A Famous Sled Dog’s Genome Holds Evolutionary Surprises

CHARLES BERGQUIST: This is Science Friday. I’m Charles Bergquist.

FLORA LICHTMAN: And I’m Flora Lichtman. Do you remember the story of Balto? In 1925, the town of Nome, Alaska was facing a diphtheria outbreak. Balto was a sled dog and a very good boy who helped deliver life saving medicine to the people in the town. Balto’s twisty tale has been told many times, including in a ’90s animated movie in which Kevin Bacon played Balto.

SPEAKER: Which way, Balto? Which way? Which way?

KEVIN BACON AS BALTO: Uh, this way!

[DOGS BARKING]

FLORA LICHTMAN: But last month, scientists uncovered a new side of Balto. They sequenced his genes and discovered he wasn’t exactly who they expected. The study was part of a project called Zoonomia, which aims to better understand the evolution of mammals and our own genome by looking at the genes of other mammals from narwhals to aardvarks.

Here to tell us more are my guests. Elinor Karlsson is an associate professor in Bioinformatics and Integrative Biology at UMass Chan Medical School and director of Vertebrate Genomics at the Broad Institute of MIT and Harvard. She’s based in Boston, Massachusetts. Katie Moon is a postdoctoral researcher at UC Santa Cruz in Santa Cruz, California. Beth Shapiro is a professor of Ecology and Evolutionary Biology at UC Santa Cruz in Santa Cruz, California. Welcome all to Science Friday.

ELINOR KARLSSON: Thanks for having us.

FLORA LICHTMAN: Katie, you were the leader of the pack on the Balto study. Were there any surprises that jumped out of Balto’s DNA?

KATIE MOON: Yeah, I think not surprising, but I think you never really know when you sequence something’s genome, what you’re going to find. And I think what was cool about Balto is that we had some ideas about what we’d find. And a lot of those were confirmed with the genomics, but we also found some really neat other things, which we didn’t predict. One of my favorite things is that we were able to predict his physical phenotype from his genotype, so everything from his coat coloration to his eye color to skin thickness, muscle development, things like that. That was really cool because you can imagine why a dog like Balto would have needed those things where he was living.

FLORA LICHTMAN: So he had genes that might have made him better adapted to pulling a sled in very cold conditions?

KATIE MOON: Exactly right. Body weight things, joint formation, coordination, things like that. So that’s exactly what you would expect from Balto and his population, the larger group of sled dogs that were pulling these large weights through icy conditions 100 years ago.

FLORA LICHTMAN: What about Balto’s pedigree? How does he compare to modern sled dogs?

BETH SHAPIRO: One of the really cool things about looking at a genome from an animal that lived 100 years ago is that we can’t really think of it as what of today’s breeds are in Balto because Balto lived before today’s breeds existed. So he is kind of that ancestral population, and his ancestry, parts of his ancestry have also contributed to the ancestry of what we think of as dog breeds today. So it’s kind of a hard question to answer what breeds is he because it’s not really the right question to ask. He lived before the breeds, so he’s kind of representative of all of them together.

ELINOR KARLSSON: So one of the things that I got really excited about looking at Balto and Balto data was that Balto was actually called a Siberian husky. And his epic sled run in Alaska is one of the things that might have inspired them to establish the Siberian husky breed. So having an opportunity to look at Balto’s DNA and compare that to Siberian huskies today and try to figure out what their actual relationship was, was something that I was quite curious to find out.

And what we saw was that when you establish a sled dog breed, like a breed like we do today, you create these closed populations of dogs. These are dogs where only Siberian huskies only get to have puppies with other Siberian huskies. And so we found two things. We found, one, that Balto had a lot more genetic diversity in his population than is in the modern sled dog breeds today, including the Siberian husky, and also that it looked like he probably had fewer changes in his genome that might have been damaging to his health. So it might have been kind of overall a healthier population as well.

FLORA LICHTMAN: Katie, how did you fetch Balto’s DNA in the first place?

KATIE MOON: [LAUGHS] Great pun. Well, so he’s actually on display at the Cleveland Museum of Natural History. And you can still see him today, his taxidermied remains there in a glass case. So we actually grabbed a little piece of his underbelly skin, so we gave him a little tummy rub and extracted the DNA. Now, in our clean lab here in Santa Cruz, so we have a clean lab where no modern DNA goes into, and we keep everything spic and span. And we extracted it with some in-house preparation. We’ve made a lot of leaps forward with ancient DNA extractions and preparation techniques. He actually ended up being quite well preserved and not as damaged as you would expect.

BETH SHAPIRO: But certainly more damaged than if we were to get DNA from a dog that’s alive today. We know that as soon as an animal dies or a plant, the DNA in all of its cells starts getting chopped up into smaller and smaller pieces until eventually they’re so small that you can’t recover them or make use of them.

So even though Balto was only about 100 years old, his DNA was chopped up into really tiny fragments, like only about 60 letters long or so, compared to modern DNA that might be hundreds of millions of letters long after you extract it, which is why we had to use that special clean facility that Katie was talking about. So he was really well preserved compared to the things like mammoths and giant bears that we often work with, but not as well preserved as the dogs that Elinor gets to work with.

