Sunday, May 18, 2014

Dwarfism in Labradors: A Look at Genetic Disease and Inbreeding

Labradors used in a study published last year. Upper left is a dwarf female. Upper right is a dwarf mother and her unaffected daughter. Bottom left are three litter-mates, two unaffected and one dwarf.
One heritable condition many people are not aware of in the ever-popular Labrador retriever breed is dwarfism. As can be seen above, some of the dwarfs have only slightly shortened legs, which can explain why the trait can be easily glossed over. Interestingly enough, there are at least two different forms of dwarfism in the breed: one (osteochondrodysplasia) with a more obvious bent-legged phenotype and the other (skeletal dysplasia 2 aka SD2) with more normal appearing, only subtly shortened legs. I will be concentrating on the latter.

So, why should we even be concerned about dwarfism? Whereas some forms of dwarfism can lead to severe limb malformations and subsequent joint issues, as well as eye problems, SD2 does not. Instead, the gene may be linked to deafness. There hasn't been an examination of SD2 dogs to see if they do in fact have any hearing impairments, but similar genes in other animals lead to at least some deafness. In truth, any sort of abnormality should be concerning, at least to some degree. In the case of these dwarf Labradors, all from working- or field-type stock in a recent study, the decrease in leg length would lessen effectiveness as a working dog, as would any impairment to hearing.

Variation in the Labrador retriever. There is some more extreme type on both ends of the spectrum.
This form of dwarfism also brings up some interesting questions about breed type. Labrador retrievers vary significantly in size and shape, most notably between the comparatively lanky, lightly built working lines and the far more stocky, low-slung show lines. Some less-than scrupulous breeders could use SD2 to their advantage, taking a dog like the third one in the above image and getting it to resemble something more like the first two dogs. I honestly wouldn't be overtly surprised if someone used such a tactic as there are people that are that desperate to win a ribbon. Low-slung and stocky is what's winning right now, after all.

The average height difference between affected and unaffected dogs is only about 6 cm (2.4 in). Scientists were able to identify the likely source of SD2: a single allele change in a gene that is involved in collagen development. The trait is a recessive, which explains the generation jumping seen in the following pedigree.

Pedigree of the dogs in the study. Squares are male, circles are female. The dark individuals are all affected with dwarfism, with the red showing a form not caused by the same gene as the others. The arrow indicates the likely source of the gene, a popular sire who is the common ancestor of every dwarf in the study.
What else is remarkable about this pedigree? Do you see it? There is quite a bit of inbreeding going on. Though it's very difficult to trace all of the relationships (this chart has serious organizational issues), this pedigree is rife with shared ancestors, though most of the duplicates are a few generations back. For example, LA101, who is the black square closest to the top of the pedigree, has a grandfather and a great-great-grandmother who are full siblings. In fact, every affected individual can indeed be traced back to a common ancestor on both their sire's side and their dam's side.

And that's the problem.

This is a classic example of inbreeding leading to genetic disease. Inbreeding is risky business as it leads to an increase in homozygosity. Related individuals are more likely to have identical versions of a certain gene, and if you breed them together, it's quite likely that you will end up with offspring getting two copies of this gene, one from each parent. A lot of dog breeders think this is advantageous, allowing them to more easily select for a desirably trait. However, in all likelihood there will be bad that comes with this perceived good. There are numerous genetic diseases found in purebred dogs, and almost all of them appeared through inbreeding. This is why so many conditions can be traced to a single, common ancestor.

Often, the founding populations of a given dog breed are disturbingly low when viewed from with an eye toward population genetics. When you have breeds numbering in the thousands that are descended from maybe seven individuals, it's no wonder there is so much disease. If there are any detrimental recessive alleles in that small of a population, homozygous individuals affected by that detrimental gene are bound to occur. Labradors, to some extent, are lucky. Their popularity has persisted long enough that there have been fewer genetic bottlenecks, at least not to the extent of, say, the long list of breeds whose populations plummeted around WWII. The fact that retrievers were once interbred is also an advantage, giving a fairly large gene pool for all of the retriever breeds before they were separated. While some breeds are severely lacking in genetic diversity, such as the collie's paltry effective population size of 33, Labradors in Great Britain have an effective population size of 114.

This, however, is still far from spectacular.

For those not in the know, conservation biologists use something called the 50/500 Rule when assessing endangered species for extinction risk. At an effective population size of 500, there is concern that the species will not be able to maintain genetic diversity over a long period of time. At an effective population size of 50, the species is at immediate risk for extinction. They're circling the drain. Domestic animals have the advantage of veterinary care, but no owner in their right mind would prefer to have a sick pet. While the 50/500 Rule definitely doesn't bode well for the health of the aforementioned collie, the Labrador isn't in much better shape. When nearly one hundred thousand dogs have genetic variation equal to little more than one hundred individuals, there is a serious problem. For one thing, it makes it that much harder to avoid mating a certain dog to another that doesn't share a significant percentage of its genotype.

Since purebred dogs are closed populations, lack of genetic diversity is a serious problem. Comparing these populations to endangered species is very appropriate given the tiny effective populations sizes. Inbreeding serves to eliminate heterozygosity, and the more it is done, the more diversity is lost forever. If registries continue to insist on keeping studbooks closed, inbreeding has to stop or the only savior is going to be systematic outcrossing.

Sources are images from Wikimedia Commons for the type comparison (1, 2, 3, 4: all being copyright free or under Creative Commons licenses), Princeton University PressPopulation Structure and Inbreeding From Pedigree Analysis of Purebred Dogs, and most importantly, A COL11A2 Mutation in Labrador Retrievers with Mild Disproportionate Dwarfism published in PLOS One, a peer-reviewed, free to access, Creative Commons licensed publication. Authors are Mirjam Frischknecht, Helena Niehof-Oellers, Vidhya Jagannathan, Marta Owczarek-Lipska, Cord Drögemüller, Elisabeth Dietschi, Gaudenz Dolf, Bernd Tellhelm, Johann Lang, Katriina Tiira, Hannes Lohi, and Tosso Leeb.