Canine Genetics: Studying Disease Susceptibility and Cancer Risk

Part 1: Canine Genetics: Dog Genes Tell Surprising Tales

00:00:12;17 Hi, everybody.
00:00:13;20 I'd like to welcome you to today's presentation.
00:00:16;19 We're going to be talking about domestic dogs and some of the really exciting advances that
00:00:21;27 have happened in the last few years because of both genetic and genomic studies that have
00:00:26;21 gone on in man's best friend.
00:00:28;25 So, our topics for discussion today are as follows.
00:00:32;23 We're first gonna talk about determining the genomic architecture of modern dog breeds.
00:00:38;04 We're gonna talk about how we identify genes for traits that are under selection in the
00:00:43;19 development of breeds, and we'll focus a lot on morphologic traits.
00:00:47;08 And finally, we'll move it over to disease, and we'll be talking about studies of canine cancer.
00:00:54;00 So, let me just go ahead and summarize a few things that we all need to know about dogs
00:00:59;16 before we really dig into the data.
00:01:02;09 First of all, I should make it clear that our lab is in a long-term partnership with
00:01:06;22 dog owners, dog lovers, dog trainers, veterinarians.
00:01:10;22 Basically, anyone who cares about dogs, we want to talk to you about what you're doing,
00:01:16;24 what you know about dogs, and what samples you can provide [for] us.
00:01:20;18 We collect and we bank DNA from all US breeds and, now, many of the international breeds as well.
00:01:27;24 So, we don't breed dogs ourselves.
00:01:29;22 We don't keep dogs in kennels.
00:01:31;18 Ours is probably the largest collaborative experiment that's ever been done between scientists
00:01:37;24 and the general public.
00:01:39;13 Now, the American Kennel Club, also known as the AKC, currently recognizes around
00:01:46;09 190 different dog breeds.
00:01:47;28 And each breed is a closed population.
00:01:50;22 And that's an important concept, because it means that in order to be registered as a
00:01:56;06 member of that breed your parents had to have been registered members of the breed,
00:02:00;12 and your grandparents, and so on and so forth.
00:02:03;16 So we get a lot of advantages at the genetic level from studying these closed populations.
00:02:08;20 Now, we do in human genetics as well.
00:02:11;12 We study Icelandic pedigrees, Finnish pedigrees, Bedouin pedigrees, but there are only,
00:02:17;08 you know, a very small number of closed human populations, whereas we can see in dogs
00:02:23;10 we have literally hundreds.
00:02:25;07 There are in fact over 400 dog breeds that are recognized worldwide.
00:02:30;04 Now, these are some of my favorite dog breeds this week.
00:02:34;03 If you were to ask me next week, I would probably put up a completely different set of breeds.
00:02:38;13 But this is for this week.
00:02:39;27 So, three things to keep in mind during this talk.
00:02:42;27 All domestic dog breeds are members of the same species, Canis familiaris, or sometimes
00:02:49;02 called Canis lupus familiaris.
00:02:50;19 It doesn't matter how different they look -- and they look very different, different
00:02:55;25 breeds have amazing extremes of morphologic diversity as well as disease susceptibility --
00:03:02;10 they're still all members of the same species.
00:03:06;05 And the fact that breeds have been genetically isolated in order to develop them into
00:03:12;20 the dogs that we know today means that they also get a fair amount of disease, and there are
00:03:18;28 certain diseases that we tend to see in excess in only a subset of breeds.
00:03:23;19 And we'll be talking about that in the second half of today's presentation.
00:03:27;24 So, if you think about dog breeds as a whole, one easy way to kind of stick it in your mind
00:03:35;17 is to remember that within a breed there's a lot of homogeneity or sameness.
00:03:42;23 There's a lot of sameness in terms of the genome sequence.
00:03:46;24 And there's obviously a lot of sameness in terms of how these dogs look.
00:03:51;25 So in this example here, we have lots and lots of different breeds, and we have
00:03:56;20 multiple puppies from each breed, and you can see they really look very similar.
00:04:01;10 But when we look between breeds, we see heterogeneity.
00:04:05;17 The dogs look very different, and their genomes end up being much different as well.
00:04:12;03 And that's gonna be the basis of many of the things that we'll talk about today.
00:04:16;21 Now, one of the questions I get asked most frequently is, how and when were modern breeds created?
00:04:23;27 Well, domestic dogs were created -- or they were domesticated, I should say -- from wolves
00:04:30;09 anywhere from 13-30,000 years ago.
00:04:34;06 The intermediate canid dog-wolf is not living on the earth today, so we have wolves,
00:04:41;24 which were the progenitors, and we have domestic dogs.
00:04:45;00 Alright?
00:04:46;00 Now, previous studies have struggled to address a variety of questions like, how were
00:04:52;16 these modern breeds formed?; what's the role of hybridizing different breeds or of immigration,
00:04:59;13 bringing in different breeds and the movement of breeds from place to place?;
00:05:04;17 what role did those have in breed formation?; and of course, when did it all happen?
00:05:09;04 In fact, at a genetic level, we've struggled for many years to understand, what exactly
00:05:14;23 is a breed?
00:05:16;04 So, in recent years, Dana Dreger in my lab has been working to answer exactly that question.
00:05:22;05 I know this is a busy slide, but I'll take you through it in just a couple of steps.
00:05:27;22 So, what Dana has done is she's analyzed DNA from about 85 different dog breeds.
00:05:36;07 And then she's used that data to ask the question, how many individual dogs of any given breed
00:05:43;25 would I need in order to capture all the variation that exists in their genome?
00:05:50;22 And you can see that she's got data for Chihuahuas, for Miniature Poodles, for Shetland Sheepdogs,
00:05:59;04 as well as [unknown], the Bull Terrier.
00:06:01;28 And down in the bottom panel is really where the data is that you want to look at.
00:06:06;12 So, if we're thinking about Chihuahuas, well, we can capture most of that diversity
00:06:12;09 just by looking or getting genome sequence from about 13 dogs.
00:06:16;20 For Miniature Poodles, it's gonna be about 7.
00:06:19;28 For Shetland Sheepdogs, it's gonna be about 19.
00:06:24;07 And then for this Bull Terrier, it's gonna be about 12.
00:06:27;06 So, this really speaks to the inbred nature of dogs.
00:06:30;26 It takes very few individuals to capture most of the variation that exists in the geno...
00:06:37;19 in the genome sequence.
00:06:39;18 And that's going to turn out to be really useful and really important as we move on.
00:06:44;15 Now, following on the heels of that, Heidi Parker wanted to understand, how do all the
00:06:50;11 different dog breeds relate to one another?
00:06:53;01 I mean, just because dog breed A looks like dog breed B, are they in fact closely related?
00:06:59;28 Did one derive from another?
00:07:01;20 So, to address that question, she used something called a SNP chip.
00:07:06;24 SNPs are single nucleotide polymorphisms.
00:07:10;26 They're points of variation in the DNA sequence.
00:07:15;00 And she used a little chip.
00:07:16;26 These are little glass chips, and it had 170,000 SNPs that we could interrogate.
00:07:24;15 Now remember, every SNP is gonna have two alleles: the one you get from mom and the
00:07:28;17 one you get from dad.
00:07:29;26 Now, she used these SNP chips to look at the DNA from 161 different breeds that varied
00:07:37;11 in all possible ways.
00:07:39;17 She also included a few wolves and she included a few golden jackals as well.
00:07:44;10 And then she took all of that data and she built what's called a neighbor-joining tree
00:07:50;07 that addresses population structure, breed formation, and eventually we'll use it for
00:07:55;06 genome composition and trait mapping.
00:07:57;21 And here's what it looks like.
00:07:59;07 One slide, probably two years of work in my laboratory.
