By David N. Leff

In recent criminal trials, defense attorneys have invoked their defendants' childhood tribulations to explain — and excuse — adult crimes.

Now it's beginning to look as if future not-guilty pleas will be: "My behavioral genes made me do it."

Scientists have reported on a variety of genes responsible for traits ranging from altruism and aggressiveness to politeness and novelty-seeking.

So far, tracking down these allegedly genetic attributes has relied on gene-mapping affected populations, but with no molecular evidence linking a given behavior to a specific brain function. Now, apparently, that barrier has been breached.

Today's Science, dated Aug. 8, 1997, carries a paper titled: "Natural behavior polymorphism due to a cGMP-dependent protein kinase of Drosophila." Its principal author is behavioral geneticist and molecular biologist Marla Sokolowski, of York University, in Toronto.

Over the past two decades, Sokolowski has determined that the common fruit fly, Drosophila melanogaster, comes in two persuasions. One of its genetic variants, she discovered — about 70 percent of the fly population — travels farther afield in search of food than the other. So she named the long-distance forager "rover" and the stay-at-home scrounger "sitter."

A rover maggot might cover 12 centimeters (five inches) in five minutes; a sitter, seven or eight. An adult rover insect walks 26 or 27 cms in 30 seconds, after feeding. A sitter, 10 cms or less.

Now the York scientist and her co-authors report finding the gene that masterminds the molecular and cellular bases for this inherited behavioral variation.

Fruit flies, which are only one-tenth the size of house flies, have been the favorite animal model of geneticists for a century. The Drosophila genome contains four pairs of chromosomes, harboring at least 5,000 essential genes. A single female lays 100 eggs in a day, and 12 days later they are adult insects, ready to repeat the reproductive cycle.

But the flies' research charm goes a lot deeper and wider than mere convenience.

"We find genes of similar homology in the fly, in mice and in humans," Sokolowski told BioWorld Today. "One of them is even thought to be important to mammals as well as flies, in learning and memory."

This DNA-sequence resemblance includes the rover/sitter gene of her Science paper, named foraging, a.k.a. dg2. It expresses forms of a protein kinase, PKG, which adds phosphates to proteins, and which the human genome also produces.

"Both fly and human structures," Sokolowski observed, "are often very similar. Surprisingly, in many cases, the functions are similar as well — certainly at the level of the nervous system, cell communication and signal transduction. Whether the functions at a more gross level in food-search behavior are going to be similar or not, we can't say now. But given the resemblance between fly and mammal in the function of developmental genes, there's a good possibility of a role for this PKG kinase in regulation of feeding in humans.

Gene Product Tells Flies How To Hunt For Food

"We know in the fly," she pointed out, "that slightly higher concentrations of the enzyme in the brain make rovers move for food, while slightly lower ones keep sitters close to home. So this could suggest an enzyme that researchers who work on humans might look for, and its relative abundance in the brain, in individuals who have eating disorders."

Analyzing the expression pathways of PKG by the rover/sitter gene, she recalled, "we saw things in the fruit fly brain, in the sensory system, that might be involved in tasting or smelling food, and in the stomach, which may involve signals as to whether the insect is full or not."

Sokolowski went on to cite an unpublished experiment in which "we've fed these flies nitric oxide synthase, that's been used to make obese animal models change their meal intake and interval, so they eventually became thinner, or even anorexic. It also changed the behavior of our flies.

"That chemical," she continued, "is involved, we think, in this probable PKG pathway. So it would be reasonable for people to think about that kinase in regulation of feeding in mice, and maybe even in humans."

To prove that their foraging/dg2 gene was responsible for the difference in behavior between rover and sitter flies, Sokolowski's team took the gene from a rover insect and genetically transformed it into a sitter. To perform this transgenic feat, she recounted, "we put the DNA between the ends of jumping genes — transposons — and injected the sequences into Drosophila sitter embryos. That DNA jumped into the genome, so when the larva grew up, it was a sitter genetically, but had a functional rover DNA inserted into it. To get the kinase levels high enough," she added, "we put in four copies of the DNA.

"Those transformed sitter flies had completely rover behavior, which," Sokolowski pointed out, "was the ultimate proof that we were dealing with a PKG gene, and that environmental factors alone couldn't account for the rover/sitter behaviors."

Another experiment they reported in Science involved inserting a mutation that jumped into the gene. "That turned a rover into a sitter, and when we jumped it back out, it reconverted the sitter to a rover."

Behavioral Traits Are Polygenic

Sokolowski made the point that no single gene is likely to be found, of which the only function is to control a specific behavioral trait. "It's eye-catching," she observed, "to hear there's a gene for this or that. But genes generally have pleiotropic functions; they affect many things. Our foraging/dg2 gene encodes an enzyme that likely has a lot of different roles in the animal. One role is that when there's a subtle difference in the brain of the enzyme it expresses, you end up with a difference in behavior."

Besides possible therapeutic interest, Sokolowski suggests that "Drosophila can be used as a model — which hasn't been done before — to test various drugs that may influence the PKG pathway, and may be involved in how mammals regulate their food intake. We have the behavioral assays to do that," she added, "to look at how often they eat, and when, their weight gain, etc. And we're beginning to understand what goes on at the cellular level, so in the long term the fly may be a good model — cheaper than mice — to assess these different things. And maybe we can do more with it genetically, like expressing gene products in certain places in the brain, at certain times, rather than just feeding the animal the drug and letting it go everywhere."

She concluded: "We're beginning to be able to do that in fruit flies."