Wolf in dog's clothing? Stanford study reveals twist in fur color evolution

- By Krista Conger

STANFORD, Calif. - Slipping through trees or across snow, the wolf has glided into legend on paws of white, gray or - in North America - even black. This last group owes an unexpected debt to the cousins of the domestic dog, say Stanford researchers. In an unconventional evolutionary twist, dogs that bred with wolves thousands of years ago ceded a genetic mutation encoding dark coat color to their former ancestors. As a result, the Gray Wolf, or Canis lupus, is no longer just gray.

The effect was more than just cosmetic: the resulting black wolves, which are found nearly exclusively in North America, seem to have a selective advantage over lighter-colored wolves in forested areas. It's a rare instance of domestic animals - in this case, probably the dogs of the earliest Native Americans - contributing to the genetic variability of their wild counterparts in a way that affects both the recipients' appearance and survival.

"We usually think of domestication as something that is carried out to benefit humans," said genetics professor Greg Barsh, MD, PhD. "So we were really surprised to find that domestic animals can serve as a genetic reservoir that can benefit the natural populations from which they were derived. It's also fascinating to think that a portion of the first Native American dogs, which are now extinct, may live on in wolves." Canine geneticists generally agree that North American dogs today are all descended from European dogs.

Barsh and graduate student Tovi Anderson collaborated with, among others, scientists at the University of California-Los Angeles, the University of Calgary, the National Park Service at Yellowstone National Park and the National Human Genome Research Institute to conduct the research, which was published on Feb. 5 in the journal Science. Scientists from Sweden and Italy also participated in the international effort.

Anderson and her collaborators compared DNA collected from 41 black, white and gray wolves in the Canadian Arctic and 224 black and gray wolves in Yellowstone National Park with that of domestic dogs and gray and black coyotes. Their intention was to build on previous work in the Barsh lab that identified a mechanism controlling pigmentation in dogs that differs from most other mammals.

"We expected this to be a short research project to confirm that wolves and dogs shared the same genetic pathway that determines black coat color," said Anderson. "But the story got much more interesting when we expanded our research and began asking about the origin of the mutation in wolves."

Dark-coated wolves are significantly more prevalent in forested areas of the Canadian Arctic than they are in the icy tundra (62 percent vs. 7 percent of the total population, respectively). Biologists have long suspected that something about having black fur is particularly advantageous for the woodland wolves, but they weren't sure what. Because black wolves gray with age, it seems that the root cause might be deeper than just coat color.

Barsh's laboratory, which has spent years studying genes affecting coat color and other biological pathways in mammals, discovered in 2007 that the gene responsible for black fur in dogs, called beta-defensin, belongs to a family of genes previously believed to be involved in fighting infection. One version of the gene produces light or yellow-colored dogs and wolves; a mutant version missing three nucleotides produces black animals.

"Wildlife biologists don't really think that wolves rely much on camouflage to protect themselves or to increase their hunting success," said Barsh. "It's possible there is something else going on here. For example, the protein responsible for the coat color difference has been implicated, in humans, in inflammation and infection, and therefore might give black animals an advantage that is distinct from its effect on pigmentation."

Although the "why" of this selective advantage remains a mystery, the "how" is becoming more clear. Anderson's study confirmed that the black-coat gene shows evidence of positive selection in forest wolves. She also showed that the gene is dominant, meaning that an animal with only one copy of the gene would still have a black coat. Ten of fourteen pups of a mating between a black wolf and a gray wolf carried the gene and were black.

She and her collaborators used a variety of genetic tests to determine that the mutation was likely introduced into wolves by dogs sometime in the last 10,000 to 15,000 years, about the same time the first Americans were migrating across the Bering land bridge. These humans were probably accompanied by dogs, some of which carried the black-coat mutation estimated to have arisen about 50,000 years ago. The rest, as they say, was history.

"It may have been easier for dogs to interact with wolves in North America than in Europe," said Anderson. "There was probably a higher concentration of wolves, and the dogs, like the humans, were more migratory."

Unfortunately, it's not yet possible to tell whether there were any black wolves prior to the domestication of dogs. It may be that the mutation arose in the wolf population prior to the domestication of the dog somewhere between 15,000 and 40,000 years ago and then died out in the wild. Alternatively, it may have made its first appearance in a domestic dog and never entered the wild until the Native Americans migrated from Europe. Regardless, it's the seemingly beneficial aspect of the mutation coupled with its origin that has the researchers excited.

"This is a mutation that had been cultivated by humans in the form of the domestic dog for thousands of years," said Anderson. "Now we see that it not only entered the wild population, but also is benefiting them." The researchers speculate that the loss of the wolves' tundra habitat may encourage the spread of the black-coat gene even further. They're interested in finding out exactly how the mutation works to help forest wolves.

The research underscores the idea that evolution may involve other instances in which traits are passed in unexpected directions. "We now know that dogs have been the caretakers of a genetic legacy that may be very beneficial to wolves," said Barsh. "It should lead us to think more broadly as to how this might apply to other animals and plants."

Barsh and Anderson's Stanford collaborators include Hua Tang, PhD, assistant professor of genetics, and Sophie Candille, PhD, postdoctoral fellow in the Tang lab. The research was funded by the National Institutes of Health, the National Science Foundation and the Swedish Research Council.  

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu.

2023 ISSUE 2

How the environment and health interact