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Genetic Cousins

TIMES MEDICAL WRITER

New studies of the sex lives of the fruit fly are shedding rare insights into one of the most controversial areas in neurological research--the extent to which human behavior is genetically controlled.

Although it may seem like a long leap from the flings of fruit flies to the matings of humans, scientists are emboldened by more than five decades of research on the insects, which are the geneticist’s version of the laboratory rat.

Virtually every important gene identified in flies to date has been shown to have a counterpart in humans, and researchers see no reason why genes controlling behavior should be any different.

Genetic links to behavior in humans have been extremely difficult to document. Recent reports have trumpeted the identification of genes that produce anxiety, impulsive behavior and schizophrenia, while earlier studies have claimed genetic links to manic-depression and other mental disorders.

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Virtually all such claims, however, have proven resistant to replication in other laboratories, throwing doubt on their accuracy. Nonetheless, many scientists are convinced that genes are responsible for a large portion of human behavior, and they have turned to the fly for answers.

One of the most striking successes was the recent report that virtually all sexual behavior in male fruit flies is controlled by a single gene, a startling finding that may force at least some naysayers to rethink their objections to genetic control of behavior.

A team of researchers from Stanford and three other universities reported in December that a series of mutations in one gene in the brain of the fruit fly can produce changes in the spectrum of male sexual behavior, including the ability to recognize females, courting behaviors and the capacity to produce progeny.

“Showing that a behavior as complex as sexual behavior is controlled by a single gene, at least in flies, raises the obvious possibility that other behaviors will be similarly controlled,” said Stanford biologist Bruce Baker.

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“This is an important tool,” added biologist Barbara Taylor of Oregon State University, a co-author. “Here we have a gene that allows us to extract some behavioral element and then go into the nervous system and see how it is organized.”

That will serve as a model for studies of other behaviors.

“The question now is not whether the actions of a given gene influence some interesting aspect of behavior, but how,” concluded biologist Jeffrey Hall of Brandeis University, another co-author.

The relevance of the newly discovered gene to humans is still a subject of debate, however.

An examination of computerized databases shows that no one has discovered an analogue of the new gene in humans. But that does not necessarily mean it is not present, Baker said.

The fruit fly gene is active in only 500 of the 100,000 brain cells in the insect, and a gene with that low a level of activity in humans would probably not have been stumbled upon accidentally, he said.

The gene in question was first observed in the 1960s by researchers at Yale, who noted that irradiation could cause males to lose the ability to distinguish other males from females. The males also did not reproduce, so the gene was named fruitless or fru for short.

For 30 years, it was little more than a curiosity, its location on the fruit fly genome noted but its composition and normal purpose a mystery.

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Hall and Baker’s labs both were searching for genes that control sexual behavior in male fruit flies when it became clear that the gene they were looking for was fru. Pooling their resources, the four laboratories located the gene and sequenced it, identifying the order of each of the chemicals (called bases) that compose it.

That, in itself, was a major task because the gene contains 140,000 bases, about 70 times the number found in a normal drosophila gene.

They also found that different mutations in the gene produce different effects on behavior. Normally, the instant a male fruit fly recognizes an eligible female by sight and smell, he begins an elaborate courtship dance that involves following the female, stroking her, licking her, playing a rhythmic courtship song by vibrating one wing, and finally bending his abdomen and attempting to mate.

The team found that, the more severely the fru gene was mutated, the more courtship behaviors were lost. In severe mutations, the flies were barely interested in courting, even though they could walk and fly normally. In the most severe mutations, the flies died in infancy because a male-specific abdominal muscle did not develop.

Although the researchers are still attempting to understand how the gene works, it is clear that it exists in segments that can be assembled in different combinations. The proteins produced from each unique gene assemblage then apparently act to turn on other genes that are more intimately involved in controlling the courting behavior.

The researchers do not know if there is a comparable gene that controls sexual behavior in female fruit flies. In part, that is because female behavior is more subtle and thus more difficult to study.

Earlier this month, however, geneticist Michael McKeown and his colleagues at the Salk Institute for Biological Studies reported the discovery of a gene, called dissatisfaction, that controls some aspects of sexual behavior in male and female fruit flies.

Normal females are quick to respond to courtship behavior. Those with a mutation in dissatisfaction, however, fail to adopt a proper mating position--and may, in fact, assertively reject the male’s advances, kicking the male or running away. Males with the mutation attempt to mate with both females and other males.

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The discovery of fruitless could have immediate applications in agriculture because some related species of fruit flies destroy crops. Researchers could use the new knowledge, Baker said, to breed large numbers of sterile male fruit flies to interfere with the normal mating cycles of the pests in the wild--a technique that already is used in fighting the Medfly.

Meanwhile, geneticists are searching in other species, including humans, for analogues of the new genes.

“It’s certainly possible there is going to be a human analog to fru,” said Steven Wasserman of the University of Texas Southwestern. “What is certain is, if it’s there, it won’t control behavior, it will merely influence it.”


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