00:08:02;18 So, what are you looking at here.
00:08:05;18 Well, we call this our Wheel of Life, because we care about dogs.
00:08:09;24 So, this is a dog's life.
00:08:12;16 As you go around the circle, you're looking at different dog breeds.
00:08:17;13 Now, we've only put pictures of a few breeds on here, but there are actually 161, and that's
00:08:23;20 what all the little black printing is that I know is very hard to read.
00:08:28;11 And then we've used mathematics to say, okay, which breeds are related, one to another?
00:08:34;00 And that's what the color coding is.
00:08:35;26 So, these 161 breeds actually devise... or divide into about 23 different groups.
00:08:44;07 And members of any one group are actually a set that are closely related.
00:08:48;07 So, over here in yellow we have breeds like the Shiba Inu; we have the Akita;
00:08:54;00 we have the Greenland Sleddog; the Siberian Husky.
00:08:56;18 So, that's a group of breeds that are very closely related.
00:09:00;11 And we can look over... let's see, maybe down here.
00:09:06;07 And then we're gonna be looking at some of the hound dogs.
00:09:09;14 And if we move over here, right over here we're gonna be looking at some of the herding dogs.
00:09:15;01 Now, why do we care so much about this.
00:09:17;12 Well, here's why.
00:09:19;11 Let's say I'm studying a complex disease like epilepsy.
00:09:22;03 We care about it in dogs; we care about it in humans.
00:09:26;06 And let's say that I'm gonna study it just in this one set of breeds, alright?
00:09:31;16 The French Bulldog, let's say, is the one who walked into my veterinary clinic.
00:09:35;09 Well, the French Bulldog is in this blue clade.
00:09:38;27 And what that means is that everybody else in the blue clade probably got the disease
00:09:44;04 because they share the same mutation from a recent common ancestor.
00:09:48;08 So, also in that blue clade are the Boston Terrier, the Bulldog, the Boxer, the Miniature Bull Terrier.
00:09:55;16 So, all of those that have epilepsy, they probably all have the same mutation.
00:09:59;14 So suddenly, if I'm trying to find the gene for epilepsy, I have a lot more power to do so.
00:10:04;28 Now, let's say I'm also gonna study it up here in the Terriers, where the second blue arrow is.
00:10:11;09 Well, I can make the same hypothesis.
00:10:13;26 Let's say it's a Scottish Terrier that walked into my office.
00:10:16;26 I can reasonably hypothesize that these other terriers
00:10:20;02 -- Cairn Terrier, the West Highland White Terrier, the Skye Terrier --
00:10:25;04 any of those dogs that have epilepsy, got it because
00:10:27;19 they also share a recent common ancestor that's in that aqua coloring.
00:10:33;09 But it'll be different than what we saw in those bully dogs.
00:10:37;21 And so this is a way for us to capture the multiple genes that are responsible for
00:10:45;05 seemingly very complex diseases.
00:10:47;15 We use this wheel over and over to devise our hypotheses, because this is what we go to
00:10:53;12 to figure out which dogs we should put in which little grouping in order to do
00:10:58;12 our genetic studies.
00:11:00;06 So, we can now take this data... and Heidi and Dana together have said, well, great.
00:11:07;25 We know which breeds are most closely related to which other breeds.
00:11:11;16 But can we tell when it happened?
00:11:13;10 Can we tell when breeds were actually formed?
00:11:16;11 Now, we know from historical records that most breeds have only been around for
00:11:21;27 a few hundred years.
00:11:22;27 In fact, most breeds were developed in Europe during the Victorian times.
00:11:27;24 So, how well can we unravel this?
00:11:30;17 Well, it turns out, using the exact same kind of data, we can unravel it pretty well
00:11:36;04 using a concept called haplotype sharing.
00:11:39;15 So, a haplotype is a group of variants that are inherited together from a single parent.
00:11:46;19 So, at a given place in the genome, you'll have a haplotype from mom and you'll have
00:11:51;09 a haplotype from dad.
00:11:53;17 We look at something called identity by descent.
00:11:56;11 So, haplotypes are shared between individuals because they're inherited from a common ancestor.
00:12:02;05 The longer the haplotype, the more recent the ancestor.
00:12:07;27 We find that about 95% of median cross-clade sharing -- so, going across colors --
00:12:16;11 is less than about 9 million base pairs.
00:12:19;06 Alright?
00:12:20;06 So, what does that mean, practically?
00:12:21;21 Well, if you look over to the panel, what you're gonna see is that, when we look
00:12:27;24 over here in green, that's the amount of haplotype sharing we get when we look across clades.
00:12:33;15 Alright?
00:12:34;15 Now, when we look within a clade, at the purple, it's gonna be more.
00:12:39;25 And when we look within a single breed, at the aqua, that's where it's gonna be the most.
00:12:45;14 So, we can take advantage of that.
00:12:49;10 And this is what the formation of dog breeds looked like.
00:12:54;19 So, what are you looking at here.
00:12:56;10 Well, you're looking at another one of our Wheels of Life, as we like to call this.
00:13:00;06 But this is now a ribbon plot.
00:13:03;03 And what each of those ribbons are telling you is what was mixed and matched to create
00:13:08;20 each breed.
00:13:09;20 So, the color coding is the same as what you saw before.
00:13:13;20 And the names of the breeds are the same as what you saw before.
00:13:16;21 And they're in the same order.
00:13:18;21 But everywhere there's one of these ribbons that crosses back and forth, that's telling you
00:13:23;28 some breeds got mixed and matched in order to form a particular breed.
00:13:30;22 There's a lot of it.
00:13:32;06 And that makes sense, because we know from records that a lot of breeds were in fact
00:13:36;27 formed by mixing and matching different breeds, and then selecting for very specific traits.
00:13:43;06 So, we can now use this data to figure out exactly when these breeds were formed.
00:13:51;04 So, let's go ahead and start up at the top.
00:13:54;08 We now know, using that data, the same data you saw in the previous slide,
00:13:58;20 that the Norfolk and the Norwich Terrier were divided into separate breeds.
00:14:02;22 If you look on the axis, here, down at the bottom, it's about 20 years ago.
00:14:09;22 We know that the Eurasier began with a Chow Chow cross, and that happened about 40 years ago.
00:14:16;00 The Irish Wolfhound... that's an interesting breed.
00:14:18;04 It was recreated using the Scottish Deerhound and a Great Dane, several years after the war.
00:14:25;24 And we in fact know that that's something -- again, when we look down --
00:14:29;06 that happened about 70 years ago.
00:14:31;12 The Silky Terrier, that was created from our very favorite, Yorkshire Terrier, as well
00:14:36;12 as the Australian Terrier.
00:14:38;06 And we can even figure out really pretty complicated scenarios.
00:14:40;26 So, look at the bottom scenario.
00:14:42;06 The Bulldog, the French Bulldog, the American Staffordshire Terrier.
00:14:47;04 They all came together to form the Boston Terrier.
00:14:50;25 And that's something that we know happened about 150 years ago.
00:14:55;18 So, this is very, very powerful data.
00:14:58;05 It's really giving us a window into how all these dogs and all these breeds, in fact,
00:15:05;16 were created, that we see running around the dog park today.
00:15:09;01 Alright.
00:15:10;09 How else can we use this data?
00:15:12;07 Well, we can also use it to understand disease migration.
00:15:18;11 So remember, when we first started talking, we talked about finding diseases in a single gene,
00:15:23;27 using a single dog breed.
00:15:26;04 And then we talked about using a whole clade.
00:15:29;09 Now, we can take advantage of what we know about breed formation to do the same.
00:15:33;19 So, I'll give you the example of CEA, which is called Collie eye anomaly.
00:15:39;22 It's a recessive developmental disorder.
00:15:41;19 It's reminiscent of several human diseases.
00:15:45;03 It's caused by a failure of the optic vesicles to express growth hormone, and so that
