Merle Genetics

Deafness and the Merle Gene

George M. Strain, PhD

Professor of Neuroscience

Louisiana State University, Baton Rouge, LA

Of all the domestic species, the canine has the greatest variation in size, shape, and skin pigmentation pattern.¹ Results from classical genetic studies in the last century identified at least ten20genetic loci that determine coat color and pattern, represented by the letters A, B, C, D, E, G, M, P, S, and T.² Two of these genes, S (piebald) and M (merle), have been linked to the appearance of congenital hereditary deafness. The S series has one dominant and three recessive alleles: the dominant S allele produces a solid coat color, while the recessive alleles sⁱ (Irish spotting), s^p (piebald), and s^w (extreme piebald) produce increasing amounts of white in the coat and skin. The Dalmatian breed is homozygous for s^w and is the breed with the highest prevalence of deafness: 30% are deaf in one or both ears. Other breeds carrying recessive piebald alleles with deafness problems include the bull terrier, English setter, English cocker spaniel, Australian cattle dog, and Jack Russell terrier.

The second pigmentation gene associated with deafness is merle. The dominant allele M acts on uniform pigmentation to produces an alternating pattern of dark versus light that is also known as dapple. The recessive allele produces uniform pigmentation when the dog is homozygous (mm). Heterozygous merle (mM) in an otherwise black dog produces a blue merle, and in an otherwise brown=2 0dog produces a red merle. Dogs homozygous for the dominant allele (MM) can be mildly affected to the naked eye or severely affected, depending on breed and even varying within a breed. Severely affected MM individuals are often nearly all white, deaf, sterile, and blind or affected by various visual abnormalities. Merles are commonly seen in the collie, border collie, Australian shepherd, Shetland sheepdog, Cardigan Welsh corgi, dachshund, and Great Dane breeds; other breeds less commonly known to carry merle are the Chihuahua, American pit bull terrier, American Staffordshire terrier, Beauceron, Catahoula leopard dog, Koolie, poodle, Pyrenean shepherd, Old English sheepdog, American cocker spaniel, Pomeranian, Hungarian Mudi, Norwegian dunkerhound, and others.

Many of the breeds that carry merle also carry piebald. Whether it linked to S, M, or other causes, congenital deafness has been identified in nearly 90 breeds,³ nearly all of which carry piebald, merle, or both. While we know that the piebald gene is inherited as a simple recessive and the merle gene as a simple dominant, the inheritance of deafness resulting from either gene does not appear to be inherited in a simple Mendelian manner – I’ve bred deaf Dalmatian to deaf Dalmatian and gotten bilaterally hearing puppies. Our data analyses suggest that the inheritance involves more than one gene: M or s and another gene that modifies how strongly the first gene acts.

Relatively few studies of the merle gene have been published, most coming from studies of a breeding colony of merle dachshunds kept at a university in Hanover, Germany. One study⁴ examined auditory function in the animals, and several (e.g. reference 5) examined visual function. From these limited studies of an inbred population in one breed, subsequent authors have, unfortunately, extrapolated the reported findings to apply to all merle-carrying breeds. Current work in our and other laboratories and the experiences of many breeders have shown that the actions of merle have usually been over-stated. Reetz et al.⁴ reported hearing results for 38 dachshunds (Tekels in German): 11 double merles, 19 single merles, and 8 non-merles. They found hearing loss – slight to total, unilateral or bilateral – in 54.6% of double merles, in 36.8% of single merles, and in none of the non-merles. Hearing was tested using the brainstem auditory evoked response (BAER), determining the threshold to click stimuli under sedation. Any threshold above 20 dB was considered to be abnormal, not because that is an accepted standard, but because one of their non-merle dogs had a 20 dB hearing threshold. Only one dog – a double merle male – was totally deaf in both ears (threshold > 90 dB) and none of the dogs were totally deaf in only one ear (unilaterally deaf). Looked at this way, true bilateral deafness occurred in 9.1% (1/11) of the double merles and 0% of the single merles.

