Finding the Genes for Diseases (and Behaviors)PUBLISHED ON September 16, 2017
We know that many canine diseases, from hip dysplasia to cancer, are affected by genetics. But we don’t know the exact genes that are responsible for the more complex of these diseases, and we’d love to have more genetic tests to warn us when a dog has a genetically elevated risk of a particular disease (before he’s bred!).
So if you were a researcher who wanted to explore the genetic basis of a particular disease, what would you do? You might do a genome-wide association (GWA) study. Basically, you’d get a large number of genetic markers and a large number of dogs with and without the disease. Then you’d look for correlations: which genetic markers show up more often in dogs who have the disease compared to dogs who don’t? Those markers are probably located in or near genes that have something to do with the risk of getting the disease.
These studies are done pretty commonly in research on human diseases, and the good news is that they do find some interesting associations between genes and diseases. The bad news is that depending on the strength of the association you’re looking for, you might need a lot of people in the study (thousands or tens of thousands) to get useful results. The problem is that complex diseases like cancer or diabetes are controlled both by large numbers of genes and by difficult-to-quantify environmental factors. Want to find out the genetic basis of a particular kind of cancer? You not only have to sort through the interactions of many genes affecting the level of cancer risk in an individual, but must also take into account whether environmental differences – “living healthy” – mean that some people whose genetics put them at high risk are nevertheless cancer-free, and therefore throw off your calculated association.
Human medicine is set up to make it possible to collect genetic data from thousands of people for studies like this. But it’s harder when you’re studying dogs – the institutions just aren’t in place to make it easy to get genetic samples from thousands of dogs (a problem Darwin’s Dogs is tackling by contacting dog owners directly). So does that mean that GWA studies are doomed in dogs?
Enter a massive dog GWA study, published this January, 2016, in Nature Communications: Complex disease and phenotype mapping in the domestic dog. The researchers tested 4,224 dogs from 150+ breeds, 170 mixed-breed dogs, and 350 “village dogs.” Village dogs are dogs whose genetics, researchers believe, are similar to the genetics of dogs before the introduction of breeds. Unlike the typical mixed-breed dog, who may have ancestry from lots of different breeds, village dogs have little or no ancestry from any purebreds. They are a very interesting population to look at in a GWA study, because they can help researchers try to untangle the relationships between genetic markers and diseases in specific breeds or groups of breeds. For example, golden retrievers are at higher risk of lymphoma just due to being goldens, so genetic markers that are associated with lymphoma risk in golden retrievers may not be associated with lymphoma risk in other breeds or in village dogs.
This paper is open access so you can go read it yourself, but let me tell you about some of its coolest findings.
They found new genetic marker associations for diseases, including hip dysplasia and epilepsy. This is exciting, although it doesn’t mean there will be genetic tests for those diseases any time soon. Because we expect many genes to interact to produce a significant risk of either of these diseases, these new associations are just a small step in the direction of finding all those genes. Some associations that previous studies had found between particular genetic markers and diseases didn’t show up in this study. This may seem surprising, but I wonder if it has to do with the introduction of village dogs to the mix, diluting the effect of some associations which may only exist in dogs of particular breeds. (The diseases in question were cranial cruciate ligament tear, lymphoma, portosystemic shunt, mast cell tumor, and mitral valve disease.)
They found a new genomic association for shedding. Thank god, I can look forward to a genetic test to find out if my dogs are at risk of shedding! Seriously, finding the genes associated with shedding will help us better understand the mechanisms that make the variety of kinds of dog hair different.
They found that dogs who are more inbred tend to weigh less than dogs of the same breed who are less inbred. They hypothesized that this was due to the negative effects of inbreeding resulting in reduced growth.
For Darwin’s Dogs, another finding is the most important one in this paper. Darwin’s Dogs is collecting information right now with the hope of doing GWA studies to find genomic associations with behavior. A big question in this sort of study is: how many dogs do you need, and what breeds, before you have a decent chance of finding what you’re looking for? Because purebred dogs are so similar to each other, doing a GWA study within a single breed can be very powerful, compared to doing a study with dogs of multiple or mixed breeds. But it’s really hard to collect samples from lots of dogs of a single breed! It’s much easier to collect samples from whatever dogs you can, no matter what breed. So understanding this trade-off is important in designing a GWA study.
This paper gave Darwin’s Dogs some hard numbers to help quantify this trade-off: using 400 dogs of a single breed (200 with the behavioral trait and 200 without) is the equivalent of using 1000 dogs of many breeds (500 with the behavioral trait and 500 without). It gives some other useful guidelines that will help in designing GWA studies in dogs as well, such as how many dogs are needed in a study to provide a decent chance of finding an association with a particular strength.
This study pulled together a really impressive number of dogs with the help of multiple researchers collaborating, and provided some useful stepping stones for genetic association studies to follow it. We’re very happy to see dog genetics moving forward!
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