00:15:51;22 affects differentiation of other eye cells.
00:15:54;06 You get choroid hyperplasia... hypoplasia; you get scleral pitting; you get retinal detachment.
00:15:59;21 Alright.
00:16:00;21 So, watch what happens when we look at the affected breeds.
00:16:04;00 Wow.
00:16:05;26 Look at this.
00:16:06;26 We can now trace the migration of this disease as it's migrated around the dog world.
00:16:13;26 So, it starts at the bottom, over here with the herding dogs.
00:16:19;22 In fact, our favorite Collie over here was really the first one to get the disease.
00:16:24;28 And that breed generously shared it with all the other herding breeds.
00:16:30;08 And then it's migrated, right?
00:16:31;25 We see it over here in the Boykin Spaniel.
00:16:34;26 We see it further in the Nova Scotia Duck Tolling Retriever.
00:16:38;27 And we see those breeds sharing with the Chinook, sharing with the Airedale Terrier, and then finally,
00:16:46;10 as we move all the way over, all the way over here, we see sharing with the Pug.
00:16:52;13 So, some of these breeds already have the disease.
00:16:55;14 Some we suspect are gonna get it pretty soon.
00:16:57;12 And so if a dog walks into your veterinary office with an eye disease that you
00:17:02;05 don't recognize, this would be the one to look for.
00:17:05;02 So now we have a tremendous amount of power, because we can take advantage of all this history
00:17:10;01 in order to narrow down exactly... not just where a gene is but what the gene is
00:17:14;27 and what the precise mutation is.
00:17:17;14 Alright.
00:17:18;14 So, we're gonna go back in the second part and we're gonna talk more about disease.
00:17:22;20 We're gonna focus a lot on cancer.
00:17:24;12 But I thought, since dog breeds look so different and the most common question I always
00:17:30;06 get asked is, how can that be?, how can they all be members of the same species
00:17:34;15 and look so different?, I thought it'd be fun to spend a little bit of our time on morphology.
00:17:39;07 So, this is one of my favorite pictures.
00:17:42;02 This is a Harlequin Great Dane, and down here at his feet we have this little Chihuahua.
00:17:48;28 Members of the same species -- isn't that amazing?
00:17:52;26 So, when we think about different dog breeds, we think about how they differ in body size
00:17:58;01 and leg length and skull shape and fur length, texture, their bite position, the...
00:18:04;04 the weight of their legs, the thickness of their legs, ear position, and so on.
00:18:08;24 And in the past several years, I've been fortunate to have some very, very talented postdocs
00:18:13;12 and graduate students who have studied and published on each one of these.
00:18:18;06 I'm just gonna focus on a couple today.
00:18:20;09 I'm gonna talk first about fur.
00:18:22;24 I had an amazing graduate student named Edouard Cadieu.
00:18:26;03 And he came to my lab to study cancer, but it turned out that he was also studying fur.
00:18:32;08 And I didn't really know this at first.
00:18:34;06 But it turned out to be a spectacularly successful story.
00:18:37;20 So, he was interested in everything about fur.
00:18:40;11 So, the first thing he did was he found the gene that's responsible for those eyebrows
00:18:46;05 and those mustaches that you see in that Standard...
00:18:49;08 Standard Schnauzer.
00:18:50;08 Right?
00:18:51;08 You don't see it on the other side in the Irish Setter, of course.
00:18:54;15 And it's due to an insertion in a gene called R-spondin 2 in the untranslated 3' region.
00:19:01;28 So, we think it's something that affects post-transcriptional regulation or maybe messenger RNA stability.
00:19:09;04 So, then he went to study long versus short fur.
00:19:13;03 And he found that one of the primary things that was important in that was an alteration
00:19:19;08 in a very highly conserved amino acid in the first exon of a gene called FGF5.
00:19:24;21 So, if you compare the long-haired Cocker Spaniel on the left and the very short-haired Whippet
00:19:30;09 on the right, you can see that this is a pretty important gene.
00:19:34;18 And then, of course, we have to think about curl.
00:19:37;01 So, these are two different kinds of Portuguese Water Dogs.
00:19:41;10 The one on the left just has a wavy coat, and the black one on the right has
00:19:45;22 a very, very tight curly coat.
00:19:48;00 And that's caused by a mutation, again, in a single amino acid, in a coding position,
00:19:54;02 exon 2, and this is in the gene keratin 71.
00:19:57;16 So, if you think about all the dogs that you see running around at the dog park,
00:20:03;28 most of their variation in coat -- with the exception of color -- is gonna be due to these
00:20:09;16 three genes and the different combinations of these three genes.
00:20:12;24 So, this was just an amazingly clever story that Edouard figured out, and so, you know,
00:20:18;20 I had to let him graduate and get his PhD and all that stuff after he finished all of this up.
00:20:23;25 Now, the other thing that we've studied quite a bit is body size, because, really,
00:20:30;09 that's one of the most striking things that we use to describe a dog breed.
00:20:34;02 It's big.
00:20:35;02 It's small.
00:20:36;02 It's little.
00:20:37;02 It's huge.
00:20:38;02 So, we've been interested in finding the genes that underpin that.
00:20:41;07 Now, we began this story several years ago as a collaboration with Gordon Lark at the University of Utah
00:20:47;11 and Kevin Chase.
00:20:49;02 And they had a very large collection of DNA samples from Portuguese Water Dogs.
00:20:54;18 But in addition to those samples, importantly, they had X-rays.
00:20:59;11 And from those X-rays they developed a set of about 92 metrics or measurements that we
00:21:07;00 could use as phenotypes, or traits, to try and find the underlying genetics of.
00:21:13;05 And so we did that.
00:21:14;05 We scanned the entire genome, and we got this great hit, this great signal that there
00:21:21;20 was a single gene that was really important at this position.
00:21:24;17 Now, I'll show you a lot of data that looks like this.
00:21:29;01 If we look over here on the y-axis, that's a measure of significance.
00:21:33;21 It's given as minus the log.
00:21:36;11 And if we look down here at the x-axis, that's the position in megabases as we move
00:21:43;18 along the chromosome.
00:21:44;18 So, this signal is at about 44 megabases, or 44 million base pairs.
00:21:51;04 Now, when Nate Sutter walked into my office with this piece of data, I knew we had it.
00:21:57;26 So, what Nate was doing was, in this region of the genome, he was comparing the heterozygosity,
00:22:04;23 which we talked about, between large breeds and small breeds.
00:22:09;08 And look what he found.
00:22:10;10 He found that as you started your walk along the chromosome, you had this sort of
00:22:15;10 baseline level of 1.
00:22:17;10 And then when you got to this position, it plummeted.
00:22:20;11 And then when you moved through this position, it shot back up.
00:22:24;10 And then it continued on.
00:22:25;24 And then it continued on as 1.
00:22:28;04 So, that told me, unambiguously, that where that big dip was was where this gene was.
00:22:35;09 And indeed, that turned out to be true.
00:22:36;15 It's a gene called IGF1, or insulin-like growth factor 1.
00:22:41;03 Now, if you were to be in my lab at Tuesday lab meetings, you would spend
00:22:47;06 an awful lot of time looking at data like this.
00:22:49;18 And I know you can't read the details -- don't worry about it.
00:22:52;04 So, what you're looking at here is a linear representation of IGF1 gene.
00:22:58;03 And everywhere you see a number, there's one of those SNPs.
00:23:01;02 We talked about those, single nucleotide polymorphisms.
00:23:04;15 And down here are haplotypes, the different combinations of alleles that you can have.
00:23:10;11 And there’s about a dozen possible, or even more, haplotypes in this region across dogdom
00:23:16;01 as a whole.
00:23:17;13 But, when you look just at small dog breeds, you don't find a dozen possible haplotypes.