How can the reported hearing loss in the remaining single and double merles be explained? The pigment-associated deafness seen with the piebald and merle patterns typically presents as total deafness in one or both ears, based on all of the histological studies that have been reported, so the partial hearing loss reported by Reetz is not likely to be genetic and associated with the merle gene. Instead, it most likely reflects a combination of poor aural h ygiene (dirty ear canals), middle ear infections, and noise-induced hearing trauma. The noise level in institutional kennels is notoriously high, and exposure to high noise levels produces cumulative hearing loss. Dogs in large kennels also usually do not receive regular ear cleaning, leading to build up of excess cerumen and infections, both of which muffle the sound reaching the inner ear. Interestingly, of the 15 “hearing impaired” ears with thresholds between 25 and 50 dB, only 3 were in males. Perhaps differences in kennel housing for females exposed them to greater noise levels in the whelping kennels. Regardless, the hearing loss reported in these dachshunds that can be attributed to a genetic cause is much lower than stated in the published English abstract of this German publication.

In 2006 the gene responsible for the merle pattern in dogs was identified and sequenced⁶ and a commercial DNA test is now available to determine whether a dog is a single or double merle. In an unpublished study performed by myself and these investigators at Texas A&M University,⁷ 70 merle dogs from five b reeds (Shetland sheepdog, Australian shepherd, collie, Great Dane, and Catahoula leopard dog) had BAER hearing tests performed and merle genotype determined by DNA tests. Of 22 double merles, 8 were bilaterally deaf (36%) and 2 were unilaterally deaf (9%). Of 48 single merles only one was unilaterally deaf (2%), a Great Dane that also carried the piebald gene, raising a questions as to the cause for the deafness, and none was bilaterally deaf. Based on Reetz’s study about one third of the single merles would have been expected to have significant hearing loss.

An interesting finding came from our group of 70 dogs: 15 of the double merles were Catahoulas, but only 4 of them were deaf in one or both ears (27%), while 86% of the double merles in the other breeds (Shetland sheepdog, Australian shepherd, collie) were deaf. This suggests a breed difference for the impact of the merle gene on hearing status, which may not be surprising since most double merle Catahoulas are heavily pigmented compared to double merles in the other breeds. We are continuing to test additional dogs to further document and understand these differences.

What do experienced breeders in merle-carrying breeds have to say? I cannot present any numbers because I have not done formal surveys, but I’ve repeatedly heard from long-time breeders who say that they seldom if ever get deaf or blind dogs from breeding merle ✕ merle, especially in the dachshund and Catahoula breeds. There is no denying that such outcomes do occur, especially, it would seem, in the collie-type breeds, but we do not at this time know the determinants or conditions that produce deaf or blind dogs.

What is to be done, then, about the merle gene? It seems clear that merles in some breeds, especially double merles, present a problem. In other breeds the problem is significantly less problematic. It might be said that recent efforts in several national breed clubs to ban merle completely from the breed standard is throwing out the baby with the bath water. Others would argue that the production of even small numbers of puppies with auditory or visual defects is an adequate reason to eliminate the pattern. If we completely understood how merle works and what determines deaf or blind merle puppies, it might be easier to assert with confidence the right way to proceed. Leaving aside the ascetics of the merle pattern appearance, a matter of personal preference, we can say with confidence based on current data that single merles have a very low likelihood of deafness. Double merles in some breeds – Catahoula, dachshund – have a finite but still low probability of being deaf, while double merles in some other breeds – the collie-type breeds – have a high likelihood of producing deaf. Knowing how strongly double merle dogs are impacted within a breed should provide guidance to breeders on whether they should avoid breeding double merles. Researchers will provide some guidance, but unfortunately the studies will take some time. In the mean time it seems prudent to delay making difficult-to-reverse changes in breed standards based on limited information. In most cases the breed standards have been in place for many decades; a few more years of waiting won’t bring about the end of the world while we develop a better understanding of merle.

