About the Project
A Dalmatian Study
The Genetic Correction of Health Problems
By Robert H. Schaible, Ph.D.
Strict selection of certain traits described in breed standards has frequently resulted in making all animals of a breed homozygous for a gene that is associated with health problems. Two types of associations will be considered here: (1) The health problems are additional effects of the gene responsible for the desired trait. (2) A second gene which is responsible for the health problem is linked (located nearby on the same chromosome) to the gene responsible for the desired trait. It is impossible to distinguish between the two types of associations in pure breeds. The desired breed trait is always present. Thus there is no opportunity for health problems determined by a second gene to occur without the desired trait, even if the second gene exists. Crosses to breeds which do not have the desired trait and health problems are required to distinguish between the two types of association.
Two examples of breed traits that have associated health problems and a different means of genetic correction in each example will be discussed. In the first example, achondroplasia, the type of association is of little practical importance because selection has apparently been successful in eliminating the health problems. But in the second example, Dalmatian-type spotting, selection has not been effective. Knowing that the health problems are attributable to a second gene in the latter example, provides the basis for different approaches to the genetic corrections of the problem.
Achondroplasia (short, bowed legs)
A gene that is responsible for achondroplasia seems to be homozygous in all members of the Dachshund, Basset Hound and Pekingese breeds because those breeds uniformly have short legs. The genetic studies conducted by Stockard (1941) indicated that modifying genes responsible for the straightening of achondroplastic legs could be accumulated by selection. Cross of Basset Hounds and German Shepherds produced hybrids that were intermediate in leg length. The hybrids were inter-crossed to produce the F2 generation in which approximately 25% had legs of normal length (homozygous for the normal allele), 50% had legs of intermediate length (heterozygotes) and 25% had short legs (homozygous for achondroplasia). The legs were so crooked in some of the short-legged animals that they were crippled. Apparently, the modifying genes were no longer present in adequate numbers of the right combination in the F2 generation to be effective in straightening the achondroplastic legs. Two conclusion can be drawn from the breeding experiments: (1) The German Shepherd contributed few or no modifiers for the straightening of achondroplastic legs because there had never been a need for selecting those modifiers in the breeding of German Shepherds. (2) Selection for modifying genes in Basset Hounds had been a successful means of correcting the health problems (crippling) associated with achondroplasia.
Dalmatian-type Spotting, Urinary Stones and Hives
Dalmatians generally are born with pure white hair because those that do have patches of pigment (large spots like those of the English Pointer and Brittany Spaniel) are usually not retained for breeding. Many of the Dalmatian-type spots are present in the skin at birth but they do not appear in the hair coat until about two weeks of age. The spots become fully pigmented. Few, if any, white hairs are interspersed through the spots. Evidently almost all of the white hairs of the birth coat located within the spots are replace with pigmented hairs as the spots form in the coat.
The Dalmatian-type spotting is found in many of the hunting breeds but is called “ticking”. Ticking and Dalmatian-type spotting are both believed to be determined by the same gene (Little, 1957). The tick spots of other breeds differ from Dalmatian-type spotting in that the spots are smaller and have white hairs interspersed throughout. Apparently, the white hairs of the birth coat of the other breeds are not replaced with pigmented ones during the formation of the spots.
Trimble & Keeler (1938) observed that the absence of interspersed white hairs in Dalmatian-type spots was associated with a defect in the metabolism of uric acid, not only in the Dalmatian breed, but in the offspring resulting from Dalmatian-Collie hybrids being backcrossed to purebred Dalmatians. In the remainder of the backcross progeny, interspersed white hairs in Dalmatian-type spots were associated with normal metabolism of uric acid. In 1971 and 1972, I repeated Trimble & Keeler’s crosses and found that the same associations generally, but not always, occurred in the backcross progeny. Because the composition of the coats of Collies and Dalmatians differ so much it was possible that variation in the coats might have had the effect on the distribution of white hairs within the Dalmatian-type spots of the backcross progeny. The Collie was not the best choice of breed to use in genetic analysis.
In 1973-1976, I repeated the breeding experiments again except that the Dalmatian was crossed to its nearest relative, the English Pointer, to minimize genetic differences except for the pair of genes controlling uric acid metabolism (Schaible 1976). The hybrid offspring had normal metabolism of uric acid and small tick spots containing interspersed white hairs (Fig. 1). When the hybrid animals were backcrossed to Dalmatians, 16 of the 36 offspring (nearly the expected 50%) had normal metabolism of uric acid. But 5 of the 16 were exceptions to Trimble & Keeler’s observations in that those 5 had few or no white hairs interspersed within the Dalmatian-type spots. The following conclusions are based on these results: (1) Absence of interspersed white hairs in Dalmatian-type spots is not an additional effect of the gene responsible for the defect in uric acid metabolism. (2) The absence of interspersed white hairs in Dalmatian-type spots is the effect of a separate recessive gene. (3) The locations (loci) of both genes are close together on the same chromosome (closely linked). (4) Absence of interspersed white hairs in Dalmatian-type spots and the defect in uric acid metabolism are associated in the Dalmatian breed because the gene for the uric acid defect, instead of its normal allele, just happened to be present with the gene for absence of interspersed white hairs in the primary progenitor of the breed. As selection for absence of interspersed white hairs made the responsible gene homozygous in all members of the breed, the gene for the uric acid defect was inadvertently made homozygous as well because of its close linkage on the same chromosome. The fourth point is speculative but the events are likely.