00:23:23;16 You just find one.
00:23:24;22 You find this B haplotype.
00:23:26;20 So, that tells us something very important, that somewhere in this very small region is
00:23:32;20 where the gene... or, it's where the mutation is in IGF1.
00:23:37;11 And because all small dogs, all small breeds, have the same haplotype, this is something
00:23:42;17 that occurred a long time ago.
00:23:44;28 It's very, very old.
00:23:46;09 Now, we've since progressed our studies.
00:23:49;07 We've found several other genes that are important.
00:23:51;23 So, these include IGF1, its receptor, growth hormone, HMGA2, STC2, and SMAD2.
00:23:59;00 But the funny thing about this is when we first published this, we realized that
00:24:04;21 mutations in these genes pretty much account for variation in small dogs, not in large dogs.
00:24:11;13 As a matter of fact, they account for about 60% of the variance in small dogs,
00:24:15;15 but less than 5% of what we see in large dogs.
00:24:18;04 So, Joce Plassais in the lab decided to try and figure out, what makes big dogs big?,
00:24:22;28 since we knew what made small dogs small.
00:24:25;08 And he found that there were two loci on the X chromosome that were really very important.
00:24:30;08 And they were located, oh, about a million base pairs away from each other.
00:24:34;06 Alright, this can be a kind of busy slide, so I'm gonna go ahead and take you through it.
00:24:39;09 So, if we look over here on the y-axis, we're looking at weight in pounds.
00:24:44;04 And if we look down here on the x-axis, what we're looking at are all those genes
00:24:50;20 that I just mentioned to you.
00:24:53;02 Alright?
00:24:54;02 And the first several of these are important in making small dogs small.
00:24:57;08 And as you're going to see, these last two over here are important in making big dogs big.
00:25:03;20 Okay?
00:25:04;20 So, what's the color coding, the red and the yellow?
00:25:06;26 Well, it measures derived allele frequency.
00:25:10;01 So, the derived allele is the one that we see in modern dogs, and that's coded red.
00:25:15;12 The yellow is the ancestral allele, so that's the one that we see in the wolf population.
00:25:20;24 So, when you look at really small dogs, at all of these genes, overwhelmingly the story
00:25:27;28 is one of the derived allele.
00:25:30;16 But as dogs get bigger and bigger and bigger and bigger, the breeds get bigger and bigger,
00:25:35;16 we see very little red and we see mostly yellow.
00:25:39;25 And that fits because wolves are big, and in these big dogs we're seeing the wolf allele.
00:25:47;03 And you know, the genes are informative until you get to about 90 pounds.
00:25:52;15 And then it's just a sea of yellow.
00:25:54;04 Virtually nothing, really, is very informative.
00:25:57;06 So, Joce Plassais in the lab tackled those two loci on the X chromosome.
00:26:03;11 And so, the first is a mutation in a gene called immunoglobulin superfamily 1.
00:26:08;21 Now, we see that over here.
00:26:11;26 Okay?
00:26:12;26 This first... this first red and yellow, over here.
00:26:17;19 Now we've had to flip our coding, because now the derived allele is the one that
00:26:21;21 makes you bigger than the wolf.
00:26:23;13 So, we see this derived allele in 90% of large breeds.
00:26:26;25 We also see it in a subset of medium-sized breeds.
00:26:30;08 It's strongly associated with being heavily muscled.
00:26:33;03 And in humans, it's associated with obesity.
00:26:36;22 Then there's acetyl-CoA synthetase long-chain family member 4.
00:26:42;10 This causes a bulky phenotype.
00:26:44;12 It's characterized by back back... back fat thickness and muscle.
00:26:48;07 It has a role in lipid biosynthesis and fatty acid degradation.
00:26:52;10 And in humans, when mutated, it causes insulin resistance.
00:26:56;23 So, understanding what these genes do is really helpful for studying various conditions in humans.
00:27:03;00 And I put this here to make this point.
00:27:04;25 This is the Great Dane.
00:27:05;28 We would consider this a non-bulky breed, whereas this is the Mastiff, and this is
00:27:10;17 a bulky breed.
00:27:11;26 And I should say that ACSL4... we did not discover that first in dogs.
00:27:16;22 It was actually discovered first in pigs.
00:27:19;18 And it's responsible for the back fat that you see in pigs.
00:27:22;21 So, I love studying body size.
00:27:26;01 You know, in humans there are literally hundreds of places in the genome that account for
00:27:31;10 variation in body size, whereas in dogs there's only a few dozen.
00:27:35;02 And that's going to be a reoccurring theme.
00:27:37;08 Small numbers of genes account for a lot of variation.
00:27:41;04 The genes that we've studied are in well-known pathways.
00:27:45;09 They're associated with obesity in humans.
00:27:47;24 And they present the question of, why are some alleles only relevant in
00:27:53;00 the presence of others?
00:27:54;00 So, various combinations matter more than each one singly alone.
00:27:58;11 So, this just gives you a brief summary of what we're talking about.
00:28:02;13 If you're a wolf, you're not going to have the variant allele at any of these.
00:28:08;02 If you're a small dog, you'll have the variant allele at IGF1.
00:28:13;00 Over here, if you're one of these stocky breeds, at IGF1 and IGSF1, if you're muscled and small.
00:28:19;09 Over here, if you're a Great Dane, well you're gonna have these big alleles.
00:28:23;11 You're certainly not going to have the small allele, but you won't have the bulky allele.
00:28:27;27 And over here, if you're a Mastiff, you're gonna have both the muscle allele as well
00:28:32;15 as the bulky allele.
00:28:34;03 Alright, in the last two minutes I'm just gonna tell you about one more quick trait.
00:28:38;15 This is chondrodysplasia.
00:28:39;20 It's a breed-defining trait for about 20 domestic dog breeds.
00:28:44;03 These are the dogs like the Basset Hound and the Dachshund.
00:28:47;03 The ratio of height to body length is less than one.
00:28:50;01 Skeletal structure is heavy, well-boned.
00:28:52;23 And the forelimbs are bowed or curved out.
00:28:56;01 So, we asked the question, do all these dogs have the exact same mutation, or is it
00:29:00;26 like IGF1, where there's a single ancient mutation?
00:29:04;04 And what this is telling you is there is a single ancient mutation.
00:29:07;22 So, as we're looking long the genome, and each one of these represents a different chromosome,
00:29:13;19 we're getting this great big signal with a p-value of 10^-102, and that's where
00:29:20;01 the gene and the mutation are.
00:29:21;27 It turns out the mutation is a retrogene.
00:29:24;26 So, it's a place where a gene has gotten rid of all of its regulatory machinery and introns,
00:29:30;21 and the exons have gotten zipped together.
00:29:33;12 And then whether and where the gene's expressed are signals that it picks up from the genes
00:29:37;26 around it.
00:29:39;03 And so this is a retrogene in fgf4.
00:29:42;17 And these two panels here are giving you evidence of what they look like in a chondrodysplastic dog
00:29:47;06 the cDNA made from messenger RNA, and in a non-chondrodysplastic dog.
00:29:52;06 So, we think overexpression of the RNA, or the mistimed production, leads to
00:29:58;01 premature closure of the growth plates.
00:29:59;02 So, you have these otherwise normally proportioned dogs with these thick but very short limbs.
00:30:05;00 And sure, we find dogs who have this all over the Wheel, so we know this is a very ancient mutation.
00:30:11;07 So, this is gonna conclude Part 1.
00:30:14;00 What I hope you got out of this is that most breeds are created pretty recently,
00:30:18;17 and we have the data in hand to figure out when and how.
00:30:22;10 Genomic analysis really, really opens our eyes to all of that.
00:30:27;20 And that most morphologic traits are controlled by a small number of genes of very large effect.
00:30:33;09 And that's very different than what we see in humans.
00:30:36;00 So, in the second part, we're gonna take some of the same data and we're gonna apply it
00:30:40;23 to studies of cancer, so please join us.

