Jeff Schoenebeck: Building a boopable snoot
Ruffy. Image Credit: Shannon Parker, All rights reserved.
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Kat: One of the most important elements of a dog is its nose - and it is very important indeed to boop that snoot. But when it comes to the length of the snoot itself, from long-nosed greyhounds to flat-faced pugs, genetics has a big part to play.
Jeff Schoenebeck from the Roslin Institute at the University of Edinburgh has made it his mission to understand how genetic variations contribute to the wide range of shapes and sizes of dog skulls, using CAT scans, as well as lab tests.
Jeff: I primarily work on companion, animal genetics. I would say 80% of what we do in my group is concentrating on trying to understand the genetic underpinnings of skeletal, morphology and health in dogs, and we also dabble in cats to a lesser extent and some other species. But we love animals, and so we're really trying to understand, at it's heart, the genetics of health and longevity and just healthy living, let's put it that way.
Georgia: Right, and you mentioned morphology, dogs are quite... I mean, everyone knows dogs are a bit weird, right? Because you've got a Great Dane in one place, you've got a Chihuahua in another, you've got Greyhounds, you've got the massive Boxers. They're very, very different looking from each other.
Jeff: Yeah, I mean, this is exactly why I fell in love with dog genetics, it's exactly that. This disparity in sizes and skull shapes, and even I'm not a hair person, but the differences of hair patterns and furnishings, does a dog have long eyebrows or short eyebrows? Are the ears upright and pricked, Or did they flop over or do they drag on the ground like a Basset Hounds? It's so varied and it sounds very esoteric. Why are we studying these ridiculous traits, like ear length and face length and so on and so forth, but they have a developmental underpinning, and what we can learn from what has caused these differences actually has, we believe and many other folks believe as well, relevance to human health and medicine.
Georgia: And so how do you go about studying this?
Jeff: In the early days when I was turned on to dog's morphologies and I was working at a place where dogs weren't allowed on the research campus and so what I'd have to do is go to museums that have these dusty bone collections. And I would go, or the assistant that was working with me at the time would go to these collections and we would measure dog bones from known breeds of dogs. And that would kind of give us like a breed average, a breed metric of face length, or the overall size of a particular dog breed skull. And we made an assumption that it was representative of the dog whose DNA that we acquired at dog shows or acquired through veterinary hospitals.
However, our modus operandi has changed because I'm now based out of, next door to, a veterinary school. And the beautiful thing here is we have a hospital for small animals. It's a referral hospital, so it has a lot of specialised kit.
One of those bits of specialised kit is a computed tomography scanner. Every day at the hospital for small animals there's patients, dogs, coming in that have some kind of medical reason to be scanned. So we're able to take that data and computationally reconstruct the bone of interest, the skull, look at it in 3D space and do all of our sophisticated measurements and morphometrics if you will at the same time, because that dog has been administered and typically they're under sedation. There's a little bit of blood work that's usually done for these dogs when they're getting their diagnostics. Well, that's anything that's left over from after they do all their tests and so forth, we get that little bit of residual. We can turn it over to DNA.
Now we have DNA and the physical morphometrics for one patient, it broadens our ability to conduct our study and we're doing it passively. It's really just taking data that's being produced passively, and we can use it to map all types of skeletal traits.
Georgia: Fantastic, so has anything started to come out of your datasets yet?
Jeff: Yeah, so the first thing that came out was that the data recapitulated some of the things that were already known. So, for example, years ago there were studies looking at body size and what are the genetic underpinnings of that? And some of the big players that came out of those studies like insulin, like Growth Factor 1 and HMGA 2 and SMAD 2, these different genes that are suspected of causing these differences in body size among dogs, well, they were already known, but they emerged out of our data very, very quickly.
And then the thing that we're really interested in, because we're basically studying skull morphology, is this association that emerged on Chromosome 1, here again, this association was known for a long time. It's known that this particular region on Chromosome 1 is what's responsible for a reduction in face length. So when you look at an English Bulldog or a French Bulldog or a Pug or a Boston Terrier, all these dogs share this common signal on Chromosome one.
