The inheritance of several coat color patterns in dogs has been the subject of controversial debate for decades. Researchers, including Tosso Leeb from the Institute of Genetics at the University of Bern, have finally been able to solve the riddle. Not only did they clarify how the coat color patterns are genetically controlled, but the researchers also found that the light coat color in white arctic wolves and many modern dogs is due to a genetic variant native to a species that passed away a long time ago. The study has just been published in the scientific journal Nature Ecology and Evolution.
Two pigments and a “switch” for all coat colors
Wolves and dogs can make two different types of pigments, black, called eumelanin, and yellow, pheomelanin. Precisely regulated production of these two pigments at the right time and in the right place on the body results in very different coat color patterns. Before the study, four different models had been recognized in dogs and several genetic variants had been theorized at the origin of these models. However, commercial genetic testing of these variants on several thousand dogs has yielded conflicting results, indicating that existing knowledge about the inheritance of coat color patterns is incomplete and not entirely correct.
During coat color formation, the so-called agouti signaling protein is the body’s main switch for the production of pheomelanin yellow. If the agouti signaling protein is present, pigment-producing cells will synthesize yellow pheomelanin. If no agouti signaling protein is present, black eumelanin will be formed. “We realized very early on that the genetic variants responsible had to be regulatory variants which modulate the rate of protein production and lead to higher or lower amounts of agouti signal protein”, explains Tosso Leeb.
Five instead of four separate coat color patterns
The agouti signaling protein gene has several initiation sites for reading genetic information, called promoters. Dogs, on the one hand, have a ventral promoter, which is responsible for the production of the agouti signaling protein in the belly. On the other hand, dogs have an additional hair cycle specific promoter that mediates the production of the agouti signaling protein during specific stages of hair growth and allows for the formation of banded hair.
For the first time, researchers have characterized these two promoters in detail in hundreds of dogs. They discovered two variants of the ventral promoter. One of the variants mediates the production of normal amounts of agouti signaling protein. The other variant has a higher activity and causes the production of an increased amount of agouti signaling protein. The researchers even identified three different variants of the hair cycle-specific promoter. Starting with these variants in individual promoters, the researchers identified a total of five different combinations, which cause different coat color patterns in dogs. “The manuals need to be rewritten because there are five of them instead of the four different models previously accepted in dogs,” says Leeb.
Unexpected insights into the evolution of wolves
As many wolf genomes from different regions of the earth became publicly available, the researchers further investigated whether the identified genetic variants also existed in wolves. These analyzes demonstrated that the ventral and hair-cycle-specific hyperactive promoter variants were already present in wolves before the domestication of modern dogs, which began about 40,000 years ago. Most likely, these genetic variants facilitated the adaptation of wolves with a lighter coat color to snow-rich environments during past ice ages. Today, completely white Arctic wolves and light-colored Himalayan wolves still carry these genetic variants.
Further comparisons of the gene sequences with other species of the Canidae family have given very surprising results. The researchers were able to show that the overactive variant of the specific hair cycle promoter in light-colored dogs and wolves shared more similarities with very distant species such as the golden jackal or coyote than with the European gray wolf.
“The only plausible explanation for this unexpected finding is an ancient origin of this variant, over two million years ago, in a now extinct relative of wolves,” says Leeb. The gene segment must have been introgressed over two million years ago into wolves by hybridization events with this now extinct parent of wolves. So a small piece of DNA from this extinct species is still found in yellow dogs and white arctic wolves today. “This is reminiscent of the spectacular discovery that modern humans carry a small proportion of DNA in their genomes from now extinct Neanderthals,” adds Leeb.
Reference: Bannasch DL, Kaelin CB, Letko A, et al. Dog color patterns explained by modular promoters of ancient canid origin. Nat Ecol Evol. 2021: 1-9. doi: 10.1038 / s41559-021-01524-x
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