ELINOR KARLSSON: Yes, I know, Beth. Your life is so much harder than mine is with your clean DNA.

[LAUGHTER]

FLORA LICHTMAN: Elinor, the Balto study used the Zoonomia data as well. Will you tell me more about that project? What is the mission?

ELINOR KARLSSON: Yeah, so the Zoonomia project is a big project where we sequenced the genomes, the DNA, from hundreds of different mammalian species. So we had 240 different species of placental mammals in there. We didn’t include all the crazy mammals from Australia that are marsupials because they’re basically just too weird. They’re too far away. So we were focused on the placental mammals, things that were reasonable. You don’t want to get too crazy.

And so we sequenced their DNA. And lots of other people did, too. We basically took advantage of these big public data sets. And then we aligned all the genomes. And what we do, by aligning all the genomes, it means that we can look at a given position in the DNA. So you take a human. A human’s genome is about 3 billion bases or letters long. And once we’ve aligned it, we can actually look at a given position in the human genome and see what it looks like in every other species in our data set. So we can see what that position looks like in a dog, looks like in a bat, looks like in a mouse. And that allows us to understand how things are changing over evolutionary time.

FLORA LICHTMAN: Has Zoonomia revealed any hidden superpowers of animals that we didn’t know about before?

ELINOR KARLSSON: I’m getting more and more interested in superpowers of mammals, but I hadn’t really thought about hidden ones. We sort of actually go the other direction, where we’ve observed that animals have amazing superpowers, and we’re like, how do they do them? The biggest challenge in genomics is that we’ve gotten very, very good at sequencing DNA. We can sequence every individual very easily. We can look at all their A’s, C’s, G’s, and T’s, figure out what order they go in. We can even do it for ancient DNA, like mammoths and Balto.

The problem is, is we don’t actually understand what most of it means. We don’t know how to read out that string of A’s, C’s, G’s, and T’s and actually say, hey, that’s what this piece of DNA is doing, and this is why it’s important. And so by sequencing the genomes of a lot of species and then also going and studying those species and understanding how they’re different, we can start analyzing those two things together, the phenotype of the animals and the sequence of the genome, and try to figure out which parts of the genome are actually giving them those exceptional abilities.

FLORA LICHTMAN: Beth, what about DNA from extinct animals? Is there any plan to incorporate ancient DNA into Zoonomia?

BETH SHAPIRO: Absolutely. So I think one of the really awesome innovations that comes from Zoonomia is this alignment, the lining up of all of the genomes from these various different mammalian species. So what is on chromosome one from a human is not necessarily on the same chromosome from a bat or from a bear or from a cat. And so you have to use really sophisticated statistics to be able to line them up so that you can compare these sequences because they’ve been sort of shuffled around the genome by evolution, recombination, over the many tens of millions of years of mammalian evolution.

So now that we have this base alignment of all these different things, we can start sticking in other species that we don’t have. And that could include extinct species where we can generate genome sequences from things like mammoths and saber toothed cats and giant bears and begin to ask where they are different from their closest related living species using this same sort of structure that Elinor’s been talking about, but also filling in some of the gaps that aren’t there. I think it’s been pointed out several times now– and Elinor, you really do have to explain yourself– there is no raccoon, for example, in the Zoonomia alignment. [LAUGHS]

ELINOR KARLSSON: Ugh. I know about the missing raccoon. [LAUGHS]

BETH SHAPIRO: Actually, it’s really funny because we didn’t even think about the raccoon until the press conference that Elinor had and people kept bringing it up. And I’ve just been teasing Elinor about this ever since. I think a bunch of people have as well. So why people are so fascinated by the raccoon, I don’t understand, but it’s not there.

FLORA LICHTMAN: Are there animals on your bucket list?

BETH SHAPIRO: Yeah, I don’t know. I mean, I’m interested in species that are struggling, so species that are on the endangered species list and how we might be able to use the sort of resource to identify species that we should be focusing conservation efforts on. And so I think that it would be useful to generate genome sequences from species that we often don’t think about, those that don’t immediately come to mind, because these are the ones that maybe we need to be focusing on from a preservation of biodiversity perspective. Elinor, do you have a bucket species?

ELINOR KARLSSON: The ones I’m most interested in are the ones that we don’t know anything about. So one of the things I learned working on this project was that you’d think that sequencing a whole lot of mammals would be really easy. You just go down to the zoo and you work with the zoo people, and you get a sample of DNA. And then you sequence it, and then you’ve got your genome made. And it turned out, what I discovered during the course of this project was that most species, including most mammals, don’t tolerate being kept in captivity. They don’t do well. They don’t reproduce. They don’t have babies. And often, they just can’t survive. They just don’t do well in that environment.

And that includes, for example, most bats. Like, except for a couple of fruit bats, most bats just don’t do well in captivity. And so in order to actually study these species, somebody’s got to go out to where they’re living and find them in the wild and get samples from them. And I’m really curious to know what’s out there that we don’t even know that we’re missing yet.

