Hidden details of world’s most famous sled dog revealed in massive genomics project | Science

In 1925, a sled dog named Balto made headlines around the world when he braved fierce winds, a raging blizzard, and splintering river ice to bring lifesaving serum to an isolated Alaskan town struck with diphtheria. (Although another sled dog, Togo, may deserve most of the credit.) Now, researchers have pieced together a fuller picture of the celebrated canine from DNA taken from the underbelly of his stuffed, faded carcass. Aided by hundreds of newly sequenced genomes and an extensive database of dog DNA, they were able to glean details about Balto’s size, appearance, and stamina not captured in historical photos of the famed canine.

“Even with the genome of a single individual, you can learn a lot,” says Nathan Upham, an evolutionary biologist at Arizona State University who was not involved with the research.

The work, reported today in Science with 10 other papers about a massive sequencing effort called Zoonomia, speaks to the power of having many accurately sequenced genomes on file, says Greger Larson, an evolutionary geneticist at the University of Oxford who also was not involved in the research. He says the project will permit scientists to better assess the looks, physiology, and perhaps even the conservation status of species based on single genomes. “The predictive ability is just staggering.”

For the Zoonomia project, researchers from around the world obtained and compared complete DNA sequences of 240 placental mammals, from tiny bumble bee bats to giant whales, then matched up all the genomes to see what DNA was the same, or conserved, in all of them. This conserved DNA reveals genes critical to a mammal’s survival, as harmful deviations are less likely to have been passed down. “We can learn exciting things about how species diverged and adapted,” says Zoonomia collaborator Beth Shapiro, a paleogeneticist at the University of California, Santa Cruz.

But Shapiro and her postdoc, Katie Moon, also wanted to know what this new resource could reveal about individuals. So, they sequenced DNA from a pencil eraser–size tissue sample from the 100-year-old sun-bleached belly of the stuffed Balto, who is on display at the Cleveland Museum of Natural History.

That feat was “extraordinary,” says Elaine Ostrander, a dog geneticist at the National Human Genome Research Institute (NHGRI) not involved with the work. “It gives us a very clear picture of dogs who were selected for [sled dogs] at that point in time.”

Kathleen Morrill, a geneticist now at Colossal Biosciences, looked to see how well Balto’s conserved DNA matched that in other species within the Zoonomia data set. She also compared his DNA with more than 600 genomes of wolves, coyotes, and dogs of different breeds. These included modern sled dog breeds such as Siberian huskies, more physically and genetically isolated sled dogs in Greenland, and “village dogs”—ownerless canines that live in Africa, South America, and Asia and make up 80% of the world’s dogs.

From Balto’s DNA, Morrill, Moon, and their colleagues determined that he was a relatively small sled dog. At 55 centimeters at the shoulders, he was smaller than most Siberian huskies and Alaska malamutes, sled dogs later recognized as American Kennel Club breeds. They also predicted that Balto would have had a double layer of black fur twinged with tan; modern sled dogs tend to have just a single layer. All of this matched up with and further clarified the dog’s actual appearance, Moon says. “It was something that I never thought would be possible.”

The team also determined that Balto had some genes useful for digesting starch—a helpful innovation for living among people—but not as many as more modern dog breeds. Moreover, he had versions of genes important for developing strong bones, muscles, and joints that helped make him so capable of pulling sleds such long distances even in the dead of winter.

In the past, characterizing an individual’s traits based on DNA—say the red hair of ancient humans—“you just have to go on faith” that they are right, Larson says. With Balto, scientists actually know what he looked like, he says, so he’s “a brilliant control. You can make all these predictions that turn out to be absolutely true.”

But Balto’s genome carries a sobering message for dog lovers today. Being the product of generations of mating of different kinds of dogs, Balto and his peers were much more outbred and had more genetic variation and fewer harmful genes than modern dog breeds. “Turning dogs into breeds was a process with negative consequences [that] we only now are starting to understand,” says Mikkel Sinding, a paleogeneticist at the University of Copenhagen. Ostrander hopes Balto’s suite of healthy developmental genes could lead to genetic tests for hip and other skeletal problems all too common in some dog breeds; it could also guide breeders as they try to introduce those helpful genes into their dogs.

A single genome can also reveal key information about how vulnerable a species is to extinction, says Aryn Wilder, a conservation geneticist at the San Diego Zoo Wildlife Alliance, the parent organization of the San Diego Zoo. A single genome may be easier to obtain than the data about population size, range, and other ecological factors that help researchers assess whether a species is in trouble, she says.

In a separate report, Wilder, Shapiro, and their colleagues counted the changes in the conserved regions in each of the Zoonomia genomes and looked at whether each species had different versions of various genes. The former is a reflection of the number of deleterious mutations; the latter provides clues to the species’ genetic variation. A lot of variation helps a species be more resilient to stressors such as climate change or habitat loss.

Wilder wrote a computer program that used this and other information gleaned from the genome, such as ancient population size, to predict the likelihood of the species becoming endangered. The researchers then compared those predictions with the species’ status as designated by the International Union for Conservation of Nature (IUCN).

The computer’s predictions closely matched those designations, the team reports today. There were three species among the 240 for which there wasn’t enough data for IUCN to determine their status: the Middle East blind mole-rat (Nannospalax galili), the killer whale (Orcinus orca), and the Java mouse-deer (Tragulus javanicus). Of those, killer whales are most at risk, Wilder says, and should be a higher priority for further evaluation than the other two. “We are not yet to the point where can say with single genome what the exact level of threat is,” she says. “But we are getting there.”

Such studies are just the beginning of Zoomania’s use, says Tatiana Feuerborn, a paleogeneticist at NHGRI. “They will be an amazing resource for future studies.” Larson agrees. “You can do sorts of analyses that would have been unthinkable a decade ago.”