References

1. Ostrander EA, Wayne RK. 2005. The canine genome. Genetic Research 15: 706-1716.

2. Little CC. 1957. The Inheritance of Coat Color in Dogs. New York: Howell Book House, 194 pp.

3. Str ain GM. 2007. Deafness in Dogs and Cats. http://www.lsu.edu/deafness.deaf.htm.

4. Reetz, I, Stecker, M, & Wegner, W. 1977. Audiometrische Befunde in einer Merlezucht [Audiometric findings in dachshonds (merle gene carriers)]. Deutsche Tierärztliche Wochenschrift 84, 273-277.

5. Klinckmann G, Koniszewski G, & Wegner W. 1986. Light-microscopic investigations on the retinae of dogs carrying the merle factor. Journal of Veterinary Medicine A 33:674-688.

6. Clark LA, Wahl JM, Rees CA, & Murphy KE. 2006. Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog. Proceedings of the National Academy of Sciences103:1376-81.

7. Clark, LA, Wahl JM, Rees CA, Strain GM, Cargill EJ, Vanderlip SL, & Murphy KE. 2007. Canine SINEs and their effects on phenotypes of the domestic dog. In: P. Gustafson, ed. Genetics of Disease (in press).

The Author

George M. Strain is a professor of neuroscience at the LSU School of Veterinary Medicine, where he has studied deafness in dogs and cats for over twenty years. His training is in electrical engineering, biomedical engineering, physiology, and neurology. More information on deafness can be found on his Deafness in Dogs and Cats web site: www.lsu.edu/deafness/deaf.htm.

Merle Strain
George M. Strain, PhD

Recent issues of Top Notch Toys have printed dialog about the merle gene, especially relating to its presence in the Chihuahua breed. One particular article (1) cited research of mine (2) with an incorrect interpretation that I wish to correct. In addition, I would like to provide unbiased up-to-date information on the merle gene that may inform and clarify the debate on this issue. I have been performing research on hearing and deafness since the late 1980's, and am identified as a leading authority on deafness in dogs, so I am well positioned to provide this information. I should point out that publications and writings of mine from past years discussing the merle gene no longer represent my opinion, as recent research has led me to change my position.

The above cited article contained the statement that According to Dr. George Strain merle and piebald dogs with blue eyes are 50% more likely to be deaf.@ The research from which this was drawn only applied to the piebald gene and only applied to the Dalmatian breed, where blue eyes and deafness are a wide-spread problem (30% of US Dalmatians are deaf in one or both ears). My research did not apply to dogs with merle, and I am unawa re of any study examining this issue using adequate numbers of dogs and dogs from breeds other than Dachshund, where the published studies have limitations (see below).

Two pigment genes are associated with deafness in dogs: piebald (s) and merle (M). Piebald, which is present in Dalmatians, bull terriers, cocker spaniels, Jack Russell terriers, Chihuahuas and others, is a recessive gene. There are three recessive alleles for piebald: Irish spotting (si), piebald (sp), and extreme white piebald (sw); dogs that have uniform color without white carry the dominant allele (S). The piebald gene produces areas of white by suppressing pigmentation cells (melanocytes). Merle, which is present in Shetland sheepdogs, Australian shepherds, Dachshunds, Great Danes and others, is a dominant gene. Merle produces a color pattern where patches of color are diluted or absent (white); animals homozygous with the recessive allele (mm) have solid color. Dogs with piebald must be homozygous to have areas of white, while merles can be either heterozygous (mM) or homozygous (MM). There is no evidence to suggest that dogs carrying both the piebald and merle genes have an increased likelihood of deafness.

Much of the literature on merle in the past focused on problems seen in homozygous merles and in breeds where the merle gene can produce dramatic effects B in some cases including deafness, blindness and microphthalmia, and sterility. Even heterozygous dogs in these breeds can have less serious visual and auditory deficits. This indeed happens with some breeds, but unfortunately many people have taken this truth and extrapolated it to apply to all breeds carrying the merle gene, which is not true. For example, dogs in the Catahoula breed can be homozygous merle without any of these health defects, and heterozygotes do not seem to be affected. Until recently it was not possible to even distinguish between mM and MM merles in some breeds.

