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Solo stars among the genes

From maggots’ movements to voles’ roles, sometimes single genes can have outsize effects on behavior

Emily Underwood • knowable
Oct. 22, 2020 14 minSource

Solo stars among the genes

From maggots’ movements to voles’ roles, sometimes single genes can have outsize effects on behavior

10.22.2020

If you want to annoy a geneticist, talk about a single gene as if it, alone, is responsible for a complex behavior — whom a person is sexually attracted to, say, or whether or not they believe in God. Even for psychiatric diseases that run strongly in families and have a large genetic component, such as depression and schizophrenia, decades of research have shown that there’s rarely one lone gene to blame. Instead, our behavioral susceptibilities and strengths lie in many genes with small effects, combined with environments and experiences.

“It’s a mistake to buy into the idea that a gene is single-handedly responsible for just about anything,” says biologist Joel Levine of the University of Toronto — be it in a human being, a fruit fly or a mouse.

But some genes stand out as powerful regulators of behavior. The following examples, scattered across the animal kingdom, show how tweaking a single gene’s activity can lead to profound behavioral changes. People carry versions of some of these genes, so they may even hold lessons for our own species.

The roaming gene

Marla Sokolowski discovered her life’s work early, in an undergraduate biology class. Watching fruit fly maggots wriggling in a petri dish, she noticed that some of the larvae were more active, crawling farther in search of food than their couch-potato-like companions. Sokolowski, now a behavior geneticist at the University of Toronto, dubbed the more active maggots “rovers” and the more sedentary ones “sitters,” and went on to demonstrate that the difference could be traced to a single gene, called foraging, or for.

The foraging gene encodes an enzyme known as a cGMP-dependent protein kinase, or PKG; various forms of it can be found in animals ranging from single-celled paramecia to people. The enzyme’s job is to add phosphates to important molecules in cells, boosting or inhibiting different chemical reactions. And the difference between rovers and sitters, it turns out, lies in how active the foraging gene is, and thus how much of the enzyme gets made. The more PKG in a maggot’s tiny brain, the farther the maggot roams.

Since the gene’s discovery, Sokolowski and colleagues have found that activity of foraging changes over time as a maggot develops, as well as in response to environmental conditions such as lack of food. “The context matters. So it could be how dense the population is for the larva, how much food is available, how many other friends are around, what the social environment is,” says Sokolowski, who coauthored a 2019 article on forager in the Annual Review of Genetics. The gene also influences a range of other behaviors, such as pain response. When a parasitic wasp inserts its stinger into a fruit fly larva, attempting to lay eggs inside it, for example, rovers respond more vigorously, rolling away from the pain, Sokolowski and colleagues have shown.

Variations of forager have been found in many other species, including mice, ants and people. In honeybees, increased forager activity levels trigger young nurse bees that care for the queen to leave the hive to become worker bees. In people, a forager-like gene called PRKG1 may influence responses to early life traumas: Two broad scans of variants in the human genome (an approach known as a genome-wide association study, or GWAS) reported that people who had a certain version of PRKG1 and also experienced childhood trauma were slightly more prone to substance abuse.

Sokolowski suspects that the gene might affect other human behavioral patterns: In a 2019 study, she and her colleagues asked 437 college students to gather virtual berries in a computer game, and found that different forager variants were linked to tendencies to either stay put or to boldly explore their surroundings, a pattern similar to the fruit fly rovers and sitters.

Stay home or play the field?

With their soft brown fur and plump bodies, prairie voles and meadow voles look pretty similar. But the two species live strikingly different lifestyles: Prairie voles tend to form lifelong bonds with their mates, while meadow voles are more promiscuous, apt to play the field of potential partners.

The difference lies in a gene called avpr1a, which encodes a protein that serves as a receptor for the hormone vasopressin. Like its closely related molecular cousin oxytocin, vasopressin plays a vital role in social bonding, attachment and parental care. “When you look at the brains of those two species and ask, where is the receptor for vasopressin, what parts of the brain can vasopressin unlock, it’s very different across the two species,” says neuroscientist Zoe Donaldson of the University of Colorado.

In 2004, neuroscientist Larry Young and colleagues at Emory University injected a virus carrying the vasopressin receptor gene into a region of meadow vole brains where that gene isn’t generally very active. Compared with voles that didn’t get the gene, the creatures were much more likely to stick with their first sexual partner than flit from liaison to liaison.

That such a behavioral shift can result simply from changing the distribution of the vasopressin receptor in the brain has important implications for the evolution of mating systems, Donaldson says. Monogamy, for example, is a complex behavior with many different components: preferring the company of one’s partner, sharing the burdens of parenting and being aggressive toward potential competitors. Vasopressin, it turns out, influences each of these components via different brain regions, so changing where avpr1a is activated enables mating styles to flexibly adapt as environmental conditions change, Donaldson says.