Jeff: And so it's been known and the region has been mapped and there's some genes that were suspected, but the mechanism, the thing, that mutation that underlies that reduction in face length just was never mapped. And possibly because of this breed average, coupling breed average phenotypes with genetics. But here with our one-to-one data, where we have the phenotype and the genetics from the same individual, we can really fine map with confidence in our population data set.
And what we found is this little snippet of DNA, it's a transposon that inserted itself within a gene, not the portion of the gene that creates protein or encodes protein, but between those portions within genes, there's segments of DNA, that kind of intersperse the important coding parts, well this little bit of DNA, at some point back in breeding history, inserted itself into this non-coding portion.
And yet somehow is able, when we looked at it in further detail what we found out is, It somehow causes the gene to mis-splice. Every gene, or many genes I should say, have to create a temporary copy out of what we call RNA, and it's from that RNA then proteins made. But what we found is the dogs that have this little insertion, that temporary copy is kind of miswritten, it's scrambled, if you will. And not only is it scrambled, we find that the copy that's made that precedes production of protein is reduced further. So we strongly suspect this gene, which turns out to be involved in bone development, is what's causing that reduction in face length and Pugs and French Bulldogs and English Bulldogs and so forth.
We don't know if it's the whole story. Exists this little snippet of DNA that inserted itself. It could be that it's projecting effects elsewhere in the region that have gone undetected. So there's still some questions mechanistically going on, but we're getting there.
Georgia: Right, So it's not even a gene, it's like a tiny little bit of DNA jumped into a gene and this we think could have such a big impact on dog face shape.
Jeff: Yeah, so the little bit of DNA that jumped in, in this case, this flavour of little bit of DNA is called a line element. And these transpose on themselves, another name for them is a transposon, it carries two genes, basically so it can make copies of itself, and so some people think that these line elements, which also occur in you and I, and many other species, that their the drivers of evolution because they kind of slowly make a copy of themselves re-insert themselves somewhere else, and maybe when they do that, sometimes it's a little bit sloppy, it carries a bit of DNA with it from the host, perhaps it's slowly scrambling the genome and over time, this gives genetic diversity that can be selected upon.
And, in dogs is a school of thought that perhaps dogs are more active, that they have more of these transposons that are active, and this perhaps could explain their amenability to selection. This plasticity and morphology. I think the jury's still out, but certainly there's quite a few different traits that are caused simply by these jumping genes. These transposons that occur in dogs.
Georgia: And with the dogs and the genetic story behind the flat faces. So we're getting answers. Why is this research important?
Jeff: So what is also well-known about these flat face breeds is they have enormous challenges, health challenges. So when we talk about animal welfare, dogs like English Bulldogs, Pugs, they have among some other pretty terrible conditions that can occur, they have difficulties breathing by and large. And I think there's, there's a lot of evidence that suggests that it is this reduction in face length that can increase air resistance.
So when the dog breathes in and breathes out, perhaps all these bones have squished in and not only is that bone squished in, but the soft tissue that surrounds the bone, the nasal passages that epithelium in the skin, well that's kind of stayed the same. So the bone is squished in the same amount of soft tissue is all around there. So you take a breathing passage like an airway, and it's occluded, it's shrunken down and so it's much more difficult for a dog to breathe in and breathe out.
So many of these dogs are gasping for air, and I should say, it's quite a bit of variation, even within breeds, how severely affected a dog is. So we want to understand, what can we do? How can we advise breeders to at least make some changes, either in terms of the physical, the morphology of the dog to alleviate this problem. And so that is one aspect that we're studying closely.
Going back to human health, we know that brachycephaly, that's the medical term that we use to describe dogs that have a flat face, well, that terminology itself is borrowed from human medicine. So children can be diagnosed with brachycephaly that occurs in a number of different syndromes where the outward face growth arrests early.
And so we think, by studying dogs, it's almost a two for one in the sense that, well, we want to address the animal welfare aspect and at the same time, whatever we learn from the mechanisms and the genetics of dogs. Well, obviously we have to turn our attention back to human medicine, because there are many children who are born with a craniofacial anomaly, and the genetic diagnosis is still missing. So we'd like to think that what we learned in dogs can also inform human genetics as well.
Kat: Jeff Schoenebeck from the University of Edinburgh, speaking with Georgia Mills.