In 1925, a sled dog named Balto made headlines around the world when he braved fierce winds, a raging blizzard, and splintering river ice to bring lifesaving serum to an isolated Alaskan town struck with diphtheria. (Although another sled dog, Togo, may deserve most of the credit.) Now, researchers have pieced together a fuller picture of the celebrated canine from DNA taken from the underbelly of his stuffed, faded carcass. Aided by hundreds of newly sequenced genomes and an extensive database of dog DNA, they were able to glean details about Balto’s size, appearance, and stamina not captured in historical photos of the famed canine.

“Even with the genome of a single individual, you can learn a lot,” says Nathan Upham, an evolutionary biologist at Arizona State University who was not involved with the research.

The work, reported today in Science with 10 other papers about a massive sequencing effort called Zoonomia, speaks to the power of having many accurately sequenced genomes on file, says Greger Larson, an evolutionary geneticist at the University of Oxford who also was not involved in the research. He says the project will permit scientists to better assess the looks, physiology, and perhaps even the conservation status of species based on single genomes. “The predictive ability is just staggering.”

For the Zoonomia project, researchers from around the world obtained and compared complete DNA sequences of 240 placental mammals, from tiny bumble bee bats to giant whales, then matched up all the genomes to see what DNA was the same, or conserved, in all of them. This conserved DNA reveals genes critical to a mammal’s survival, as harmful deviations are less likely to have been passed down. “We can learn exciting things about how species diverged and adapted,” says Zoonomia collaborator Beth Shapiro, a paleogeneticist at the University of California, Santa Cruz.

But Shapiro and her postdoc, Katie Moon, also wanted to know what this new resource could reveal about individuals. So, they sequenced DNA from a pencil eraser–size tissue sample from the 100-year-old sun-bleached belly of the stuffed Balto, who is on display at the Cleveland Museum of Natural History.

That feat was “extraordinary,” says Elaine Ostrander, a dog geneticist at the National Human Genome Research Institute (NHGRI) not involved with the work. “It gives us a very clear picture of dogs who were selected for [sled dogs] at that point in time.”

Kathleen Morrill, a geneticist now at Colossal Biosciences, looked to see how well Balto’s conserved DNA matched that in other species within the Zoonomia data set. She also compared his DNA with more than 600 genomes of wolves, coyotes, and dogs of different breeds. These included modern sled dog breeds such as Siberian huskies, more physically and genetically isolated sled dogs in Greenland, and “village dogs”—ownerless canines that live in Africa, South America, and Asia and make up 80% of the world’s dogs.

From Balto’s DNA, Morrill, Moon, and their colleagues determined that he was a relatively small sled dog. At 55 centimeters at the shoulders, he was smaller than most Siberian huskies and Alaska malamutes, sled dogs later recognized as American Kennel Club breeds. They also predicted that Balto would have had a double layer of black fur twinged with tan; modern sled dogs tend to have just a single layer. All of this matched up with and further clarified the dog’s actual appearance, Moon says. “It was something that I never thought would be possible.”

The team also determined that Balto had some genes useful for digesting starch—a helpful innovation for living among people—but not as many as more modern dog breeds. Moreover, he had versions of genes important for developing strong bones, muscles, and joints that helped make him so capable of pulling sleds such long distances even in the dead of winter.

In the past, characterizing an individual’s traits based on DNA—say the red hair of ancient humans—“you just have to go on faith” that they are right, Larson says. With Balto, scientists actually know what he looked like, he says, so he’s “a brilliant control. You can make all these predictions that turn out to be absolutely true.”

But Balto’s genome carries a sobering message for dog lovers today. Being the product of generations of mating of different kinds of dogs, Balto and his peers were much more outbred and had more genetic variation and fewer harmful genes than modern dog breeds. “Turning dogs into breeds was a process with negative consequences [that] we only now are starting to understand,” says Mikkel Sinding, a paleogeneticist at the University of Copenhagen. Ostrander hopes Balto’s suite of healthy developmental genes could lead to genetic tests for hip and other skeletal problems all too common in some dog breeds; it could also guide breeders as they try to introduce those helpful genes into their dogs.

A single genome can also reveal key information about how vulnerable a species is to extinction, says Aryn Wilder, a conservation geneticist at the San Diego Zoo Wildlife Alliance, the parent organization of the San Diego Zoo. A single genome may be easier to obtain than the data about population size, range, and other ecological factors that help researchers assess whether a species is in trouble, she says.

In a separate report, Wilder, Shapiro, and their colleagues counted the changes in the conserved regions in each of the Zoonomia genomes and looked at whether each species had different versions of various genes. The former is a reflection of the number of deleterious mutations; the latter provides clues to the species’ genetic variation. A lot of variation helps a species be more resilient to stressors such as climate change or habitat loss.

Wilder wrote a computer program that used this and other information gleaned from the genome, such as ancient population size, to predict the likelihood of the species becoming endangered. The researchers then compared those predictions with the species’ status as designated by the International Union for Conservation of Nature (IUCN).

The computer’s predictions closely matched those designations, the team reports today. There were three species among the 240 for which there wasn’t enough data for IUCN to determine their status: the Middle East blind mole-rat (Nannospalax galili), the killer whale (Orcinus orca), and the Java mouse-deer (Tragulus javanicus). Of those, killer whales are most at risk, Wilder says, and should be a higher priority for further evaluation than the other two. “We are not yet to the point where can say with single genome what the exact level of threat is,” she says. “But we are getting there.”

Such studies are just the beginning of Zoomania’s use, says Tatiana Feuerborn, a paleogeneticist at NHGRI. “They will be an amazing resource for future studies.” Larson agrees. “You can do sorts of analyses that would have been unthinkable a decade ago.”