Cornell researchers have played a major role in an international scientific team that has compared the complete set of genes of 12 closely related fruit fly species. As well has having implications for human health -- from genetic adaptation to evolving immune systems -- the analysis paves the way for better understanding the evolution of each species.

From the results of the research, the Cornell scientists coordinated one of the two papers published this week in the journal Nature. The team, known as the Drosophila 12 Genomes Consortium, represented 16 countries and was supported by the U.S. National Institutes of Health National Human Genome Research Institute.

"By looking at a wider number of species, we had much greater power to detect genes and regulatory elements from the way the sequences diverged between species, and to test models of what evolutionary pressures those genes and regulatory elements must have faced," said Andrew Clark, Cornell professor of population genetics and one of the paper's co-authors.

Drosophila (fruit flies) are one of most studied and most important model organisms used in genetics research. Many fruit fly genes are also found in humans and control the same biological functions. As a result, fruit fly research has led to discoveries related to the influence of genes on diseases, animal development, population genetics, cell biology, neurobiology, behavior, physiology and evolution.

The comparative method of this study allows researchers to see which genes have stayed the same and which have diverged, since all 12 species shared a common flylike ancestor some 60 million years ago. The directions in which genes have diverged provide evidence of evolution within each species.

"Methodologically, the study demonstrates the effectiveness of contrasting multiple genomes," said Clark. He and his Cornell colleagues coordinated the evolutionary analysis and worked with colleagues around the world on writing the paper. "It underscores the utility of doing comparative genomic analysis," he said.

In comparing the genome sequences of the 12 species, the team of scientists discovered, for example, that D. melanogaster shares only 77 percent of about 13,700 protein-coding genes with all of the other 11 species. The 23 percent of genes that differ are most likely the ones that have adapted themselves due to environmental pressures and sexual selection. For example, one specialist fruit fly, D. sechellia, eats only one type of fruit and is losing taste receptors five times faster than other fruit fly species that eat a wider range of foods.

Clark said there also is evidence of an evolutionary battle in immune systems of the flies as they repeatedly adapted their defenses against mutating bacteria. As bacteria find new ways to infiltrate a system, species evolve their own new defenses. Most of the genetic changes have been in each fruit fly species' ability to detect and recognize bacteria they confront, Clark said. Although species may respond differently to particular bacteria, overall their innate primary immune responses are similar and even share many features in common with human innate immunity.

One species, D. willistoni, surprised researchers because it had no genes that produce selenoproteins, which sequester selenium, an antioxidant found in many foods and a required mineral for nearly all higher organisms including humans. D. willistoni appears to be the first case of an animal that does not have genes to make selenoproteins, though the researchers cannot rule out the possibility that the species may have another way to encode selenium in its proteins.

In the cells of the tiny fruit fly (Drosophila), researchers in the 1930s found valuable resources known as polytene chromosomes -- giant bundles of chromosomes, banded into distinct segments corresponding to specific genetic loci.

Polytene chromosomes give geneticists a window on the mechanics of gene activation and transcription, particularly with the advent of new optical and molecular imaging techniques that allow studies of living tissue in real time.

John Lis, the Barbara McClintock Professor of Molecular Biology and Genetics at Cornell, notes in the current issue of Nature that those new studies -- combined with other genetic and biochemical data on Drosophila and mammals -- could lead to a shift in the way scientists understand how gene expression is regulated in cells.

A key question is the regulation of RNA polymerase II (Pol II), an enzyme that binds to DNA and catalyzes the production of messenger RNA. Researchers have long thought that the rate of transcription is limited by the time it takes Pol II to be recruited to the promoter region, where it copies a strand of DNA into RNA. But increasing evidence in Drosophila and other organisms indicates that Pol II frequently exists in a "paused" state at the promoter: Already having made a short RNA, it awaits further regulatory signals before completing transcription. This is leading to new questions about the regulation of transcription.

"The field is changing," said Lis. But many of the answers may still lie with the tiny fruit fly.