Part 2: Genomics of Dogs disease: Dog Genes Tell Surprising Tales

00:00:12;23 Hi.
00:00:13;23 Welcome to Dog Genes Tell Surprising Tales, Part II.
00:00:17;13 I'm Elaine Ostrander, and I'm from the National Human Genome Research Institute,
00:00:22;04 which is one of the National Institutes of Health.
00:00:25;08 So today, we're going to be talking about disease.
00:00:28;22 And we're gonna try and relate what we've learned about disease in dogs to what we
00:00:33;27 need to learn about disease in humans.
00:00:36;11 So, let's start by reminding ourselves how much dogs and humans share both genetic
00:00:42;10 and genomic features, and as a result several advances as well.
00:00:46;11 So, dogs and humans share a lot of the same medical concerns.
00:00:50;22 There's very similar disease risk for most of the common disorders.
00:00:56;20 The disease presentation, again, for most disorders is very similar, and that includes
00:01:02;04 the underlying pathology.
00:01:03;21 And how dogs and humans respond to various treatments is also quite similar.
00:01:09;18 Dogs and humans also share a lot at the genetic level.
00:01:13;07 The organization of the chromosomes and the genes is pretty much the same.
00:01:17;11 So, the same genes are in the same order on chromosomes.
00:01:21;09 The dog genome is just divided into more chromosomes.
00:01:25;01 Over the years, my lab, together with those of collaborators, has been able to build maps
00:01:29;09 that have allowed us to navigate the dog genome very, very efficiently.
00:01:34;23 There are a large number of genomic resources that are available for doing dog genetics today.
00:01:40;18 Over 800 dogs have had their genome fully sequenced.
00:01:45;04 And this data, and portions of this data, have become very useful at finding disease genes
00:01:50;23 or genes that control virtually anything that we care about in dogs.
00:01:56;17 Studies of disease in dogs have illuminated similar conditions in humans, and those include
00:02:01;19 cancer, autoimmune disease, neurologic disease.
00:02:04;11 Really, anything you care about in human health we care about in veterinary health.
00:02:08;25 And today, we're gonna focus our discussion on cancer.
00:02:11;23 So, I've listed for you, here, the top ten diseases that we see in dogs.
00:02:18;15 And you can see at the top of the list is cancer.
00:02:21;12 And that's because about one in three dogs will get cancer in their lifetime,
00:02:25;14 which is pretty similar to what we see in humans.
00:02:28;08 So, this is really a major concern in veterinary medicine.
00:02:31;27 So, we're gonna go through some examples that illuminate some of the points I think
00:02:36;13 are important.
00:02:37;13 And we're gonna start with a disease called canine hereditary multifocal renal cystadenocarcinoma
00:02:44;14 and nodular dermatofibromatosis.
00:02:46;10 I know that's pretty much a mouthful, but we'll just call it RNCD.
00:02:49;14 So, this is a disease that we see in German Shepherds.
00:02:53;17 And it's an autosomal dominant form of kidney cancer.
00:02:58;02 Diagnosis can be made early on by observation of these microscopic renal cysts.
00:03:03;04 Now, we also see skin-fibrofolliculomas.
00:03:08;09 We can see lung cysts and pneumothoraxes, but the really important take-home is that
00:03:13;06 if you have a mutation in the relevant gene the chances of getting renal cancer go up
00:03:18;02 7-fold.
00:03:19;06 And that's a bad disease.
00:03:20;16 That's a bad disease for dogs, and it's a bad disease for humans.
00:03:23;18 So, we really want to understand as much as we can about this.
00:03:27;09 Now, several years ago, a young woman from Norway came into my lab and she said,
00:03:32;14 you know, I'd really like to study this disease.
00:03:34;04 I'd like to be a graduate student in your lab.
00:03:36;12 Her name was Thora Jonasdottir.
00:03:39;06 And I said, well, I don't know, maybe, I'm not sure.
00:03:42;05 And then she showed me this pedigree.
00:03:44;14 And my eyes really bugged out, because this is an extraordinary pedigree by genetic standards,
00:03:50;07 no matter what organism it is that you're studying.
00:03:54;00 So, in this pedigree, as always, the circles are females, the males are squares.
00:04:02;01 And those individuals that are affected, like this one here, are colored in black.
00:04:07;10 And in fact, it's this individual with the red circle who's responsible for all the problems.
00:04:12;22 So, he's affected with the disease.
00:04:15;04 And he spent time with an awful lot of females.
00:04:18;13 And in every case, every litter was big, and it produced a combination of white and black,
00:04:25;16 affected... unaffected and affected individuals.
00:04:28;16 So, when I looked at this pedigree, I realized, oh my gosh, we should be able to find
00:04:33;04 the disease gene just using one single pedigree, because this pedigree is so remarkable.
00:04:38;28 And indeed, that turned out to be the case.
00:04:41;13 So, I know the numbers and letters are distracting.
00:04:44;24 Those are markers, like the SNP we talked about in Part 1, that we use to navigate
00:04:50;00 our way up and down the relevant chromosome.
00:04:52;28 And in fact, we were able to use that data to get to a really tiny, tiny portion of
00:04:57;04 the chromosome, where the disease gene was.
00:05:00;06 So, it turns out that the disease in both humans -- and in humans, the disease is called
00:05:05;17 Birt-Hogg-Dube syndrome -- and dogs is caused by mutations in the gene folliculin.
00:05:10;27 Folliculin is a tumor suppressor, so its job is to keep cancer from happening.
00:05:16;17 So when it's mutated, it can't do its job, and cancer is more likely to happen.
00:05:21;22 There's a signaling link between folliculin and the mTOR pathway and cancer susceptibility.
00:05:27;14 So it fits in a space that's not really unexpected.
00:05:30;25 Now, this is an interesting case, because the gene region or the locus was first found in dogs,
00:05:36;19 but the actual mutations were found in humans.
00:05:39;25 So, it's a great example where putting together data from humans and dogs really allowed us
00:05:45;11 to make a very rapid advance in a disease that was both interesting and really important.
00:05:51;05 Now, I should tell you that canine pedigrees like the one I showed you in the previous slide,
00:05:55;26 they're not common but they certainly do occur.
00:05:59;11 And when we see them, we jump on them, and we show them to everyone because they're so remarkable.
00:06:04;28 In humans, you just don't see these kind of pedigrees.
00:06:07;20 So again, it's the bringing together of human resources and the canine data that
00:06:15;16 really helps us advance these diseases that we care about for both.
00:06:19;14 Alright.
00:06:20;14 So, that was our first example.
00:06:23;03 It's also true, and as many dog owners will tell you, that there are many breeds
00:06:28;06 that have elevated risks for specific cancers.
00:06:30;28 So for instance, osteosarcoma is particularly common in Scottish Deerhounds, Irish Wolfhounds,
00:06:36;27 very long-lived breeds, Great Danes and Rottweilers.
00:06:40;21 Bladder cancer we see in the Scottish Terrier, the West Highland White Terriers,
00:06:45;04 and the Shetland Sheepdogs.
00:06:47;14 Histiocytic sarcoma in the Bernese Mountain Dog and the Flat-coated Retriever.
00:06:51;05 As a matter of fact, 25% of each of those breeds are going to go on to die of the disease.
00:06:57;17 It's a terrible disease for those two breeds.
00:07:00;17 Gastric cancer we see in the Belgian breeds, and we see it in the Chow Chow, shown here.
00:07:05;15 This is a very lethal disease in humans.
00:07:07;22 It's a very lethal disease in dogs.
00:07:10;19 Veterinarians tell me that diagnosis to death in dogs can really just be a few weeks.
00:07:16;00 So, that's one we'd really like to understand as well.
00:07:18;26 So, we're gonna talk a little bit about invasive bladder cancer.
00:07:23;02 We want to identify the loci, the genes, and the variants that predispose dogs to
00:07:28;19 invasive bladder cancer.
00:07:30;00 And we're gonna do it using some population structure-based approaches.
00:07:33;23 So, we want to specifically find the loci that increase risk of getting the disease
00:07:40;18 and the drivers in the tumors that make those tumors so successful.
00:07:45;11 And ultimately, of course, we'd like to be involved in developing diagnostics for
00:07:50;24 invasive cell... invasive transitional cell carcinoma of the bladder, which we're going to be calling
00:07:55;15 InvTCC.
00:07:57;23 And my lab has also been involved in a transcriptome analysis of invasive transitional cell carcinoma,
00:08:03;08 the bladder tumors, to help identify predictive features as well as drivers of that tumor progression.
00:08:10;19 These are the three breeds that are at pretty much the highest risk of getting the disease.
00:08:16;13 And over here I have the Scottie.
