usually microsatellites, tiny bits of non-coding DNA that lie between genes. They are highly polymorphic, which means they have many different alleles, or forms. When DNA gets shuffled through the process of recombination prior to the formation of eggs or sperm, things that are on the same chromosome are likely to be passed on together. The closer together they are, the more likely this will happen. If the gene itself is illusive, researchers look for microsatellites that are close to the gene. Desirable microsatellites will have a particular allele associated with a particular allele of the gene, so the test result will indicate whether the dog has a desirable or undesirable form of the gene and whether it has one or two copies of it. Multiple markers are used as back-ups to prevent false positive or false negative results in case gene and marker go their separate ways during recombination. Markers are likely to be breed-specific, so it is vital that each affected breed contribute to efforts aimed at developing marker tests. Last but hardly least comes money. Research does not happen without funding. Little is available for research into canine diseases from governments and large granting agencies unless affected dogs are being used as a model for a similar human ailment. If we want a strictly canine problem researched, we need to put our money where our mouth is. The American Kennel Club’s Canine Health Foundation (CHF) and Morris Animal Foundation (MAF) both regularly fund canine health research grants, as do a number of single-breed clubs and health organizations. While single-breed groups may not be able to gather sufficient funding on their own, they must get involved. Who better knows the needs and concerns of a breed than those who work with it and breed it? By teaming up with CHF or MAF or forming a coalition with other like-minded groups even a small club can help fund important research. With sufficient, energy, determination and cooperation, a club can do it on its own. The American Border Collie Association (ABCA), an organization of working Border Collie owners and breeders, is largely responsible for funding research into CEA at Cornell University. ABCA approached the Collie Club Foundation (most collies have or carry CEA) as well as the Australian Shepherd Club of America asking if they would like to help fund the project. They were turned down. A smattering of other donations were made toward the work, including a substantial one from a single Australian Shepherd breeder, but the bulk of the funds came from working Border Collie people. If this research results in a direct gene test, or even a series of marker tests, breeders of Australian Shepherds, Collies, Shelties and show Border Collies will owe the ABCA and that one Aussie breeder a debt of gratitude. They will be able to eat from a loaf that wouldn’t have been baked without the hard work of ABCA. We all have to start doing more to help bake the bread, both individually and through our local and national clubs. The clubs must educate members about genetic disease, encourage involvement in research and the sharing of information with other breedersl. They must also make monetary support of breed health research a regular item in their budgets, not something done if and when the club might have some spare change. National breed clubs should encourage members and regional clubs to donate to MAF, CHF and breed health foundations. Individual breeders, whether club members or not, also have responsibility for seeing that the bred is baked, by compiling and sharing data on hereditary disease in their dogs—with each other as well as with researchers—and by making donations toward research a mandatory part of their personal budgets. There are many Little Red Hens in the world of purebred dogs sewing, harvesting and milling grain to bake the bread for genetic disease research. But they are too few to see that all of our breeds get "fed." It's time the rest of us stopped emulating the lazy animals in the Red Hen's barnyard, and pitched in to help.