The Nurture of Nature How do you get from genes to behavior

The Nurture of Nature

How do you get from genes to behavior (and back again)?

For weeks, avid birders have been congregating along a stretch of busy roadway near my home, giant scopes at the ready. Fender-benders have even occurred as drivers crane to see what they're looking at. They've been watching a nest with three red-tailed hawk chicks, hoping to see these fluffy raptors take their first flight.

I stopped and watched myself for a bit, but what I kept thinking about was the nest. Made solidly of stout sticks, it was huge—a yard across—and carefully wedged into a corner on a high building ledge. I wondered, How does a red-tailed hawk knowhow to build that nest? Surely it wasn't taught how, yet it knows.

In short, how does a behavior get written into the genes?


How does a behavior, such as nest-building, get "written" into an animal? Here, a red-tailed hawk chick atop a nest in Cambridge, Mass.
THE SHORT AND LONG OF IT

Well, the short answer is it doesn't. Genes generate proteins, not behaviors. But the long answer is it does—indirectly, yes, and to a greater or lesser degree of fixity depending on the behavior. Neurobiologists and other scientists are busily trying to tease out the particulars of this linkage, and discoveries are rapidly accumulating. They are finding:
that genetic factors, once thought to be straightforward and fixed, are mind-numbingly complex and responsive to outside stimuli, and they are only one of many elements that affect behavior;
that gene-derived proteins direct the formation of neural circuits in the brain, and it is these circuits that serve as the true foundations of behavior;
and, significantly, that parallels can be drawn between such genes-and-behavior systems in animals and those in humans, with hope for potential future treatment of abnormal behaviors such as schizophrenia and autism.
TIES THAT BIND

The search for genetic links to behavior has come a long way since Harvard naturalist E. O. Wilson published his seminalSociobiology in 1975. The book unleashed a heated debate over whether social behaviors such as altruism or aggression could have a genetic basis, a controversy that helped spur the now vigorous research into such mysteries. From the start it has been painstaking work, involving a kind of reverse engineering: Basically you have to knock out, disable, or otherwise manipulate a gene or genes and then see if that disrupts behavior in any way.


Each species of fruit fly has its own courtship song that it "sings" with its wings. Scientists have identified a gene linked to this behavior.

One of the first genes linked to behavior that was uncovered in this manner is one called period, identified in the early 1970s. The period gene plays a key role in circadian rhythms, and among fruit flies—that research standby—it was also found to influence courtship behavior. Each species of Drosophila fruit fly has a unique courtship song that it "sings" using its wings. In one study, scientists discovered that when they transferred a small piece of the period gene from D. simulans to D. melanogaster, the melanogaster males began singing thesimulans song.
There's no such thing as a monogamy gene—or, for that matter, a gene for altruism or aggression.

This was one of the first signs that a change in even a single gene can have profound implications for behavior—in this case, a behavior vital to reproductive success, the be-all and end-all for every organism.
REGULATION GAME

Not only what a gene does but how it is regulated factors into subsequent behavior. Genes have two parts, a coding region that generates proteins and a regulatory region that tells the coding region when, where, and for how long to make those proteins. And when it comes to certain behaviors, how a gene is regulated can make all the difference.

Take mating behavior in the vole, a mouse-like rodent. The prairie vole is faithful to its mate, the montane vole is not. Yet the genetic sequence for the hormone that governs this behavioral trait is the same in both species, as is the genetic sequence for the hormone's receptor protein.

What's different, as Larry Young, a neuroscientist at Emory University, revealed, is the regulatory part of the gene—it's longer in the prairie vole. When Young transferred the full prairie vole gene for the hormone receptor, including the regulatory part, into male montane voles, the males ceased their promiscuous ways and became monogamous.


At least four different proteins generated by four different genes are needed for a mouse to recognize another mouse, scientists have found.
FOR THE GREATER GOOD

Researchers in this field are quick to stress that there's no such thing as a monogamy gene—or, for that matter, a gene for altruism or aggression. Most behaviors, they maintain, likely result from multiple genes operating in tandem. Again, they've just begun to figure out such associations.
"It is now clear that responses to social stimuli can be massive, involving hundreds or thousands of genes."

Elena Choleris of the University of Guelph in Canada and her colleagues have helped clarify one such multi-gene system. It concerns the genetic interactions needed for one mouse to recognize another and to react appropriately, that is, in a friendly or cautious manner depending on whether or not the other mouse is familiar. At least four proteins are involved in such social recognition. In different groups of mice, Choleris's team disabled one of the genes that encodes those four proteins. In each case, no matter which gene was disabled, the resulting mice could not tell a familiar mouse from an unfamiliar one, and they acted unconcerned around strangers.

