by Drew Drabek

figures by Nicholas Lue

Foxes are not dogs. As a rule, dogs are docile and foxes are feral. You could say it’s in their DNA. But there are exceptions to every rule. A fox raised in captivity might learn to be gentle. A dog who was abused might lash out. Behavior: it’s complicated.

There has been great interest in the selective breeding of animals that can coexist with humans throughout history. In particular, biologists have been trying to understand the process of how dogs became domesticated, earning the mantle of “man’s best friend”. Taking up the challenge, scientists are searching for a specific gene, or set of genes, that predispose canines toward behaviors classified as “domestic.” In late 2018, two studies were published that helped shed some light on how these behaviors evolved. The scientists compared the genomes and brains of tame and aggressive silver foxes – an animal closely related dogs – whose behavior was studied during an impressive 60 year-long experiment on a fox farm in Russia.

Evolution of foxes, wolves, and dogs

To understand the immense challenges facing these studies, one need only look to the evolution of the modern dog from other canines, a group that includes wolves, foxes, coyotes, jackals, and of course dogs. Between 10,000 and 30,000 years ago, our ancestors domesticated the wild dog. Scientists believe that the closest ancestor of all modern dogs is the modern-day gray wolf. As cousins to wolves and dogs, foxes are a great model for dog domestication. They diverged from the wolf lineage about 12 million years ago (a brief time period, evolutionarily). It is difficult to study the process of the dog’s domestication since its wild relatives, the fox and wolf, are now different species. This means that, even though the complete set of genes, or genomes, from a dog, gray wolf, and fox have been sequenced and are available for study, there are too many genetic differences that obfuscate the path to the answer of the “domestication question.”

Breeding a domesticated fox

More than 60 years ago, a group of researchers took a first step toward understanding the genetics of domestication by breeding wild foxes and selecting for domestication behaviors. This project, termed the “farm fox” experiment, was started in 1958 by Russian scientists Dmitri Belyaev and Lyudmila Trut, who bred wild silver foxes in an attempt to make them tamer.

Breeding is man’s attempt to control heredity, the inheritance of certain traits that are passed from parent to offspring via genes. Over tens of generations, the farm fox experiment successfully showed that careful breeding could select for certain behaviors in foxes, specifically the behavioral traits of gentleness or aggressiveness toward humans. Since these behaviors are passed on from generation to generation, subsequent biologists wanted to go deeper to discover which inherited genes predispose foxes to these opposing behaviors. As an example, animal biologists can clearly document genes that determine fur color or curliness of a tail. However, it is fundamentally more difficult to document a gene-to-behavior relationship, since behavior does not have not an unambiguous and discrete physical manifestation.

Since the farm fox experiment has generated a wealth of documentation on the heredity of domestication, the direct descendants of the founder foxes have been subjected to high-profile genetic studies in an attempt to understand how specific genetic differences might contribute to their divergent behavior (Figure 1).

Genetic comparisons between tame and aggressive foxes

To identify specific genes that differentiate tame and aggressive foxes, teams of scientists from Cornell and the University of Copenhagen independently studied the genes of domesticated and aggressive Russian farm silver foxes.

The Cornell scientists compared the genes turned on in brains of the aggressive foxes with those turned on in the tame foxes, studying gene activity in two parts of the brain: the part responsible for memory and learning and the part responsible for arousal, attention, and decision making. They found hundreds of differences in the use of genes within each brain region, suggesting that molecular alterations within the brain could be the “switch” between tameness and aggression.

They also found a clue from genes that control how the brain responds to natural chemicals that affect mood. Differences in their mood-related brain chemistry could explain the tendency for tameness or aggression. For example, the chemical serotonin plays a role in feelings of contentment or happiness. And as it turns out, tame foxes use more of the genes responsible for forming feelings of happiness using serotonin, which is a possible explanation for their tolerance toward humans (Figure 2).

But serotonin is not the whole story. Glutamate, a chemical linked with aggression, is also involved. The genes affecting the brain’s response to glutamate changed directly, altering how the tame foxes’ brains respond to it. The scientists hypothesized that this change in glutamate sensing made the tame foxes more responsive toward their keepers. Together, these genetic differences predict that simultaneous changes in the equilibrium between glutamate and serotonin could contribute to “domestication-like” behaviors.

While the Cornell group looked at brain activity, the group from the University of Copenhagen instead looked for differences within the genomes of tame and aggressive foxes. Genes are the fundamental units of inheritance, and a genome is the complete collection of a foxes’ genes. This is different from the Cornell group’s comparison of the sub-set of genes that are actively used just in the foxes’ brains. By documenting the genomes of several tame and aggressive foxes, the Copenhagen scientists were able to cross reference all the changes between the different animals.

They highlight changes, again, related to the mood altering chemical glutamate. Still other differences are linked to how the brain forms new connections called synapses. Additionally, by comparing the genetic changes reported by the Copenhagen study with those found in the Cornell study, scientists discovered that there were 75 overlapping genes. This overlap indicates that the same genes that changed in foxes’ genomes were also used differently in their brains. Many of these genes were related to mood altering chemicals, like serotonin. This is an extremely valuable genetic list, and will be a key resource to allow scientists to define the gene-behavior relationship for fox domestication.

Together, these findings have given the field of animal behavior a huge hint for uncovering the molecular basis of behavior by curating a list of genes likely to directly affect a fox’s instinctual response to humans. However, more studies need to be performed to determine if a small number of genes and brain chemicals are critically important for such specific behaviors, not only in the fox, but also in other animal species.

The future of behavioral genetics

These recent genetic studies suggest that a relatively small set of genes can have a massive effect on the behavior of an animal. It is certainly possible that we might one day be able to look at a set of genes in a fox’s, or dog’s, DNA and predict certain personality traits. The possibilities for understanding the molecular basis of neurological function are tantalizing for man’s best friend. Maybe one day the gene-to-behavior relationship will be understood in humans, as well.

Despite these promises, there is still much to understand about the genetic basis of behavior. With the impressive work originating from a Russian, evolution-accelerated fox farm, we are one step closer to unraveling the mystery of how domestication evolved in canines.

Drew Drabek is a graduate student in the Harvard Chemical Biology Ph.D. Program studying mechanobiology jointly in the labs of Prof. Stephen C. Blacklow and Prof. Joseph J. Loparo at Harvard Medical School.

Nicholas Lue is a graduate student in the Chemical Biology PhD program at Harvard University. You can find him on Twitter as @nicklue8.

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