Keeler (1940) attempted to locate Dalmatians that did not have the uric acid defect in Britain, as well as in the United States, but was unsuccessful. In the subsequent 40 years, Dalmatians have been used for demonstrations and research repeated in medical schools because their uric acid level in the urine is approximately the same as that of man. All of those Dalmatians have been found to have the typical elevated levels of uric acid in the urine.
Unfortunately two serious health problems are positively correlated with the high uric acid levels resulting from homozygosity of the gene for the defect in uric acid metabolism. These are a unique form of dermatitis (hives) and the urate form of urinary calculi (bladder stones and kidney stones). There seems to be little doubt that both health problems are additional effects of the gene responsible for the defect in uric acid metabolism. Reduction of uric acid levels in the blood and urine by feeding allopurinol and meat-free diet relieves the symptoms of both stones and dermatitis. (Lowry et.al. 1973). Such a regimen of treatment is expected to be necessary for some Dalmatians and accepted as the usual way of life by most experienced breeders. However, the trouble and expense of maintaining the family pet in this manner are more than most families are willing to bear.
Dalmatians with subclinical cases of urinary calculi and dermatitis contribute considerably to the propagation of the health problems. Kidney stones can be found on autopsy of some Dalmatians that are apparently health throughout their lives. A great hindrance to effective selection is that relatively late onset of both diseases in those animals that do develop symptoms. Most Dalmatians that develop symptoms do not do so until after one year of age. Breeders are reluctant to remove animals from their breeding programs once they have selected their best show prospects and raised them to maturity. Although the breeder may seriously consider removing the dog from the breeding program when it has an acute attack of either disease, his determination to do so usually wanes when the dog regains his health and again shows good potential of winning in the ring. Most of the breeders who cannot bring themselves to the decision to removed affected mature animals from the breeding program probably could make that decision if puppies that were likely to develop symptoms could be identified by 6 weeks of age.
Although there is no method know for identifying all Dalmatian puppies that will eventually develop symptoms of urinary calculi and/or dermatitis, there is a relatively simple breeding program that will allow for the selection of puppies that will not develop symptoms. Such puppies could be produced and identified if the normal gene responsible for metabolism of uric acid to allantoin could be substituted for this defective allele in some individuals of the Dalmatian breed. This is now known to be possible.
The production of 5 puppies having normal metabolism of uric acid and absence of interspersed white hairs in the Dalmatian-type spots in the backcrossing experiments, demonstrated that the gene for the defect in uric acid metabolism was not required to achieve the spotting pattern described in the standard. Furthermore, the normal allele for metabolism of uric acid to allantoin would eliminate the prevalent form of dermatitis and thus facilitate attainment of the coat that is described in the revision of the standard currently being considered by the Dalmatian Club of America. The proposed wording is “Sleek and glossy in appearance, the coat is in healthy condition, free from blemish.”
In 1976 I advised the Board of Governors of the Dalmatian Club of America that I was going to attempt to breed dogs that would fit the standard as well as most show-quality Dalmatians but would also have normal metabolism of uric acid. From the 5 exceptional puppies produced by the backcross of the Dalmatian-English Pointer hybrid to Dalmatian, I selected the one that fit the standard best (Fig. 2) and backcrossed him to a registered Dalmatian. Fifty-percent of the resulting puppies had normal metabolsim of uric acid and consistently had Dalmatian-type spots without interspersed white hairs. The same procedure was continued for two more generations, through backcross four.
The pedigree of the progeny of the fourth backcross shows the English Pointer as one of the 32 ancestors in the fifth generation, the other 31 being registered Dalmatians. Therefore, the offspring of the fourth backcross are 31/32 Dalmatian.
The spotting pattern and overall type improved with each backcross to the point that the progeny of backcross four (Figs 3&4) are indistinguishable from purebred Dalmatians. Although 10 of the 12 pups were patched in the litter produced by the cross of the Dalmatian and English Pointer (Fig 1, see patch on side of head including ear), the portion of patching decreased to 1 of 13 puppies being patched in the litter resulting form backcross four. The latter frequency of patching is well within the normal range for the Dalmatian and is probably less than the average.
The American Kennel Club is considering* registration of the dog and bitch shown in Figs 3 and 4 so that breeders will have an opportunity to select for Dalmatians that have normal metabolism of uric acid. Given that registered Dalmatians having normal uric acid become available, they may have to be proven in the show ring before the majority of breeders will be interested in them. I have been showing dogs for 33 years and will show Dalmatians with normal uric acid metabolism if registration of them is granted. Stud service and breeding stock will be available to other breeders at the usual price of registered Dalmatians. Many breeders, who are concerned about the health problems in Dalmatians, have already offered assistance in the backcross breeding program even though the dogs are not registered. If registration is granted, I am sure that a number of them will breed show-winning Dalmatians with normal uric acid metabolism and thus help to establish them in the breed.