00:08:18;22 If you're a Scottish Terrier, your odds of getting the disease are 22-fold higher
00:08:25;00 than the average mixed-breed dog walking down the street...
00:08:28;19 22-fold higher.
00:08:29;19 There's some amazing genetics buried in that breed.
00:08:33;10 Alright.
00:08:34;10 So, from a human genetics viewpoint, why do we care?
00:08:37;20 Well, in humans, the same disease, the cause is unknown in about 50% of people who get it.
00:08:45;08 Front line therapy, removal of the bladder, is a complex and it's an expensive operation.
00:08:50;07 At least half of the patients who undergo cystectomy will subsequently die of metastatic cancer.
00:08:57;26 Now, there are chemotherapeutic approaches.
00:09:01;02 They can initially be successful, but resistance then usually ensues.
00:09:05;09 And there's really no second line treatment.
00:09:07;13 Metastasis is common.
00:09:09;08 And the median survival times really haven't changed in the last 20 years.
00:09:13;07 So, we like dog models.
00:09:15;15 It's really the best model for human invasive bladder cancer for the reasons that are listed for you here.
00:09:22;05 So, it is spontaneous.
00:09:24;09 This isn't something that has to be induced, like a lot of mouse cancers.
00:09:27;24 The age of onset, symptoms, drug response, site of metastases, and pathology are all
00:09:33;01 very, very, very similar between humans and dogs.
00:09:36;02 So, one of the first things that we did was to look at a series of tumors.
00:09:42;06 These were bladder tumors provided by a very valued collaborator, Debbie Knapp,
00:09:48;01 from a series of different dog breeds.
00:09:50;28 And when we looked at them, we found that 85% of the tumors carried a mutation in a
00:09:56;11 gene called Braf.
00:09:58;20 And the mutation -- every tumor -- was at the exact same position.
00:10:02;20 It was amino acid 600, and it was this valine to glutamic acid change.
00:10:08;27 So, that set off all kinds of bells, because mutations in the exact same gene in the
00:10:15;24 exact same position... position are really important in human cancers.
00:10:20;14 As a matter of fact, we see them in about 40% of melanoma tumors; we see them in thyroid cancers,
00:10:25;22 as well as in colorectal cancers.
00:10:28;12 In humans, if you have this mutation in your tumor, it's associated with poor outcomes,
00:10:32;03 and the same thing is true in dogs.
00:10:34;14 So, we were really interested to find this because it represents a target, a druggable target.
00:10:42;08 So now, for canine bladder cancer, we have some ideas about how to treat it,
00:10:47;17 because there are drugs developed for human melanoma and others that directly target
00:10:53;22 this particular mutation.
00:10:54;22 So, we now have a route to advancing our studies.
00:10:59;28 This result also gave us a route into some diagnostics.
00:11:03;15 So, we've been doing sequencing of urine samples from dogs who have this disorder.
00:11:10;18 And we can tell pretty early on if a dog, in fact, has bladder cancer.
00:11:16;00 And we have a sensitivity where if there's even one mutation, one mutant sequence read,
00:11:22;23 in the background of 10,000 normal reads we can pick it up.
00:11:27;06 So, this is a place for genomics has really, really helped us advance something about
00:11:32;09 a disease that we care about a lot in canine health -- it's pretty common --
00:11:36;09 and in human health as well.
00:11:39;01 Now, the last tumor I want to tell you about is called transmissible tumor.
00:11:45;12 As a matter of fact, I call this part of the talk "The Long and Lonely Life of a Canine
00:11:49;24 Venereal Transmissible Tumor" because this is a venereal tumor.
00:11:54;06 So, this is what we call a clonally transmissible parasite.
00:11:59;09 Now, not a parasite like a virus, or a bacteria, or a little bug crawling around.
00:12:05;17 This is a transmissible cancer.
00:12:07;11 So, there was a single founder, who we'll talk about, thousands of years ago who
00:12:12;18 originally got the tumor.
00:12:14;06 And the tumor has now spread from dog to dog to dog to dog via sexual transfer.
00:12:19;26 So, that is, one dog has the tumor and it spreads to the other dog by the transfer of
00:12:26;03 malignant cells.
00:12:27;14 So, that's kind of scary, isn't it?
00:12:30;01 It's endemic everywhere in the world except Antarctica.
00:12:33;13 It is the world's oldest-known continuously propagating somatic cell lineage.
00:12:39;19 We know it's been around for thousands of years.
00:12:42;04 Now, it's transmitted during a month-long period of evasion from the host immune defenses,
00:12:48;13 and then it can later be eliminated.
00:12:51;07 Sometimes it's lethal; sometimes it's not.
00:12:53;13 We're gonna talk about those host immune defenses in just a moment.
00:12:57;02 What's important is that all of the tumors, all the dogs running around in the world with
00:13:02;04 the tumor today, if you look at their tumor sequence you can see that they have
00:13:07;08 shared origins.
00:13:08;25 There's a lot of places where there are haplotypes or sequence that's identical.
00:13:13;06 So, they have a very strong genetic identity, we would say, with one another.
00:13:18;21 And it's markedly distinct from what we call their transient host.
00:13:23;04 The transient host is the dog who walked into the clinic who had the tumor.
00:13:27;08 So, we can look at DNA sequence and we can distinguish those things.
00:13:31;26 So, the question that we asked in my lab is, can the CTVT genome, the genome sequence,
00:13:39;14 reveal the biological mechanisms that underlie the tumor's dogged appearance in canids
00:13:45;21 around the world today?
00:13:46;21 And that's my only pun, so you have to laugh at it.
00:13:50;01 Alright.
00:13:50;22 So, let's think about how this happened.
00:13:52;27 So there's a dog, thousands of years ago.
00:13:55;21 He's what we're gonna call the founder, and he unfortunately gets this tumor.
00:13:59;28 Alright?
00:14:00;28 He or she eventually... apparently gets this tumor.
00:14:03;28 It is a myeloid tumor, just so you know that.
00:14:08;11 And then lots of different things happen over thousands of years.
00:14:12;07 There are some places where there are lineages that just simply end as indicated by
00:14:17;23 the red X's.
00:14:18;25 There are other places where lineages go on and on and on 'til we have dogs that we can
00:14:24;07 sample today, like this dog in Brazil or this dog here in Australia.
00:14:30;04 And there are other places where lineages started and they just ended.
00:14:34;11 So, when we began this study, we only had two things.
00:14:39;22 We had the DNA sequence of a dog... the tumor, excuse me... the tumor sequence of a dog from Brazil,
00:14:45;27 and we had the tumor sequence of a dog from Australia.
00:14:50;25 We did not have the sequence of the actual dogs.
00:14:54;22 We only had the sequence of their tumors.
00:14:58;08 And what we wanted to do was figure out what it was that was allowing this tumor to be
00:15:06;28 so successful.
00:15:08;11 So in order to do that, we had to separate the ancient canine genome from the somatic genome
00:15:14;13 or the tumor genome.
00:15:16;26 So, if you... if you take a single dog and he has this tumor, and you just do
00:15:23;19 sequencing of the tumor, there's gonna be a lot of things in that sequence.
00:15:27;14 There's going to be DNA sequence from the host, the dog that walked into your office.
00:15:31;27 There's going to be DNA sequences from the ancient founder.
00:15:35;15 There's gonna be DNA sequence from the tumor.
00:15:38;08 There's gonna be lineage-specific mutations.
00:15:40;10 There's gonna be some systematic errors.
00:15:42;06 It's gonna be a mess.
00:15:43;06 Now, if you add a second dog, as we were able to do, you simplify the problem.
00:15:48;17 Because you get rid of the DNA sequence from the host that walks into your office.
00:15:54;04 They cancels... they cancel each other out, and you're left with two things that you
00:15:57;27 really care about.
00:15:59;02 You're left with the DNA sequence of the original founder, and you're left with the DNA sequence
00:16:03;23 of the tumor.
00:16:04;25 And that's what we want to separate.
00:16:07;07 We want to know what has made this tumor so successful.
00:16:11;08 These are the things that we want to separate.
00:16:13;03 Alright.
00:16:14;03 So, how are we going to separate those?
00:16:16;27 Remember, our goal is to understand the genomic underpinnings of CTVT's remarkable behavior.
00:16:23;01 So, we really want to figure out what we can learn about the origins of CTVT.
00:16:28;10 And we also want to learn something about that original dog in whom the tumor first occurred,
00:16:33;24 and of course that dog's been dead for thousands and thousands of years.
00:16:37;27 Now, this wasn't available at the time we did this study, but studies like this
00:16:43;07 are really enhanced, now, by the fact that there's a worldwide consortium that's formed called
00:16:48;15 Dog10K.
