A gene for flat faces?

The dog genome has been under a lot of pressure. Thanks to 150 years of breeding, the genetic variation within a single breed of dogs is really small. So for someone trying to uncover the genes behind brachycephaly, this presents both an opportunity and a challenge. Jeff Schoenebeck is that person. He told Phil Sansom how his lab at the Roslin Institute in Edinburgh uses CT scans of dogs from a nearby animal hospital...

Jeff - We take that data, we generate 3D reconstructions, and so it gives us a very quantitative description of the dog’s overall size, the length of its face, the roundness of its brain case… when there’s leftover bloods, we call them residuals, when we have owner consent we’re able to use these blood samples to extract DNA. So if we have the metrics and then we have the DNA of a dog, then we can begin building this population dataset. And so we want to understand: what are the genetics of reducing face length; and then we want to know, are there certain changes that are more responsible for this airway condition that afflicts these dogs?

Phil - If there are, they’re tricky to find. Because each breed is so related to each other, any gene they all share might code for anything from shorter faces to stumpier legs to curlier tails. And so the challenge is to separate out all these factors - and you can’t do that if you just have data from purebred bulldogs, for example.

Jeff - We're collecting data from dogs that are mixed breed as well, or dogs that maybe have a slightly shorter face but not nearly as dramatic as our bulldog. And so by utilising that mixed genetic ancestry we can help pinpoint the genetic changes that we believe are relevant to morphology, and that aren't necessarily related to some other commonality.

Phil - So if the mixed breeds with shorter faces all share a certain gene with the pugs, then you might be onto something. It’s just a matter of finding that gene.

Jeff - At its heart, what we're trying to do is we're looking across each dog’s genome at markers. And these markers are just simple genetic differences.

Phil - Specifically, a genetic marker is a certain point on a certain chromosome that you use to compare the dogs. And the point is by using a bunch of those, you can narrow in on the right place to start looking in more detail. How does that work? Well, let’s say you pick a single point as your marker, halfway down chromosome number one. The molecule at that point could be any of the four building blocks of DNA: A, C, G, or T. Let's say one dog has an A at that point, and another has a C. That’s all fine. And maybe a short faced dogs is equally likely to have an A there as a long-faced dog. But what if way more of the short-faced dogs actually have a C there? That’s a hint - maybe that part of chromosome 1 is important for short faces. You’d say that the marker is segregating according to face length. And you know what - that’s exactly what Jeff and his team found.

Jeff - It was not just one marker, it was a bunch of markers within the same region, and as geneticists we like that. And indeed, the one difference that we discovered on chromosome 1 is that there's this bit of DNA that jumped into the middle of a gene. Now, it didn't jump into the portion of the gene that encodes a protein, but nonetheless it jumped in the middle of the gene and caused the gene to malfunction if you will. The gene product wasn’t made correctly. And this gene is known to have a role in skeletal development and it's a very good candidate for being the major contributor to reducing face length.

Phil - The gene is called SMOC2. Jeff’s team are sure it’s a major player. Pugs, bulldogs, and French bulldogs all have two copies of it. But to date, there are at least two other genes that have also been found to affect a dog’s face length. So turns out it’s not that simple. SMOC2 isn’t exactly “the face length gene”.

Jeff - We describe face length reduction in dogs as being a complex genetic trait, meaning it's not just one gene, but rather it's a bunch of genes working together and depending on what kind of flavour of that gene an individual has will determine where along a continuum of face length it will reside.

Phil - And then face length is only part of the picture. Jeff and his team are also specifically looking into the breathing problem, brachycephalic obstructive airway syndrome. And they started looking in a breed you wouldn’t expect - Norwich terriers.

Jeff - They're not flat faced in the way that you think of a bulldog or a pug, but yet a certain portion of these dogs were suffering from a condition labeled "upper airway syndrome". So how can this be? The question was how could we reconcile this? Is this a condition that is simply specific to Norwich terriers, and it just kind of masquerades in a way that resembles what's occurring in bulldogs and these other breeds; or is it that it's brachycephalic obstructive airway syndrom? Maybe it's not all about face shape.

Phil - They think they’ve found a mutation that causes this "upper airway syndrome" - a problem with a gene called ADAMTS3. ADAMTS3 seems to affect the fluid in the airways, and get this - both bulldogs and French bulldogs have the same broken version of ADAMTS3.

Jeff - And as far as we know it doesn’t have anything to do with skull shape. So that observation suggests there’s the possibility that there are some things that can be selected against that may help improve their breeding without necessarily changing their skull shape.

Phil - But if it might be possible to breed out this ADAMTS3 variation, could you just do the same for the other genes the team have found? Like that one SMOC2?

Jeff - They can't breed out the SMOC2 gene in bulldogs because as far as we know, every bulldog has 2 copies of the genetic insertion that we discovered. So there is no other bulldog that doesn't carry it at least as far as we know. Even if there was, it would be such a small segment of the overall population of bulldogs that to breed just that one group of dogs would be disastrous. It would cause almost a collapse in genetic diversity in a breed who's arguably already at risk of being too homogenous on a genetic level. Probably the best way to go about reducing the effects of these problematic flavors of genes is to outcross, to bring in another dog and isn't specifically a bulldog, that doesn't have this very, very short face, to breed away from the extreme short face that exists currently. It's a viewpoint that I acknowledg, is highly controversial, but that is one way. So there isn't going to be one silver magic... magic silver bullet for for all these dogs.