The British Kennel Club requires four backcrosses to registered animals of a given breed before the backcross progeny can be registered (Burns & Fraser 1966, p25). The American Kennel Club does not currently have such a policy but it seems to be warranted when (1) all members of the breed are homozygous for a gene that is responsible for health problems and contributes nothing desirable to the achievement of the breed standard. (2) the health problems can be resolved by backcrossing the normal allele of the defective gene into the breed.
Initially, Dalmatians having normal metabolism of uric acid will all be produced from backcross mating and therefore will all be heterozygotes. They will comprise about 50 percent of the puppies in each backcross litter. They can be identified at 3 weeks of age when it becomes possible to obtain enough urine in a sample to conduct an assay for the ratio of uric acid to creatinine. Eventually, homozygous normal Dalmatians should be produced by breeding of heterozygotes together. When homozygous normal Dalmatians are bred to the current purebred type, all of the puppies will have normal metabolism and require no testing.
It is unlikely that the gene for the uric acid defect will ever be purged completely from the Dalmatian breed even if all breeders should insist on using only dogs with normal metabolism for breeding. Progeny testing would have to be employed to detect carriers of the uric acid defect in the same manner as is required to eliminate any other undesirable recessive gene (Robinson 1972). Simply selecting normal dogs for breeding without progeny testing would insure that most Dalmatian puppies would be free of dermatitis and urinary calculi. That would be a definite improvement in the breed.
*At its February 10, 1981 meeting, the Board of Directors of the American Kennel Club approved the request for registration
Burns, M.& M. N. Fraser 1966 Genetics of the Dog. 2nd ed. Oliver & Boyd, Edinburgh and London
Keeler, C.E. 1940 The Inheritance of predisposition to renal calculi in the Dalmatian. Journal of the American Veterinary Medical Association 96:507-510.
Little, C.C. 1957 The Inheritance of Coat Color in Dogs. Comstock Publishing Assoc., Ithaca. N.Y.
Lowrey, J.C.,W.G.Barron & H.C. Neibert 1973 Allopurinol in the treatment of an intractable metabolically-derived dermatosis in a Dalmatian dog. Veterinary Medicine/Small Animal Clinician 68:755-762.
Robinson, R. 1972 Catalogue & Bibliography of Canine Genetic Anomalies. 2nded. Co-operative Hereditary Abnormalities Research Team. 1 Oldpark Road, Longbrook Street, Exeter, Devon EX4 4EZ England.
Schaible, R.H. 1976 Linkage of a pigmentary trait with a high level of uric acid and excretion in the Dalmatian dog. Genetics 83 Suppl No.3, p.s68.
Stockard, C.R. 1941 The genetic and endocrinic basis for differences in form and behavior as elucidated by studies of contrasted pure-line dogs breeds and their hybrids. American Anatomical Memoirs No. 19, Wistar Institute of Anatomy and Biology. Philadelphia.
Trimble, H.C. & C. E. Keeler 1938 The inheritance of ’ high uric acid excretion’ in dogs. Journal of Heredity 29:280-289.
About the Author
Robert H. Schaible, PhD, is an Assistant Professor of Medical Genetics at Indiana University School of Medicine, teaching second-year medical students. A graduate of Colorado StateUniversity, he earned his doctorate at Iowa State University where he majored in genetics, minored in animal breeding and vertebrate embryology.
His credential include a postdoctoral fellowship in Biology, Yale University; Assistant Professor, Genetics Department, North Carolina State University; PHS Special Research Fellow, Zoology Department, Indiana University and, prior to his present appointment, Assistant Professor in the Biology Department, Indiana University-Purdue University at Indianapolis. He has also taught Veterinary Medical Genetics at Purdue University, where he has an adjunct appointment in the Small Animal Clinic. He has been a breeder and exhibitor of Dalmatians for nine years and other breeds for over thirty years.
When originally published, this message written by the current President of the American Kennel Club introduced the article.
The following article describes a ten-year research study by Dr. Robert H. Schaible into a serious genetic defect in Dalmatians. It sets forth the basis for his request for registration of two littermates, a dog and a bitch. These puppies are the fifth generation offspring of Dalmatian-Pointer breeding. A five-generation pedigree for these dogs shows all registered Dalmatians except for one of the 32 ancestors in the fifth generation which is a Pointer.
At the February 10, 1981, meeting of the Board of Directors of the American Kennel Club, Dr. Schaible’s request for registration was approved and the dog and the bitch will be registered as Dalmatians.
If there is a logical, scientific way to correct genetic health problems associated with certain breed traits and still preserve the integrity of the breed standard, it is incumbent upon the American Kennel Club to lead the way.
William F. Stifel
President, American Kennel Club
This article first appeared in the April 1981issue of "The AKC Gazette "
©1981 by Robert Schaible