00:16:49;15 So, the goal of Dog10K is to sequence 10,000 dog genomes in the next 5 years.
00:16:56;26 And there are people from 18 countries...
00:16:59;14 18 members from 9 different countries who are part of this consortium.
00:17:03;26 And they're listed for you here.
00:17:05;21 So, this is a really exciting collaboration in canine genomics, and it's gonna make
00:17:10;00 the kinds of studies I'm going to tell you about in just a moment an awful lot easier.
00:17:14;07 Alright.
00:17:15;07 So... how are we doing this?
00:17:17;14 Well, remember, we're gonna be starting out over here with the founder, who... you know,
00:17:22;11 we don't have anything from him.
00:17:24;07 But we have the sequence of these two tumors.
00:17:26;07 And because we have two tumors, the potential number of mutations
00:17:31;02 -- insertion-deletion, structural variants, single-nucleotide variants --
00:17:34;18 is initially potentially very large,
00:17:36;26 but it reduces when we compare the sequence of these two tumors.
00:17:42;02 And so then we can go ahead and we can take those variants that we see down here and
00:17:49;07 we can say, do we find them in our catalog of whole-genome sequences of hundreds of dogs
00:17:55;08 that our lab is assembled?
00:17:56;13 Now, these are dogs have been sequenced all over the world, and we've assembled the data.
00:18:00;27 If the answer is yes, well, that's probably part of the sequence of that original founder.
00:18:08;01 And if the answer is no, that's what we care about.
00:18:12;07 Those are probably some of the mutations that occurred in that original tumor that
00:18:16;19 made it so spectacularly successful.
00:18:19;12 And what do those mutations turn out to be.
00:18:22;04 Well, they turn out to be mutations in all aspects of somatic participation in
00:18:28;14 immune surveillance.
00:18:30;04 So, every part of the immune system that's important in recognizing self versus non-self
00:18:36;14 has been destroyed over the years by this tumor.
00:18:40;16 And so it's exquisitely adapted to its niche as a transmissible allograft.
00:18:45;24 We don't...
00:18:46;24 our immune system... or, the dog's immune system doesn't recognize it as foreign.
00:18:50;21 So, it just marches along doing its tumor thing, because it has so wisely knocked out
00:18:57;18 anything that would make the host immune system... system recognize it as foreign.
00:19:03;08 Now, this work was done largely by Brennan Decker and Brian Davis in my lab,
00:19:08;04 and Brennan was a graduate student.
00:19:10;09 And at this point, he wrote up a lovely paper on this and told me he was going to graduate.
00:19:13;27 And I said, well, you know, I really want to know a little bit about that first dog
00:19:18;10 thousands of years ago, that original canine.
00:19:20;26 And he said, who cares.
00:19:22;20 And I said, I care.
00:19:23;20 You have to do it before I'm gonna let you graduate.
00:19:25;12 And so, what Brennan did is he took the DNA sequence from those two tumors that we had,
00:19:31;11 and he put it on a phylogenetic tree, as you see here.
00:19:35;14 But in this case, what he did was he used DNA sequence to build that whole phylogenetic tree.
00:19:42;28 And it turned out that that original dog, the original dog who had that very first mutation,
00:19:49;16 is a Siberian Husky.
00:19:52;04 Because the two tumor sequences grouped on the phylogenetic tree with the Siberian Husky.
00:19:58;05 So, that's really interesting, because these... the disease is something that occurred
00:20:07;03 after domestication.
00:20:08;15 It didn't come up in the wolves.
00:20:09;22 It didn't come up in the coyotes.
00:20:11;18 It's something that came up post-domestication.
00:20:14;02 So, somewhere in that 13-30,000-year range, that's when this disease actually developed.
00:20:21;28 We still see it today.
00:20:23;07 We still see it all around the world today.
00:20:26;08 And it's a topic of intense interest.
00:20:29;02 Now, transmissible tumors are something we worry about in humans.
00:20:34;15 We don't have them.
00:20:35;19 We don't have them yet.
00:20:37;03 There are a couple of other examples where they occur.
00:20:39;25 You may have heard about the story in Tasmania, with the Tasmanian Devils.
00:20:46;21 And they also experience a transmissible tumor.
00:20:49;02 And in fact, their tumor is quite aggressive.
00:20:51;18 It's a facial tumor, and it can affect breathing, it can affect eating.
00:20:56;24 And it's largely responsible for the rapid movement of the Tasmanian Devil towards extinction.
00:21:02;13 So, that's a place where we really care about it.
00:21:05;15 And there's also been reports in some marine life of having transmissible tumors.
00:21:11;27 So, it'll be interesting to see how all these stories evolve in the coming years.
00:21:17;13 Okay, so I've told you an awful lot in the... in the last two videos.
00:21:24;13 And I'm sure some of you are asking, how is it that you can help us?
00:21:27;03 Well, you can help us in a lot of ways.
00:21:29;13 These are the diseases that we study most intently:
00:21:32;20 histiocytic sarcoma in Bernese Mountain Dogs and Flat-Coated Retrievers;
00:21:37;02 bladder cancer in Scotties and Westies and Shelties;
00:21:40;22 and gastric cancer in the Belgian Teurvern, the Belgian Sheepdog, and the Chow Chow.
00:21:45;15 So, if you have dogs who have any of these disorders, please contact us
00:21:50;23 -- and I'll tell you how to do that in just a moment -- because we would love to get a sample from your dog
00:21:55;12 and include him in the dog cancer genome project.
00:21:58;06 If you have an older dog who's very healthy and doesn't have any of these cancers,
00:22:04;10 their DNA could be used in our control dataset.
00:22:07;02 So, we'd like you to contact us as well.
00:22:09;21 Now, as you know, we study lots of different morphologic traits:
00:22:13;16 body size, skull shape, bone structure.
00:22:16;21 If you have an unusual dog breed, please contact us.
00:22:19;23 We would love to get DNA and include it in the dog genome project from your dog.
00:22:23;22 And if it's particularly interesting, we may even include that 10,000 dog genome project.
00:22:29;03 So, whether it's an AKC-registered breed, a non-AKC-registered breed, an internationally
00:22:35;02 recognized breed, you can go to our website, and I'll show you that in a moment,
00:22:39;22 and you can look at the breeds we're most interested in.
00:22:42;01 And of course we're always interested in breed history and phylogeny.
00:22:46;13 So, look at some of our data.
00:22:49;06 Again, it's available on our website.
00:22:52;02 And if you, again, have an unusual breed that you think that's a niche that we haven't addressed,
00:22:57;03 please contact us.
00:22:58;04 We'd love to get a sample from your dog.
00:23:00;18 So, today, these were some of my favorite dog breeds.
00:23:05;12 And these are some of the ones that we've done quite a bit of study on.
00:23:10;07 But there's an awful lot that we don't know yet about domestic dogs.
00:23:14;08 And this is, as I said at the beginning, the largest experimental collaboration
00:23:19;04 that's probably ever been undertaken between scientists and the general public.
00:23:23;07 So, we'd really love your contributions.
00:23:26;01 Alright.
00:23:27;01 So, in the... in the last several minutes, I've tried to show you that dogs are
00:23:31;12 a great system for the study of both simple and complex traits.
00:23:35;18 In the previous 30 minutes, we talked about morphology, and I showed you how canine morphologic studies
00:23:40;21 illuminate multiple genes and pathways that are of interest to people studying, really,
00:23:47;19 any aspect of mammalian biology.
00:23:50;19 An important and reoccurring theme in dogs is that most phenotypes are controlled by
00:23:55;07 a small number of genes of large effect.
00:23:58;23 And that's different than humans, where most phenotypes or traits are controlled by
00:24:05;01 a large number of genes of very small effect.
00:24:08;19 And finally, there are people in our community studying every disease you can possibly imagine.
00:24:14;01 And my lab studies cancer, and that's because canine cancers can help us understand
00:24:19;03 the genetic underpinnings of human cancers.
00:24:22;00 So, here's our contact information.
00:24:25;10 The person in our lab who collects all of our samples and will send you a kit that you
00:24:30;08 can give to your veterinarian, who will then collect a sample, is Andrew Hogan, up there.
00:24:36;15 His contact information is listed for you.
00:24:39;04 And our website is listed for you as well.
00:24:41;17 So, thank you for joining me today.
00:24:43;22 I hope you've learned something new about your dog or about any dog that you care about.
00:24:49;00 And I hope you can think about some interesting ways in which you could be part of our...
00:24:53;02 of our big collaboration and our dog genome studies.
00:24:55;28 Thank you.

