Hunting with hounds: tracking down the genetic basis of disease in dogs

A dog’s breed standard is the set of criteria used to define the archetype of each breed. My personal favourite belongs to the Beagle, which includes as part of the official definition:

The man with the lead in his hand and no dog
in sight owns a Beagle

Strict adherence to these breed standards defines each of the many different pedigree classes seen in conformation dog shows, where each breed competes to be crowned as its most perfect representation.

Such remarkable diversification is unprecedented in the animal kingdom given the level of genetic diversity seen in the species, and has largely come about through concerted efforts by human breeders to adapt them to domestic purposes– from large working breeds like the Wolfhound, to miniature toys like the Pug.

However, in some cases, maintenance of this extraordinary diversity comes at a cost.

Breeders have come under fire recently from veterinary experts because, in some instances, maintenance of desirable traits outlined in the breed standard may be promoting the continuation of recessive disease. At its most extreme, this has led some overzealous breeders to mate together individuals from the same blood line, in some cases as closely related as mothers and sons.

Although such unions may keep aesthetically desirable traits within specific pedigrees, such strong inbreeding also has an unfortunate habit of expressing inherited disorders that would otherwise remain hidden.

Keeping ahead of the pack

The UK Kennel Club has been one such organisation to come under criticism for not taking a tougher stance on this issue. However, 2012 marks the first year in the history if its annual showcase dog show Crufts, where individual dogs from breeds at high-risk of inherited disorders have been excluded from competing, following mandatory veterinary screens.

In a further development in response to this issue, the organisation has also allocated funds for research into the genetic basis of inherited disorders, in the hope of improving the health prospects of future generations without compromising historic breed standards.

An article published today in BMC Genetics by Oliver Forman and colleagues from the Animal Health Trust-Kennel Club Genetics Centre (UK) outlines one such effort. Here, the authors attempt to identify the causal mutations involved in an inherited disorder in Beagles known as cerebellar cortical degeneration. Affected dogs are unable to ambulate properly, which in severe cases can lead to permanent disability.

The researchers report the very first instance of the use of a technique of micro-RNA sequencing (mRNA seq) to screen the entire exome of a dog—the parts of the genome that encode proteins—for the specific genetic mutations responsible.

In a linked Commentary article, Elaine Ostrander and Holly Beale from the National Human Genome Research Institute (USA) reflect on what this group’s successful and novel use of this technique means for the future of canine veterinary medicine, and how it could be the first step in finding a cost-effective screening approach for inherited disorders in dogs.

Model breeds

Although urging caution regarding the broad applicability of this approach for all dog breeds, Ostrander and Beale acknowledge that this adds substantially to the range of approaches now available to tackle inherited canine disease. Indeed, as a direct result of this research, Forman and colleagues have now developed a genetic screening method to identify canine carriers of the mutation.

Although over-enthusiastic adherence to historical breed standards may be contributing to the maintenance of some inherited disorders in dogs, it is worth noting that it is the availability of such accurate pedigree records that make detailed studies such as this possible – and so powerful.

As each breed represents a closed population, this substantially simplifies the study of otherwise complex traits, meaning that the dog is a now valuable model organism for geneticists.

For Beagles in particular – historically the breed most widely used in scientific experiments – it appears that humans could now be a dog’s best friend: the causative genes involved in the etiology of this disease were first identified in a related disorder in humans, greatly facilitating the hunt for its canine ortholog. Research like this now leads the way in permanently breeding inherited disorders out of the hound.

Genome-wide mRNA
sequencing of a single canine cerebellar cortical degeneration case leads to
the identification of a disease associated SPTBN2 mutation
P Forman, Luisa De Risio, Jennifer Stewart, Cathryn S Mellersh and Elsa Beltran

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