Gene for Merle Color Pattern Discovered


Merle SheltieIn early 2006, researchers at Texas A&M University (TAMU) published an article describing their identification of the genetic mutation that causes merle coat color patterning in breeds such as the Shetland Sheepdog (Sheltie), Collie, Welsh Corgi, and Great Dane.

The work was done in Dr. Keith Murphy's laboratory at TAMU's College of Veterinary Medicine.  Dr. Murphy and his staff of graduate students and postdoctorates have received numerous grants from the AKC Canine Health Foundation for genetic research into diseases such as deafness, pancreatic acinar atrophy, Pug Dog encephalitis and canine aging and life spans.  The Murphy group has also been instrumental in developing research tools such as the multiplexing of specific microsatellite markers to enhance the efficacy of whole genome screens in disease gene detection. Dr. Leigh Anne Clark is the post-doctoral fellow who, along with doctoral student Ms. Jacquelyn Wahl, carried out the merle research with Dr. Christine Rees, a veterinarian who made seminal contributions to this work.

Growing up in Austin, Texas, Leigh Anne and her two older brothers shared their home with two Shelties, one a sable and the other a merle.  Leigh Ann also earned spending money by working for a Sheltie breeder, assisting with everything from grooming to whelping litters.  Jacquelyn owns a double merle Australian Shepherd.

After receiving her BS in Biomedical Sciences from Texas A&M University, Leigh Anne decided to pursue a Ph.D. in genetics and was recruited by Dr. Murphy to work in his lab.  As Leigh Anne's advisor, Dr. Murphy assigned her to work on the multiplexing project, as well as run the first screen for detection of the causative gene for pancreatic acinar atrophy in the German Shepherd Dog.  Leigh Anne was the first author on a paper that came from this research where linkage analysis was conducted in an effort to narrow the search for potential candidate genes.

Dr. Clark was subsequently assigned to work on dermatomyositis (a skin and muscle disease) in Shelties and Collies.  This project was the first collaboration between the Murphy lab and Dr. Rees.  As the current owner of a Collie, and because of her love of Shelties, this was a perfect project.  Leigh Anne set about working with the other investigators on the project to collect samples, pedigrees and other data that would make finding the causative gene a realistic prospect.  In 2005, Leigh Anne recognized that the merle gene had not been identified and that she had a wealth of information on both merle and non-merle Shelties, so she and Jacquelyn began working to identify the merle gene.

The color pattern merle (also known as dappling) is characterized by darker "blotches" on a lighter background of the same pigment (e.g., blue merle in Collies, red dapple in Dachshunds).1  This trait is sometimes associated with congenital defects such as deafness and ophthalmologic abnormalities, such as microphthalmia (a congenitally small eye).  Heterochromia iridis (a difference in color of the iris in the two eyes, or two different colors within one iris) has also been associated with merle coloring, and is a disqualification for several breeds.  An autosomal, incompletely dominant trait, merle coat coloring predisposes dogs to inherited deafness.  When inherited in the homozygous state, the merle mutation causes dogs to be white and have an even greater incidence of deafness, blindness and sterility.2  

The auditory and ophthalmologic abnormalities linked to merle are similar to those observed for the human auditory-pigmentation disorder Waardenburg syndrome.  Characterized by varying degrees of hearing loss and changes in skin and hair pigmentation, another common trait is two differently colored eyes.  Researchers have identified causative mutations in at least five genes for Waardenburg syndrome; however, the genetic bases for all cases have not been determined. 

A microsatellite marker that segregates with the merle phenotype in the Sheltie was identified using linkage disequilibrium (the measurement of co-segregation of alleles in a population, or non-random association of alleles at two or more loci not necessarily on the same chromosome).  This region of the human genome contains SILV, a gene important in mammalian pigmentation.  Therefore, SILV was evaluated as a candidate for merle patterning.

Upon evaluation, a short genetic insertion was found in SILV which matched the merle phenotype in multiple breeds.  Interestingly, several deletions were identified in that insertion and permit normal (or non-merle) pigmentation.  In other words, merle dogs have a mobile bit of DNA within their SILV genes and this is responsible for pigmentation, and is also associated with impaired function of the auditory and ophthalmologic systems.

This discovery is important because of the health issues that are associated with the merle coloring; this work may help explain the "cryptic" merle.  While useful in breeds such as the Collie or Australian Shepherd, this is even more valuable in breeds in which the range of acceptable phenotypic coat colors is broad, such as the Pomeranian or Chihuahua, in which some of the colors may mask the presence of the merle genotype.  In breeds that produce small litters, knowing the genotype of the parents will be advantageous in avoiding auditory and/or ophthalmologic defects.  Additionally, this will provide researchers with the launch point for identifying the function (s) of SILV, thereby ultimately shedding light on hearing, sight and pigmentation disorders that affect both dogs and humans.

The patented genetic test for merle is now available through IDEXX.

1 Taken from The Complete Dog Book (19th Edition)
2 Ackerman, L. The Genetic Connection. p. 132-133


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