Videos in this Talk

Part 1: Canine Genetics: Dog Genes Tell Surprising Tales
Audience:
- Student
- Researcher
- Educators of H. School / Intro Undergrad
- Educators of Adv. Undergrad / Grad
Part 2: Genomics of Dogs disease: Dog Genes Tell Surprising Tales
Audience:
- Student
- Researcher
- Educators of H. School / Intro Undergrad
- Educators of Adv. Undergrad / Grad

Speaker: Elaine Ostrander

Total Duration: 0:56:16

Recorded: December 2017

All Talks in Genetics and Gene Regulation

Talk Overview

Although all domestic dogs belong to the same species, different breeds display unique morphological traits and different disease susceptibility. Dr. Elaine Ostrander provides an overview of canine genetics, and explains how scientists are using genetics to decipher the molecular basis of different traits such as height and cancer risk.

In her second lecture, Ostrander explains that canine genetics can be used to understand disease susceptibility and cancer risk. By analyzing the pedigree of dogs, her laboratory identified a series of genes involved in the elevated cancer risk of particular dog breeds. Specifically, her laboratory studied invasive transitional cell carcinoma of the bladder, a disease for which breeds like Scottish Terriers have a high susceptibility. In human cases of this disease, the cause is unknown in 50% of patients. Ostrander’s laboratory identified genetic mutations that explain the elevated cancer risk in these dogs. This information may improve diagnosis and targeted therapy in dogs and humans.

Speaker Bio

Elaine Ostrander

Dr. Elaine Ostrander is the Chief and Distinguished Investigator at the National Human Genome Research Institute at the National Institutes of Health (NIH). She received her B.S. degree from the University of Washington (1981), and her Ph.D. from the Oregon Health & Science University (1987). Ostrander continued her postdoctoral training at Harvard University. A few… Continue Reading