Even among the famously faithful prairie voles, some males stray, and the vasopressin receptor appears to be involved. In 2015, biologist Steven Phelps of the University of Texas at Austin found that males with fewer vasopressin receptors in a brain region involved in spatial memory tended to wander farther from their own territories — and have sex with more females. Under some conditions, this could be an evolutionary boon: When prairie vole populations are high, the wandering males may sire more offspring because they have more opportunities to be unfaithful. But when vole populations crash, males that stay close to home to defend their mates may have a better chance of passing their genes to the next generation.

Donaldson is now studying the neural circuits responsible for bonding in prairie voles. She hopes that what she finds will offer understanding into human bonding, too, including neurodevelopmental conditions that are marked by social deficits, such as autism and schizophrenia. (Some studies have reported links between these conditions and levels of vasopressin or oxytocin.) She recently found a cluster of neurons that fire only when the voles run to meet their mates, in what may be a sort of neural signature for longing. Maybe, she speculates, the work could help illuminate causes of complicated grief, a severe, prolonged reaction to loss. “Grieving is painful, but it is also terrible for your health,” she says. “Is there a way that we can mitigate some of those health impacts?”

Off with her head

Disturb a nest of stinging South American red fire ants (Solenopsis invicta) and you’re likely to end up covered in swollen, painful welts. The insects don’t limit their aggression to outsiders: Thanks to variations in a cluster of genes known as the Gp-9 supergene, the species is split into two groups with radically different social structures. And when they meet up, murder often ensues.

The first group, called monogyne ants, carries two identical copies of Gp-9. These ants will accept only one ruler: a large, fat queen that can lay many eggs. The second group, called polygyne ants, has two different variants of the supergene. These ants are willing to follow many different, smaller queens, and even queens from other nests as long as they, too, are polygyne. If the polygyne ants encounter a monogyne queen, they assassinate her.

But how do the ants know if a queen is genetically different from themselves? The Gp-9 supergene does many things — it regulates a whole suite of social behaviors — and one of them is to produce an odor receptor. That molecule helps ants detect when a queen smells “off” — foreign — or like kin, biologists Michael Krieger and Kenneth Ross of the University of Georgia reported in 2001. More recently, biologist Laurent Keller of the University of Lausanne in Switzerland and colleagues found that it’s not just S. invicta whose social organization depends on the Gp-9 supergene. It also affects an entire group of South American fire ants that branched off from other ant species half a million years ago.

It’s hard to say for sure why a supergene that causes so much infighting has endured so long, but scientists know that the two social structures provide different advantages, depending on the circumstances. Colonies of S. invicta with multiple queens, for example, are often many times as dense as single-queen colonies, and far more difficult to eradicate. Another possibility is that Gp-9 is what evolutionary biologist and author Richard Dawkins hypothesized as a “ greenbeard gene” — a gene that gives some members of a species a distinctive, easily perceptible trait (say, a green beard), which allows others with that same trait to recognize and favor individuals genetically similar to themselves.

If the notion of a single gene overturning society sounds discomfiting, never fear: Thus far, the only other examples of greenbeard genes found in nature are in relatively simple organisms, such as slime molds.

The original clock gene

A female Drosophila melanogaster fruit fly lays about 100 eggs per day: Within 10 days or so, pale maggots emerge, grow, pupate and then metamorphose into winged insects. In the 1970s, Ron Konopka and Seymour Benzer at Caltech identified three types of mutant fly strains in which the timing of these events was topsy turvy.

In one of the three, flies emerged from their pupal cases earlier in the day than normal, in another, later than normal — and in the third, the flies emerged with no clear daily rhythm. Activity of the hatched flies was similarly perturbed — as though they were living out shorter days, longer days or were blind to daily cycles entirely. The reason: Mutations in a gene that the scientists dubbed period had messed up the flies’ internal clocks, speeding up, slowing down or completely eliminating the circadian rhythms that control how much they moved around throughout the day.

At the time, the notion that a single gene could affect something as complex as an animal’s internal biological clock was “heretical,” Levine says. But a small group of researchers dived in to study the period gene and, despite facing skepticism from other geneticists, three of them — Jeffrey C. Hall, Michael Rosbash and Michael W. Young — went on to receive the 2017 Nobel Prize in Physiology or Medicine for isolating and cloning the period gene and demonstrating that it regulates biological clocks by encoding a protein that builds up in cells at night, and breaks down during the day.

The period gene is far from being the only gene underpinning circadian rhythms, notes Levine, who worked as a postdoc in Hall’s lab. “Nobody ever believed that period was the whole story,” he says — including its discoverers who, along with others, found a number of other genes crucial to the workings of the body’s internal clocks. But period’s discovery flung open field of the molecular machinery of clocks to further study, including Levine’s own work (also with Drosophila) on how social interaction affects circadian rhythms.

Scientists now know that myriad species, including people, carry versions of the period gene. As the first demonstration that altering the function of a single gene could influence complex behaviors, Levine says, “the scope of that original finding was enormous.”

This article originally appeared in Knowable Magazine, an independent journalistic endeavor from Annual Reviews. Sign up for the newsletter.

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