Animal Copies Reveal Roots of Individuality

Genetically identical fruit flies raised under the same conditions are creating a biological map of what makes individuals unique.

Katherine Taylor for Quanta Magazine

This array of Y-mazes is used to track fruit fly behavior.


Benjamin de Bivort’s lab at Harvard University is Groundhog Day for fruit flies. In de Bivort’s version, a fly must choose to walk down a dark tunnel or a lighted one. Once it has made the choice — THWOOP! — a vacuum sucks the fly back to the starting point, where it has to decide again… and again… and again.

The contraption, which tracks scores of individual flies, makes it possible to analyze how behavior varies from fly to fly. What de Bivort found when he first used it surprised him: The animals’ behavior varied much more than he expected, even when the flies were more or less genetically identical and raised under the same conditions. “If you hold genetics constant and the environment mostly constant, you still see a lot of variation,” de Bivort said.

De Bivort and his team are now exploring this phenomenon in detail, hoping to discover what drives that unexpected individuality. He’s found that different fly strains show different levels of variability. Some strains are like a troop of well-trained soldiers, with each fly mirroring its neighbor. Other strains resemble a wild group of dancers, with individuals moving to their own beat. By comparing soldier and dancer strains, de Bivort thinks he’s identified both a gene and a neural circuit that may underlie some of these differences.

“They are suggesting that variation itself might be a genetic trait,” said Gerd Kempermann, a neurobiologist at the German Center for Neurodegenerative Diseases in Dresden. “That’s a new and interesting twist.” In other words, natural selection might sometimes favor genetic variants that produce a mix of behaviors — the wild dancers — over variants that create the same outcomes.

Katherine Taylor for Quanta Magazine

Video: De Bivort’s team developed a device called the fly-vac to study individual behavior. Upon entering a chamber, the fly must choose to walk toward the light or dark end. A vacuum then sucks it back to the starting point, and it makes the choice again.

De Bivort’s work is part of a larger effort to understand why nature produces so much variability. Is it merely a side effect of the random mutations that affect all living things? Or does natural selection reward variability and favor mutations that produce it? A diverse population might be more likely to survive changing conditions. A stand of trees that seeds at different times during the season is more resistant to an early frost or late rains than one that disperses all its seeds at once.

“Whether variance itself is a trait that can vary among individuals or genotypes has important implications and is potentially fascinating, but is very difficult to study,” said Alison Bell, a biologist at the University of Illinois, Urbana-Champaign. Comparing genetically identical, or almost identical, lines of flies, as de Bivort is doing, “is really the best tactic for getting at this question.”

A Bad Breed

Buff Orpington chickens are the lapdogs of the chicken world, known for their extreme friendliness. But the breed occasionally hatches an ornery clucker, much to breeders’ dismay. The Buffs aren’t alone. This kind of variation is widespread on both the farm and in the lab. Scientists breeding mice or flies for research have encountered similar problems — even highly inbred fruit flies raised under well-controlled conditions vary in their behavior. Despite researchers’ best efforts to contain it, individual variation persists.

“To most people, it’s an error bar in experiments,” de Bivort said. Scientists routinely include large numbers of animals to smooth out the noise from individual differences.

Where most scientists see a problem, de Bivort saw opportunity. Focusing on groups of animals rather than individuals ignores reams of potentially interesting information. For example, imagine a group of flies that, on average, fly toward the light or the dark in equal proportion. This behavior could be because individual flies have no preference, choosing each option at random. Or individual flies might have strong preferences, with the overall group composed of 50 percent light lovers and 50 percent dark lovers.

De Bivort’s team set out to distinguish those possibilities using a series of devices designed to track individual behavior. The Groundhog Day gadget — officially called the fly vac — contains 32 chambers. Each chamber monitors a single fly. Automatic tracking tools capture data on a variety of behaviors, such as the preference for light or dark, the time it takes to make a decision, and the fly’s overall activity level. Over the course of a two-hour trial, each fly can make up to 40 choices. The experimental ensemble provides researchers with an enormous amount of data.

In another device in de Bivort’s lab, a fly wanders through a tiny Y-shaped maze, choosing at the Y’s vertex whether to walk left or right. A tray of mazes under the watchful eye of a camera enables researchers to study scores of individual flies simultaneously as each walks the maze over and over. With these tools, variation “becomes a biological phenomenon, rather than a side effect or problem,” Kempermann said.

Katherine Taylor for Quanta Magazine

Video: This array of Y-mazes allows researchers to track individual behavior in many flies simultaneously. As the fly walks around the maze, it must decide whether to turn left or right.

