The gene genie is truly out of the bottle – my latest Best of Health article
January seems to have been a month of genetics for me as I’ve had some fascinating conversations with canine geneticists about emerging technologies and upcoming research projects.
It seems that it is now possible to identify new, simple recessive mutations from the DNA of a single affected dog. Not long ago, laboratories like Cathryn Mellersh’s at the AHT would typically be asking Breed Clubs to come up with cheek swab samples from 50 affected and 50 unaffected animals. For many breeds, that was probably quite a challenge and virtually impossible in the numerically small breeds. Back in the days when the AHT was looking for the mutation that caused PRA in Miniature Longhaired Dachshunds, they even had to have their own research colony of dogs. By the way, “back in the days” is just over 10 years ago.
I was told of an example where a new genetic mutation that causes a painful eye condition has been identified in a particular breed and a new DNA test can be offered to breeders. There have only ever been a couple of clinical cases reported. That may be because it is incredibly rare in the breed population, or perhaps it simply goes undiagnosed or unrecognised during BVA/KC/ISDS eye examinations. This is a breed where several other DNA tests are already available for eye conditions and breeders are expected to make use of other available screening programmes for hips and elbows.
Should the breeders be encouraged to use the new test? Should the Breed Clubs carry out a research screening exercise on a suitably random, but statistically significant, sample number of dogs? Should DNA samples that have been submitted for the other eye conditions be re-screened for the new mutation?
One danger is that breeders will find themselves faced with yet more expense; the good breeders will want to do the right thing and the bad breeders will carry on regardless (and make a bigger “profit” on the sale of their puppies).
The risk of not screening a suitable sample of the breed is that there is no way of knowing how high the mutation frequency is in the population. Although there may be currently very few known Affected dogs, if it turns out that there are a large number of Carriers in the population, then there is certainly a risk of more clinically affected dogs appearing in the future. If a Popular Sire is a Carrier, then there’s an even greater risk to the breed.
The other complication for many breeds comes when there are multiple tests available and any given pair of dogs in a planned mating could be Clear, Carrier or Affected for different DNA tests, plus have a range of different screening statuses for their clinical tests. Just how do you decide if it is “safe” to mate two animals together? I’m sure a number of breeds are already finding themselves in this situation. Presumably, the use of Estimated Breeding Values and Genetic Breeding Values holds out some hope for them, but these are very dependent on having enough data available from people participating in the the various screening programmes.
Give a dog a genome
Perhaps the most exciting news in January was the AHT’s announcement that they plan to sequence the genome of 50 different breeds. They have £50,000 of funding from the KC Charitable Trust and want Breed Clubs to match this. I’m aware there has already been a flurry of activity on various breed Facebook pages to set up fundraising activities.
We already know the potential value of this type of project because a Cornell University team has performed a large, across-breed genome-wide association study (GWAS) in dogs, uncovering variants associated with everything from body size and fur traits to dog diseases such as epilepsy, cancer, and dysplasia. They have pre-empted the AHT’s project and published their results in January.
The Cornell researchers genotyped more than 4,200 dogs for the GWAS, focusing on a dozen common dog traits and diseases. The analyses included dogs from 150 breeds and 170 mixed breeds, as well as 350 village dogs from 32 countries. This is clearly on a much larger scale than the AHT plans, but their results certainly add weight to the case for the AHT looking at breeds in the UK.
For example, the researchers used data for dogs from 82 breeds — 113 cases and 633 controls — to track down two loci linked to elbow dysplasia. One locus had stronger effects on elbow dysplasia risk in Golden Retrievers and English Setters, the other showed closer ties to the trait in Labrador Retrievers and German Shepherds. Along with the across-breed analyses, the team did several within-breed association studies, including a lymphoma analysis in Golden Retrievers, a search for idiopathic epilepsy in Irish Wolfhounds, and a Boxer-centered analysis of granulomatous colitis.
We need to be clear though; these are not “DNA tests” for these particular conditions, but they are an important finding not only for canine health, but also for helping to understand similar complex diseases in people. This ties closely to the increasingly common messages about “one medicine” that many people will have heard Professor Noel Fitzpatrick speak about on his SuperVet TV programmes. Noel’s work on treating canine patients is attracting attention among human surgeons and there are, no doubt, many more potential examples where veterinary and human medicine and surgery can learn from each other.
One of the earliest examples of that cooperation and learning was the search for the Lafora gene in Miniature Wirehaired Dachshunds. Nearly 15 years ago Dr. Berge Minassian from the SickKids Hospital in Toronto visited owners of Mini Wires in the UK and began a collaboration that led to the discovery of the gene and mutation which causes Lafora.
Lafora Disease is a late-onset myoclonic form of epilepsy that affects humans and dogs. In people, the disease, which is progressive, usually results in death in the teenage years. In Miniature Wirehaired Dachshunds, just under 10% of UK dogs have been identified as Affected by the DNA test that Dr. Minassian’s team developed.
In January, he returned to the UK to seek their support in the development of a therapy which has been shown to be effective in mice and which, it is hoped, will benefit humans and dogs. The Wirehaired Dachshund Club’s Lafora Team will be working with Berge and Dr. Clare Rusbridge to recruit a group of clinically affected Mini Wires, plus a control group of dogs, to run the trial with the new therapy over a 2 year period once funding and ethical approvals have been confirmed.
This could be a landmark moment in what is a unique collaboration between breeders, veterinary medicine and human medicine. The potential to develop a viable therapy for Lafora Disease would be life-changing, both for the people affected by the disease and for affected dogs.
The gene genie is truly out of the bottle and it opens up opportunities to benefit people and dogs that could barely have been imagined just a few years ago.