Since 1959, a unique breeding experiment has been underway in southwestern Siberia. Its founder, Dmitry Belyaev, was intrigued by the characteristics of domestication, and he observed that foxes varied in their responses to humans—some fearful, some aggressive, and a few displaying “a quiet exploratory reaction without fear or aggression.” What would happen, he wondered, if you bred just the most chilled-out foxes?

Within a few generations of doing just this, remarkable transformations were underway. The foxes were calmer and friendlier when approached—and also more baby-faced, with floppy ears, patchy coloring, and curlier tails. This group of tame foxes, along with a second group bred for their aggression, have been transformational in our understanding of domestication.

And now, genetics have entered the mix. An international team of researchers have published an exploration of the genomes of the tame, aggressive, and wild foxes, looking for clues that could illuminate the link between genes and domestication. The results point to where in the genome the most interesting differences show up, and they may help to identify genes that could be illuminating to study in more detail.

Tame, but not trained

The foxes that were used to start the experiment weren’t wild foxes—they were part of a population of that had been bred for more than 80 years for their fur. Still, they weren’t enthusiastic about humans; only a few responded calmly when they were approached, and even the calmest were still inclined to bite when they were handled.

The foxes were observed soon after they were born to find those that were friendliest to humans. After continuous observation for months, only the most sociable were selected for the next generation, with the researchers taking care to avoid inbreeding. The foxes weren’t raised as pets; they had minimal contact with humans, living out their lives in cages. So, it’s fair to assume that their behavior couldn’t be attributed to learning, but rather to underlying genetic differences.

A few generations later, this group experienced remarkably dog-like changes: “At the sight of even a strange person, they try actively to attract attention with their whining, wagging of tails, and specific movements,” Belyaev noted 20 years into the experiment. Even their voices changed to more of a dog-like bark.

In becoming domesticated, animals undergo “a host of changes in [appearance], physiology and behavior,” writes Lyudmila Trut, a colleague of Belyaev's. “What do those changes have in common? Do they stem from a single cause, and if so, what is it?” Peering into the foxes’ genomes could help researchers understand some of the links between genes and the complex bundle of traits that make up domestication.

Genetic clues

To start figuring out how genetics could contribute to such remarkable behavioral differences, the researchers sequenced the genome of the red fox, which is still a wild species. They compared it to genetic data from the three different strains of artificially bred foxes: the tame and aggressive strains, as well as a third group that had been kept going from the original population that was bred for fur and hadn't been selected for any particular behavior.

When different groups are isolated from each other for decades and multiple generations, there’s going to be a widening gap between their genes, driven largely by random changes. So what the researchers needed to look out for wasn't just differences between the genomes, but differences that looked particularly intriguing.

In the wild, groups of individuals can have different versions of the same gene. But if one of those variants makes living and breeding easier, that variant can get more common with each generation until eventually it reaches fixation: every individual carries the same version. Fixation is like graffiti that says “natural selection was here.”

Of course, with the foxes, it was humans creating the conditions, so the hunt was on for the signature of artificial, rather than natural, selection. But genes that are at fixation, or nearing it, would still be one of the biggest clues that those regions of the genome play a role in the tame or aggressive behavior.

The data pointed to 103 regions of the fox genomes that showed signs of selection, and it highlighted one particular gene that will be interesting to explore in future research. Many of those genes have been studied in various other species, since we mammals have related versions of the same genes handed down by our common ancestors. Some of the genes in question have been associated with both aggressive behavior and immune response in rats, and some have been linked to behavioral traits, like bipolar disorder, in humans.

All of this suggests that the genes are involved in regulating brains and behavior, although how this plays out will be different across species. “It might not be the case that we can directly translate to humans,” says Eduardo Amorim, a geneticist who studies human and dog evolution. “We have a different, complex system; complex in a different way from foxes. But these studies could give us a clue to take to other studies in humans.” We could look at the same genes in other domesticated species, too, he suggests.

Still, Amorim is excited about the results: it's a rich dataset and “possibly the perfect research design to study aggressive vs. tame behavior,” he enthuses. Not only does the research open up some intriguing avenues for future work, but it shows just how much evolutionary change can happen in a short timescale, Amorin explains. “Behavioral genes can potentially change really fast.”

Nature Ecology & Evolution, 2018. DOI: 10.1038/s41559-018-0611-6 (About DOIs).