De Bivort’s group analyzed “handedness” — a preference to turn left or right — in 150 different strains of flies. They found that some strains vary a lot from fly to fly, with lefties, righties and everything in between. Other strains had much less variation, with individuals that showed only mild preferences for left or right. De Bivort concluded that one source of variation must be hardwired into fruit flies’ DNA.

Missing Ingredient

What distinguishes high variability strains from more uniform varieties? The researchers identified several candidate genes that are active in the brain, including a gene called teneurin-A. When Julien Ayroles, a researcher in de Bivort’s lab, blocked that gene during flies’ development into adults, variation increased. Groups that started out more ambidextrous developed a range of preferences for left and right. The findings support the idea that specific mutations create variability.

As Ayroles searched for genetic clues, Sean Buchanan, another researcher in the lab, began to inspect the brain. He used a series of genetic engineering tricks to boost or dampen the activity of specific neurons, looking for resulting changes to the animals’ handedness. Buchanan found that he could boost variability by manipulating a specific set of neurons in the brain region called the central complex. This region is essential for processing sensory information and controlling movement.

In addition, teneurin-A is expressed in this part of the brain and is required for it to form properly. That fact suggests that two factors — teneurin-A and the central complex — somehow work together to boost variation, although it’s not yet clear exactly how.

De Bivort has some ideas, though. Scientists know that teneurin-A helps to determine how neurons wire together. Imagine the process as a color-coding scheme, where teneurin-A changes the color of a neuron, and neurons can only connect to other neurons of the same color. If you have two sets of three cells — red, yellow and blue — there’s only one possible configuration. But if another version of teneurin-A turns all six cells red, they can connect in a number of ways. In this way, teneurin-A could create the possibility for novel neural wiring even in genetically identical individuals.

Early Influences

What might work like this reveal about the nature of individuality in humans? At this point, it’s not clear. “The fly brain is not as plastic as the mammalian brain,” Kempermann said, meaning that neural wiring in mammals is much more flexible, changing in response to an individual’s experiences. “Much more of [the fly brain] is hardwired.”

In humans, of course, the environment that a person is raised in plays a huge role. De Bivort’s team did their best to rule out such variability. They standardized the flies’ living conditions, going so far as to raise some animals in isolation to eradicate differences in their social lives. (They also minimized genetic differences by using inbred fly strains.)

Despite these precautions, it’s possible that small, difficult-to-detect changes in genes or the environment might contribute to variation. For example, chance events early in development may trigger divergent behavior. Perhaps one egg got a bit more food than another; that small difference could expand over time. Assuming that flies had an identical upbringing is like “saying human twins had the same experiences up until adulthood,” said Judy Stamps, a biologist at the University of California, Davis.

Katherine Taylor for Quanta Magazine

Ben De Bivort, a biologist at Harvard University, is trying to figure out why fruit flies that are genetically identical (or nearly so) vary in their behavior.

A study in mice, published in Science in 2013, shows just how profound early differences can be. Kempermann and collaborators raised mice of the same strain in the same environment, one full of interesting places to explore and objects to play with. Over time, the mice developed different personalities. Some animals grew more bold and others more reticent. Though they don’t know the exact source of the differences, scientists theorize that early interactions with certain objects or other mice might launch a positive feedback loop: The bold mouse is exposed to new sensations and becomes even more curious.

De Bivort is running a similar experiment in flies, raising them in a rich habitat and looking for changes in behavior. Preliminary results suggest that enrichment — providing an environment that stimulates the senses — can increase variability in certain ways but not others.

“To me, the question is not why individuals would be different, it’s ‘Why would we expect them to be the same?’” Stamps said. “The only reason you would expect that is if you think genes are the only things that are important.”

Help or Hindrance

For scientists studying individual variation, one of the biggest open questions is why it exists. Is it helpful or harmful to the individual and the population? “We still know very little about the fitness consequences,” said Julia Saltz, a biologist at Rice University in Houston.

Some versions of a gene might simply have bad quality control, pumping out a shoddy and inconsistent product. (Scientists refer to this as developmental instability and generally consider it harmful.) Alternatively, perhaps some variability makes for a stronger strain. “If you are more variable, a predator can’t guess what you are going to do next,” Saltz said.

This latter theory is dubbed “bet-hedging” because it resembles diversifying one’s portfolio to protect against risk. Biological bet-hedging provides a population with a range of behaviors, some of which might cope better with mercurial conditions. For example, a population of flies that can tolerate a range of temperatures is likely to be more successful than one that only prefers hot or cold. Mutations that inherently produce variability are more flexible than those that are hardwired to a specific trait.

