Dogged genetics research identifies genes associated with skin disorder
CLEMSON — With patches of exposed skin, large lesions across her face and dull, expressionless eyes, you might think Lorelei, a Shetland sheepdog, has been abused. But that would be far from the truth: Lorelei is loved and well cared-for. She suffers from a painful condition called dermatomyositis, a genetic skin disorder that affects dogs and humans.
The discovery, by Leigh Anne Clark, an associate professor of genetics at Clemson University, and her colleagues, could improve the future for dogs with dermatomyositis. The findings could also give scientists clues into the genetic variations of the 10 in 1 million people who have the disease.
“The results from our study can be used as a tool for dog breeders to prevent the disease from affecting puppies, while preserving desirable traits and genetic variation within the breed. Using this new resource, even a dog with dermatomysitis can produce healthy puppies with a mate having a compatible genotype,” said Clark.
Before their latest study, Clark and her colleagues were aware of several factors that indicated the disease is multifactorial, deriving from a combination of genetic and environmental effects.
In dogs, dermatomyositis is seen almost exclusively in collie and Shetland breeds. A hereditary disorder will only affect certain breeds, whereas a non-genetic disorder should affect all dog breeds at the same frequency, so Clark knew the disease had a genetic basis.
Her team also recognized that the condition is a complex disorder involving several genetic components as opposed to a simple dominant or recessive disorder because of a wide range of characteristics, or phenotypes, that appear in affected dogs. And they knew that dermatomyositis involved genetic changes in the major histocompatibility complex, which functions in immune defense.
Clark also suspected that an environmental component often triggers onset of the disease because many dog owners reported the animals were under stress when the disease first appeared.
The team used genetic analyses from more than 160 dogs around the world, including Lorelei, who lives in France. Then they conducted a genome-wide association study, or GWAS, to compare genetic variants present in dogs that are affected and unaffected to determine which genetic changes are exclusive to affected dogs. GWAS allowed them to identify an association between a genetic variant and the disease phenotype.
The results displayed a very strong correlation between the dermatomyositis phenotype and variants on chromosomes 10 and 31, suggesting that risk variants for dermatomyositis were located on those chromosomes.
“I remember when we saw [the results]. We were speechless. We started looking at the genotypes and writing them down, and it was exciting,” said Clark.
Due to the complexity of dermatomyositis, Clark suspects that the genetic variants are working in conjunction to produce the disease. This is known as an additive effect, wherein multiple genetic influences combine to produce the disease phenotype.
Human juvenile dermatomyositis and canine dermatomyositis display similar symptoms and clinical expressions; they are both vasculopathies, affecting connective tissues. Clark hopes her research can be applied to identify risk alleles in humans.
Although this study is a breakthrough in understanding the genetic basis of dermatomyositis, Clark believes there is a lot more to learn about the disease. Future research will focus on dogs with moderate-risk genotypes, specifically asking why some moderate-risk dogs express the disease and others do not. Clark and her team also have a grant with the Collie Health Foundation to investigate moderate risk genotypes.
When Clark was growing up in Texas she worked for a Shetland breeder, an experience that fueled her love of dogs, taught her about breeding techniques and introduced her to genetics. She began researching dermatomyositis in 2004 as a postdoctoral fellow at Texas A&M University, but the work hit a dead end. Clark returned to the project several years later at Clemson, following the invention of new genetic techniques. She received funding to investigate the genetic basis of dermatomyositis in 2010.
Clark’s work will help breeders accurately identify which dogs to pair for breeding. By understanding the genetic risks, breeders can selectively mate the dogs to reduce the disease in the population.
Eventually, Clark thinks the disease could be bred out of dogs, leaving collies and Shetlands like Lorelei to be models for good behavior and beauty, and not for a genetic disorder.