"It looks like the four genes all need to be active and be functioning properly for the behavior to be produced correctly," Choleris says. "I believe that that is true for most behaviors—that they come to be through the interaction of multiple mechanisms."
CONSERVING GENES

Some genes related to behavior appear to be found across the animal kingdom—in the lingo of the specialists, they are conserved. The foraging gene is one of these. It was discovered in the late 1980s by Marla Sokolowski of the University of Toronto and her coworkers. In 1970, Sokolowski had revealed that one variant of this (then unknown) gene causes a fruit fly that has it to be a more active forager, a "rover," while another variant makes its owner less active, a "sitter."


A few weeks into its life, a honeybee transforms from a hive worker to a forager. This occurs after a single gene alters its expression based on social cues the bee picks up from its fellows.

But the fruit fly is only one of many organisms that possess foraging. In a 1997 paper, Sokolowski and colleagues identified PKG as the protein encoded by the foraging gene, and PKG has turned up in species as diverse as cows and puffer fish, honeybees and nematodes, green algae and humans. As with the discovery in recent years that virtually all animals rely on the same "toolkit" genes to build their bodies, this genetic sharing across species shows, as one researcher told me, that "nature, in the course of evolution, wouldn't reinvent the wheel every time but would reach back into the toolbox."

While the gene is the same, its action may vary among organisms. The foraging gene, for example, is largely fixed for life in fruit flies, meaning individuals are genetically predisposed to be rovers or sitters for life. But in the honeybee, foraging is more dynamic. A honeybee spends the first three weeks or so of its adult life working in the hive before becoming a forager that leaves the hive to collect nectar and pollen; in essence, she goes from sitter to rover. Neuroscientist Gene Robinson and his colleagues at the University of Illinois at Urbana-Champaign, along with Sokolowski, have determined that changes in the expression, or activation, of foraging in the brain facilitate this behavioral change-up.
ENVIRONMENTALLY SENSITIVE

How? It turns out that chemical signals from the bees' surroundings effect the change. If a sudden shortage of forager bees occurs, say because of some calamity, a number of worker bees will speed up their maturation to fill the gap. This is because honeybee foragers release a pheromone that depresses the genes that spur maturation in workers; if the level of that pheromone in the hive drops, the genes in some workers activate. "So what starts with a pheromone communication ends with changes in brain gene expression," Robinson says.


When a zebra finch sings, a host of genes start firing in the brains of other birds that hear it.


Aural inputs can also affect genes. In the zebra finch, another highly social species, when a male sings, it causes the expression of a gene known as egr1 in the brains of other males who hear it. The social importance of sounds the birds hear makes a difference—pure tones and white noise don't trip the switch of such expression. Whether or not a bird has heard the song before also matters: Familiar songs elicit little or noegr1 response, whereas new songs—which might indicate a potentially dangerous intruder—trigger a strong genetic reaction.
The speed with which genes can respond to environmental influences is astonishing.

Such a response isn't limited to a single gene. For one thing,egr1 itself can immediately suppress or enhance the workings of other genes. But it's more than that—altogether, a flurry of genetic activity can ensue. "It is now clear," Robinson wrote in a 2008 article in Science, "that responses to social stimuli can be massive, involving hundreds or thousands of genes and perhaps many different brain regions at once."

Erich Jarvis, who studies vocal learning in zebra finches at Duke University, agrees. "When an animal processes sounds—the same thing is happening in our own brains when we listen—that processing is a behavior that causes huge genetic regulatory changes in the brain." Altogether, Jarvis and coworkers have determined that singing engages fully 10 percent of a finch's genome. "And I don't think it's just for singing behavior alone," he adds. "I think this is reflecting the interaction between genes, brain, and behavior in general."


Cichlids undergo dramatic behavioral and even physical transformations after certain kinds of social interactions. Here, Ahl's haplochromis cichlids.

FAST AND FURIOUS

The speed with which genes can respond to environmental influences is astonishing. Among cichlid fish, another social species and one that has strict dominance hierarchies, when an alpha male is removed from a group, a subordinate male rapidly starts to exhibit dominant behavior. Within minutes, egr1is expressed in the brain of the subordinate fish, which begins to undergo dramatic physical and behavioral modifications. Its normally drab gray color becomes an alluring yellow or blue. Its gonads swell by an order of magnitude, enabling it to fertilize eggs for the first time. And it begins acting like an alpha, courting females and bullying other fish.

Such transformations, spurred by simple social interactions, are likely happening in some fashion in all animals throughout their lives, says Hans Hofmann, a neuroscientist at the University of Texas at Austin who studies cichlids. "Genes don't just generate behavior," Hofmann says in an online article on the University of Texas website. "The behavior itself, and the environment in which it takes place, feed back into the genes, leading to changes which then lead to different behavioral outcomes in the future."
"ABOVE THE GENOME"

One such feedback loop induces changes to gene expression that are heritable—meaning they get passed on to future generations—but that don't involve mutations in the gene's DNA. These alterations are epigenetic, meaning "above the genome."
"It's a very interactive interdependency among genes, environment, and behavior."