De Bivort’s team eventually hopes to test this idea with so-called common garden experiments. They’ll create fly habitats with lots of fluctuations — changes in temperature or brightness — and then assess whether low- or high-variability strains are more likely to survive. “I’m firmly in the camp that some level of bet-hedging is optimal for many traits,” de Bivort said. “Perhaps especially behavioral traits.”

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  • I’m going to go with a rather obvious suggestion here: If you study neural networks with random initialization, you’ll get some degree of variance between models that are otherwise identical, learning on the identical data sets. If there is non-uniform construction in the underlying biology of the fly’s brains, then are we so surprised to find that their behaviors contain some non-uniformity? I’m not.

  • I wonder if there was some (un)accounted for scent left by flies that might have swayed subsequent flies.
    Just a thought.

  • It could be that some flies have better vision in one eye, so regularly choose the left path if left eye gives a better view or right if right eye better and no preference if vision and other sensors equal.

    John (where does information come from) Lavelle

  • The most surprising thing reported here seems to be the investigators surprise at encountering unexplained variation.

  • @NA, srome, Len – Happy to weigh in here. Setting aside that there are significant groups of biologists who think that if genotype and environment are made constant all individuals would behave identically, I agree with you. No biological (or physical for that matter) process is noiseless, so individual differences should be our expectation. The surprise of our findings comes in two observations. First is the extent of the variability. In fly strains that are photo-positive on average, you have photonegative individuals. Greater variability seems to arise from within-genotype sources than between genotype sources, so the notion of a “photo positive strain” may be wholly inadequate. Second, we’re uncovering mechanisms that control this variability, both during development and by the acute action of neural in fully developed individuals. That is, the papers describe two kinds of knobs controlling inter-individual differences, and are not just reports of the existence of those differences.

    @ Ralph: We looked at this by asking whether individual mazes yielded consistent biases, and they did not. Also, in general, any attract (or repulsive) cue within a maze will push any individual’s behavioral sequence toward 50% Left and 50% Right, making individuals appear more similar to each other. Thus, the strong signals we see are in spite of potential artifacts like those you’re bringing up.

    @ John Lavelle: Your hypothesis is plausible. We did test the flies handedness in the dark. The variability is slightly reduced, but there remains strong individuality. So other sensory systems than vision can also drive it. If left-right differences in visual sensitivity were at play, that would be a nice mechanistic insight to explain the phenomenon.

  • Some years ago we too were asking this question about variability in terms of human personality differences. In psychology, discussions of personality tend to focus on individuals, how I might differ from you –maybe I’m more curious, or open, or neurotic, maybe you’re more agreeable and extraverted etc. Why are there personality differences? We came at it from the perspective of the group; perhaps groups need a variety of personality types to function well in competition between groups. We thought about “personality” in conventional (for psychology) terms: the “Big Five Factors” namely: Extraversion, Openness, Agreeableness, Conscientiousness, and Neuroticism. In human evolution, in the period of “evolutionary adaptive-ness” as it’s sometimes called, there were well separated small groups who, when running into one another, competed for resources. Perhaps personality differences were required to help the group in between group competition, such that a group with varieties of personality types out-performed a group with fewer varieties of personality types. It makes sense. We imagined hunter-gatherer groups –when resources (like food) were becoming scarce in a given forest. Perhaps the group members who were high in extraversion and openness went out exploring nearby but new terrain, searching for new resources, while a few group members high in neuroticism warned them to “be careful” in their hunt, and stayed home guarding the group from danger, while other group members, high in conscientiousness and agreeableness might serve as baby sitters or cooks or small game hunters. In other words, perhaps clusters of personality types were essential for a group’s survival, in competition with other groups, particularly when environmental conditions were changing.

    We had no way to come at this directly –we couldn’t study personality in individual members of the few remaining hunter-gatherer groups, to see if they generally had the similar distributions of the big five factors, or constellations of personality types. So we came at it indirectly. We decided to compare known competing groups, that is groups engaged in between group competition, to see if they resembled one another and differed from the general population, in the distribution of the five factors of personality. Two of my –then– students, Neal McSherry and Karen Davison (both now licensed psychologists), collected data from 402 Division I-A college basketball players, members of 27 women’s and 7 men’s basketball teams. All players completed a personality survey, measuring each in levels of the five factors. We found, as expected, that the groups engaged in between group competition were similar to one another, and significantly different than the distribution of personality in the general population. There were no differences between the men and women’s teams. Personality factors were categorized into three clusters, derived from prior studies in the general population. We concluded that this study provided some evidence that personality traits may function in between group competition, allowing some groups to out-compete other groups. The same may be true for other mammals and insects –personality variability may play a role in group selection, a force of selection in the evolution of our and other species.

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