Uncovering the true breed distribution of mutations causing inherited disorders - Novel research findings for American Foxhound, Japanese Spitz, Miniature Schnauzer, Norrbottenspitz, and Sealyham Terrier

Canine genetics research is advancing rapidly, with around 180 mutations underlying monogenic inherited disorders and traits discovered to date. However, most original studies are focused on one or a few breeds, with a limited number of screened reference dogs from additional breeds. Such approaches are efficient for initial discovery of a mutation, enabling development of a gene test for breeders. Knowledge on the true distribution of the mutation across breeds nevertheless often remains incomplete at the time of the initial discovery.

Some mutations are thought to be ancient, having occurred early on in ancestral developmental lineages from wolf to modern dog breeds (Figure 1). Ancient mutations are likely to be widespread across breeds, encountered in a large number of breeds that show great variability in their appearance. Examples include canine disorders like degenerative myelopathy and hyperuricosuria. Other mutations are encountered in some subgroups of related breeds but not in others, suggesting that they predate final separation into modern dog breeds. For instance, collie eye anomaly is found in several herding breeds while primary lens luxation is prevalent in terriers. Finally, many mutations are fairly recent and therefore breed-specific, like juvenile epilepsy of the Lagotto Romagnolo. Sometimes these mutations can even be traced back to a single dog in the breed pedigree.

Figure 1. Uncovering the breed distribution of mutations underlying canine inherited disorders. Some disorder-causing mutations are ancient and widespread, others recent and breed-specific. HUU = hyperuricosuria; FVII = Factor VII Deficiency; CMR1 = canine multifocal retinopathy 1; PLL = primary lens luxation; BFJE =benign familial juvenile epilepsy.

The MyDogDNA testing service is a comprehensive panel screening of genetic mutations known to underlie canine inherited disorders. It has proven to be an efficient and powerful discovery tool, enabling discovery of previously unreported mutations in breeds that would not necessarily have been screened for a mutation otherwise.  As we routinely screen each tested dog for a large number of known mutations (http://www.mydogdna.com/sites/default/files/files/mydogdna_tested_disorders_and_traits_2014.pdf), we are constantly gaining knowledge on their true breed distribution. In this way, routine DNA testing offers important supplementary information to the research community. However, whether mutations actually manifest similarly as described in the original breeds always requires further scientific investigation in the new breeds involving clinical characterization of genetically affected individuals. This is crucial before it can be concluded that a mutation should be considered in breeding.

The mutation causing canine Factor VII deficiency is widespread across breeds

Canine Coagulation Factor VII Deficiency (CFVII Deficiency), a typically mild to moderate disorder characterized by abnormal or prolonged bleeding tendency, was originally described in Beagles. The research team at MyDogDNA has previously reported on the discovery of the same mutation also in Welsh Springer Spaniels, Finnish Hound and Papillon. We now expand on this knowledge by reporting discovery of the mutation in American Foxhound, Japanese Spitz, Miniature Schnauzer, and Sealyham Terrier. This variety of affected breeds suggests an ancient mutation, and it is expected that the mutation is present in other breeds as well. To the best of our knowledge, these carrier findings are novel. However, they are as of yet based on identification of a limited number of carriers. In each case, we invite dog owners, breeders and breed clubs to pursue further genetic testing to examine whether these are widespread mutations in the breed or individual occurrences.

We are currently collaborating with breeders, veterinarians and researchers to better understand the clinical consequences of the mutation in these new breeds. So far, we have demonstrated its clinical relevance in the Welsh Springer Spaniel (manuscript in preparation). For the other listed breeds, it would be important to identify genetically affected dogs for clinical studies. Please contact us at info@mydogdna.com if you have a dog (of any breed) with symptoms of a bleeding disorder:

  • Any excessive or prolonged bleeding, even after a simple needle sting at the vet's
  • Symptoms may go completely unnoticed until trauma or surgery reveals prolonged bleeding time
  • Bruises, body cavity-, nose- or vaginal bleeding

Any tested dog of the listed breeds, even if not showing symptoms, will help us work towards understanding the prevalence of these mutations in the breed. Please do not hesitate to contact us for more information.

Mutation transfer through cross-breeding: Progressive early-onset cerebellar ataxia in the Norrbottenspitz

Mutations are encountered in novel breeds not only through shared ancestry, but also through crossbreeding (inadvertent or intentional). Comprehensive panel testing is also able to shed light on these fairly recent events. It was already previously known that at least some lineages of the Karelian Bear Dog carry the chondrodysplasia (short-leggedness) mutation originally found in Norwegian Elkhound (Figure 2). 

The MyDogDNA research team has recently also discovered the Finnish Hound mutation known to cause a severe progressive neurological disorder with cerebellar abiotrophy, in another breed – the Norrbottenspitz. This is likely not due shared ancestry between the two breeds, but a consequence of maintaining open stud books. The Norrbottenspitz is a very heterogeneous breed, with one of the highest median breed diversity levels measured with the MyDogDNA service (33.6%). Crossbreeding and bringing in new gene variants into the gene pool is definitely recommended as a way to preserve the breed’s genetic diversity, health and wellbeing. However, what is good for the breed as whole may be detrimental, and cause unnecessary suffering, for individual dogs if known single gene disorders are not tested for simultaneously. This is why we at MyDogDNA believe in the power of combined testing of genetic diversity and single gene disorders.

Figure 2. Modern day mutation transfer from breed to breed. In practice, the distribution of mutations underlying inherited disorders is not limited by lack of recent shared ancestry.