Fly by genetics

Tiny fruit fly offers clues to human genome
by Marjorie Howard

A the end of a corridor on the first floor of Barnum Hall is a lab with shelves and tables covered with boxes containing dozens and dozens of test tubes. Inside the test tubes, capped with cotton, tiny fruit flies flit around, sometimes resting on the dark brown material in the bottom of the tube that is their food.

Victoria Meller, assistant professor of biology, along with graduate student Barbara Rattner and department staff, spend countless hours monitoring and studying the flies to learn more about genetics. The fruit fliesÑfamiliar to anyone who has left an overripe banana sitting on the kitchen counter too longÑare known to the scientific community as Drosophila melanogaster. Scientists have used the tiny flies to study genetics for 90 years because they hold lessons that can be extrapolated to mammals.

The salivary gland of a fruit fly shows that in the male, left, the RNA binds to the X chromosome, and in the female, right, this process does not occur. Tufts biologists are studying the function of RNA.

New insights into RNA
Meller's lab is studying a process called dosage compensation and the role RNA plays in this procedure. Meller and Rattner's work was recognized earlier this year when a paper they wrote was accepted by the prestigious EMBO Journal, published by the European Molecular Biology Organization. EMBO selects manuscripts that offer new insights into molecular or cellular processes and is one of the world's most highly cited journals in the field. Meller's paper will be published in March.

Dosage compensation is an essential process in which an entire chromosome is regulated. "If an animal gets an extra chromosome or loses part of a chromosome, there are terrible problems associated with it," explains Meller. "We need the entire genetic complement, but we don't want any more. An example is Down syndrome, which is an example of having an extra chromosome."

In mammals, females have two X chromosomes, and males have one X and one Y. To regulate the number of X chromosomes, the female randomly selects one X chromosome and silences it. In Drosophila, the females also have two X chromosomes and the male one X, but here the process is the opposite. The female does nothing, and the male doubles the activity of the X.

Initially, Meller says, "we thought the processes in the Drosophila and mammals would have nothing in common. But in both systems, the organism must be able to identify one chromosome out of the whole set of chromosomes and regulate it."

Understanding gene regulation
"Although the mechanism in the female mammal and the male Drosophila seems to be unrelated," says Rattner, "they both employ mechanisms that modify the architecture of the chromosome. It is important to study the mechanisms to know how these occur and understand how other gene regulation occurs."

But the major discovery in Meller's work was the conclusion that RNA molecules participate in the process of dosage compensation.

"The dogma of biology," says Rattner, "is that you have the DNA sequence transcribed into an RNA molecule, which functions as an intermediate or template to the protein, which is the functional molecule. But now we are finding RNA molecules that have a function other than as the coding for protein. It's a new field in biology to study functional RNA and its properties and functions."

Meller's lab is studying two RNA molecules that code for no protein. Her paper shows that these two RNA molecules are redundant and essential components of the dosage compensation machinery in male fruit flies. If you eliminate just one, nothing happens, and the other seems to compensate. But if you eliminate both, it is lethal for the males, because dosage compensation does not work properly.

Like us in many respects
The reason the lab uses fruit flies for its studies is that they are the mainstay of the study of genetics, going back more than 90 years ago when Dr. Thomas Hunt Morgan began to identify, characterize and create mutant strains of Drosophila. Like most scientists studying the fruit fly, Meller makes stocks or obtains them from the Bloomington Drosophila Stock Center at Indiana University, which has more than 7,000 strains of the fruit fly.

For many years, the fruit fly was believed to have little relevance for the understanding of human genetics. But in the mid-1980s, scientists began to learn that there are amazing similarities between Drosophila genes and human genes. Fruit flies have approximately 12,000 to 15,000 genes compared with some 30,000 to 50,000 genes for humans. Humans share a large number of homologous genes with flies because of the degree of gene duplication that occurred as higher organisms evolved. Because fruit flies have been studied for so many years, there is a large reserve of genetic information available about them.

Meller's lab will continue to further the understanding of dosage compensation as well as the role of RNA. "It is only in the last few years," said Rattner, "that we are finding that RNA molecules have interesting and unrevealed functions."