This phenomenon first came to light in work with rats. Michael Meaney of McGill University discovered that the offspring of mother rats who lick, groom, and otherwise care for them extensively grow up to be less sensitive to stress and more responsive to their own offspring. By contrast, rats that were neglected by their mothers will be more reactive to stress and less attentive to their own pups.


Baby rats with caring mothers behave differently later in life than genetically identical rats whose mothers are less attentive.


Because of the heritable nature of such behavioral differences, scientists assumed they arose via traditional genetics. But Meaney found that they result from the fact that frequent mother-pup interactions bring about chemical changes in genes, in a process known as DNA methylation.

As this example hints, the genome has yet another kind of responsiveness—over different time frames. This includes the moment to moment of the present hour; the time an organism takes to develop into an adult; throughout an organism's lifetime; and, finally, across evolutionary time. All these time scales impact the genome, with consequent downstream effects on behavior—and subsequently back again to the genes.

"It's a very interactive interdependency, if you want to say, among genes, environment, and behavior," Marla Sokolowski, the discoverer of foraging, told me. "It's not a static thing."
PRESERVING FUNCTION

One of the most compelling recent discoveries is that while the way specific genes operate can differ by organism—asforaging does in fruit flies and honeybees—their general function may be conserved. We have different ways and means of sleeping, but we all sleep. It's still early, but forforaging, for example, Sokolowski suspects that, in all species that have the gene, the PKG protein it produces may be involved in influencing behaviors in some way related to food—and not, say, to courtship or mating.
Nailing down the physiological basis of instinctual behavior is daunting.

Such functional consistency is striking considering what it means that function gets conserved. It means that the molecular pathways, the complex neuron-to-neuron networks in the brain that ultimately generate behavior, are themselvesbeing perpetuated across species. It's hard enough to fathom how a DNA sequence, if it served a generally useful purpose, could turn up across very different types of creatures. But entire neural networks? Strange but apparently true.

"Even though the behavior patterns we observe in different animals may be incredibly different, the underlying molecular mechanisms may, in fact, be very highly preserved," Hofmann told me. And for a very long time: Hofmann believes such web-like neurocircuitry has existed in vertebrates, or back-boned animals, at least since humans and fish diverged from a common ancestor some 450 million years ago.


Efforts to understand the links between genes and behavior in study animals may someday help doctors better diagnose and treat genetic and behavioral disorders in people.


Such conservation is especially surprising when one considers the quite variable body plans, ways of life, and selection pressures that distinguish different creatures. Not to mention brains: As Robinson wrote in the 2008 Science article, "How can molecular pathways involved in behavior be conserved even when species show major differences in brain structure and the overall organization of the nervous system?" Insects and mammals, for example, have very different brains, and they diverged from a common ancestor much earlier than we did from fish. Yet the roles of dopamine and other neurotransmitters in reward-based behavior—to give one well-documented example—are similar in the brains of both lineages, he says.
THE HUMAN FACTOR

That such conservation extends to us offers hope for better understanding and treating human behavioral disorders. As Jarvis told me, "Since many genes and neural circuits are conserved, once you discover how they work using animal models, you can figure out how when they're disrupted they cause diseases."

For instance, researchers have found birds that stutter. They believe they've identified the cause—something awry in the basal ganglia region of the brain—and the same may be occurring in people who stutter. "We can actually take the genes that are setting up the circuits in the wrong way and try to re-engineer them and correct the neurocircuitry such that the animal won't stutter," Jarvis says.

Sokolowski and colleagues, for their part, are investigating howforaging might relate to seasonal affective disorder, or SAD, in people. "In our fruit flies, the sitters are much like SAD people on short days in the winter," Sokolowski says. "We thought that the foraging gene might be a good candidate for understanding variation in this human disorder, and so far we have a significant effect of the alterations in DNA in this humanforaging gene on SAD."


How did the instinctual behavior of nest-building get imprinted in this adult hawk such that it pulled off the feat with apparent aplomb? An answer awaits further research.

UNDERLYING INSTINCT

So what about that hawk's nest? Where does all this leave us when it comes to understanding how a behavior that seems largely innate, such as nest-building, gets established in a species? Interestingly, experts know more about the molecular basis of learned and other more complex behaviors than they do about the simpler, more instinctual kind.

"That, to me, is a curious inversion, because learned behavior is thought to have been built, if you will, on top of instincts," Robinson says. "Yet we know more about how to change behavior at the molecular level than we know about where these instinctual behaviors are actually encoded to begin with."

Nailing down the physiological basis of instinctual behavior is daunting, he says, because behavior is a product of the brain. Researchers in this arena don't have physical substrates to work on, such as scientists who study limb development have limbs to study, say. "We have the substrates responsible for behavior, but responsible for is different than being one and the same as," Robinson says.

So how does a red-tailed hawk know how to build its nest? No one really knows. Yet.