FLORA LICHTMAN: Beth, you mentioned conservation work. How can this genetic data tell us about whether a species is in trouble? How does that work?

BETH SHAPIRO: It’s a great question. One of the papers, there were actually 11 papers that were published together as part of the Zoonomia package, and I was fortunate to be involved in a few of them. One of those was to ask whether if we just had one genome sequence from one individual, we could learn something from that one genome sequence that would help us to prioritize our focus of conservation.

Obviously, we’re in the midst of a biodiversity crisis and extinction crisis, and there is not enough money, resources, and time to go around to focus on all of the species that we need. And there are many species that are listed as data deficient, where we just don’t have the ecological survey data, the genomic data, and any knowledge about these species as to whether they might be endangered. And it’s easy to imagine how, if you had a bunch of genomes from a bunch of individuals, you could ask how much diversity is in that population, or is that population really in trouble? Are they inbreeding? Are there mutations at these sites that seem to be important for other reasons?

But with just one genome, we were curious, is there any information in there that can really help us to focus, to do triage for this conservation prioritization? And the answer, we were able to figure out, is, yes. In the absence of any other information, we can use certain features of a single genome, things like whether the two chromosomes, because every animal has one chromosome from mom and one chromosome from dad, if they’re the same as each other for a long time in that genome, that means that there’s inbreeding going on, recent inbreeding.

The population size is small, and that can hint that there might be a problem. Or if there are mutations that are happening in these parts of the genome that are identified, as Elinor was talking about before, as constrained, where mutations don’t normally happen, if we see mutations accumulating there that change genes and potentially change functions, then this is, again, a signal that that species might be in trouble, and we should invest some more energy in trying to figure out what’s going on.

FLORA LICHTMAN: Wow. So without survey data, you can tell from the genes of one individual whether that species, the whole species might be in trouble?

BETH SHAPIRO: Yeah, it’s really impressive. And it’s not enormously powerful as an approach. I mean, it would be more powerful to go out and collect a lot of data or to do the survey data. But it is possible to use this as a first step in conservation triage. We can identify populations that we need to go and spend some time and money, potentially, to see if they really are in trouble. Yeah, it’s really fascinating that this is possible from one genome.

FLORA LICHTMAN: This is Science Friday from WNYC Studios. Elinor, this is a very human centric question, but does this data give us new insight into ourselves? Does it tell us anything about what it means to be human?

ELINOR KARLSSON: Well, I can tell you that the press conference about the papers told me they were very interested in that question. Everybody wanted to know the answer to that question. We’re apparently very excited about ourselves. What is it that makes humans different? The first part of that answer would be not nearly as much as people think that we’re different. For the most part, humans are animals and do mostly the same things as all other animals do.

But we had a few hints at things that might be different in humans. So we had two different papers that looked at the question of what’s special about humans. There was one that looked for parts of the DNA that were basically constrained, meaning that they seem to be doing something important across all of the mammals, and then started changing much more quickly within the human lineage, meaning that for some reason, that important part of the DNA was changing in humans, such that it was different from the other animals.

And then there was another paper that looked for things that were, again, constrained across all mammals, but then deleted just in the humans to try and figure out what it was doing. And both of those papers seem to point at changes in parts of the genome that regulate the expression of genes in our brains. And we don’t know exactly what they’re doing yet, but we could sort of guess that they’re taking the mammalian brain.

There’s a lot of similarities across all of mammals, but somehow in humans, it’s just tweaked a little bit maybe so that we have more neurons, or we have more connections between neurons, or maybe the sizes of different parts of the brain are changing. We don’t know exactly what effect these changes are having yet, but now that we’ve found them, now that we can say that out of the 3 billion letters that are in the human genome or 3 billion bases that are in the human genome, these are the ones that seem to be having a functional impact on how things are regulated in human brains. We can start to go back and see what it is that they’re actually doing.

FLORA LICHTMAN: That’s fascinating.

ELINOR KARLSSON: The space between figuring out if something is important and then figuring out what it does is, it’s a very long road. It’s quite impressive, but when you’ve got 3 billion bases that you’re starting with, at least knowing that you’re looking at the right thing at the beginning of all that, it makes the whole thing a lot easier.

FLORA LICHTMAN: I think that’s the perfect place to leave it. Thank you all so much for joining me today.

KATIE MOON: Thank you. That was fun.

ELINOR KARLSSON: Thank you very much.

BETH SHAPIRO: Thanks, Flora.

FLORA LICHTMAN: Dr. Elinor Karlsson is associate professor in Bioinformatics and Integrative Biology at the UMass Chan Medical School and director of Vertebrate Genomics at the Broad Institute of MIT and Harvard. She’s based in Boston, Massachusetts. Dr. Katie Moon is a postdoctoral researcher at UC Santa Cruz in Santa Cruz, California. Dr. Beth Shapiro is a professor of Ecology and Evolutionary Biology at UC Santa Cruz in Santa Cruz, California.

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