Since not all breeds carrying the merle gene experience the deleterious effects, it is incautious to proclaim that the presence of this pattern in a breed will be injurious to the breed without first investigating whether deaf or blind dogs result from breeding heterozygous merles. Are there any known deaf or blind merle chihuahuas? If so, are they heterozygous or homozygous? In many breeds carrying merle, breeders know not to breed homozygous merles, and visual and auditory deficits do not seem to be a problem in the heterozygotes. Studies have examined auditory function (3) and visual function (4) in heterozygous and homozygous dappled (merle) Dachshunds, as described in several writings by Dr. Malcolm Willis. These studies, from geographically and numerically restricted populations, found hearing loss and deafness and visual abnormalities, but only examined small numbers of dogs B 38 in the first study and 18 in the second. Dappled Dachshunds, when carefully bred to avoid MM, do not appear to have deafness or blindness in the general population, so one must be careful to not raise alarms at the presence of merle in a breed until experience shows that a true problem exists.

A large leap in understanding merle occurred when Clark and Murphy of Texas A&M University identified and sequenced the canine gene for merle in 2006 (5). The gene, named SILV, (also known as Silver in mice) plays a role in pigmentation in skin, eye, and ear. Dogs with the merle phenotype have a short piece of DNA inserted into this gene B a DNA modification known as a short interspersed element (SINE). This work was performed with Shetland sheepdogs, then confirmed in merles from eleven other breeds, including chihuahua. The sequence of the SINE was the same in all breeds, suggesting that all breeds in the study shared a common ancestor. The merle SINE insertion has three components: a head, a body and a tail; the latter contains a long string of repeated adenine nucleotides (polyA). For a dog to show the merle phenotype, it must have both the SINE insertion and a polyA tail that is of sufficient length (90-100 adenine repeats). Some merle-merle breedings produce homozygous merles called cryptic because they don=t show the merle phenotype, and when bred they do not produce any merle offspring. It turns out that the polyA tail in cryptic merles has been truncated to 65 or fewer adenine repeats. So, the merle gene phenotype can revert to the non-mer le in one generation. In the same way, it is theoretically possible for the polyA tail length to increase from genetic processing error, spontaneously producing a merle (5,6). The likelihood of this possibility is unknown but probably low.

It has been suggested that merle appeared in the Chihuahua breed from a cross to another breed, such as the Dachshund. Others have suggested that the gene has been present for many generations, but that the pigmentation pattern was incorrectly described, such as blue and tan or black and silver. A single event of the first possibility might still make it hard to explain all of the merle Chihuahuas now in existence. Regardless of the source of merle in the breed, to my knowledge there is no data at this time to suggest that merle Chihuahuas are prone to visual or auditory problems. I would encourage the breed organization investigate the prevalence of visual and auditory disorders in merle Chihuahuas prior to making decisions affecting the breed standard.

More information on deafness in general can be found on my research web page: Deafness in Dogs and Cats, www.lsu.edu/deafness/deaf.htm.

1. Lambert G. 2006. Chihuahuas - Any color (breed) marked or splashed?? Top Notch Toys 22(4):116.
2. Strain GM. 2004. Deafness prevalence and pigmentation and gender associations in dog breeds at risk. The Veterinary Journal 167(1):23-32.
3. Reet z, I., Stecker, M., & Wegner, W. 1977. Audiometrische Befunde in einer Merlezucht [Audiometric findings in dachshunds (merle gene carriers)]. Deutsche Tierärztliche Wochenschrift 84(7):273 277.
4. Klinckmann G, Koniszewski G, Wegner W. 1986. Light microscopic investigations on the retinae of dogs carrying the Merle factor. Journal of Veterinary Medicine A 33(9):674 688.
5. Clark LE et al. 2006. Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog. Proceedings of the National Academy of Sciences 103(5):1376 81.
6. Cordaux R, Batzer MA. 2006. Teaching an old dog new tricks: SINEs of canine genomic diversity. Proceedings of the National Academy of Sciences 103(5):1157 8.

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