A Novel Approach to DNA Analysis

In a milestone for the emerging field of comparative genomics, an international team of scientists has carried out a comparative analysis of the genome sequences of 12 different species of fruit flies. Not only did the researchers uncover patterns in the way that genes evolve as species adapt to different environments, but they also developed a new way of identifying the functional elements of the genome–a discovery with potentially far-reaching consequences.

For more than a hundred years, the fruit-fly species Drosophila melanogaster has been instrumental in the study of genetics, developmental biology, and animal behavior. Because a significant number of human genes have fruit-fly analogues, researchers have also used the insect to study many human diseases, including cancer, diabetes, and neurodegenerative disorders such as Alzheimer’s. In 2000, scientists published the genome sequence for D. melanogaster; the sequence of a second fruit-fly species followed several years later.

There are 1,500 species of fruit flies, however, and they vary in appearance, behavior, and habitat. To fully understand the fruit-fly genome and how it has evolved, a consortium of more than a hundred labs around the world sequenced an additional 10 species and compared all 12 sequences. The group details its findings in two reports published in the November 8 issue of Nature.

“If you want to get a crystal-clear picture of how genes influence what an animal will look like, what it will eat, what behavior it will exhibit, this is a completely unparalleled resource for doing that,” says Leslie Vosshall, a neurogeneticist at Rockefeller University, in New York.

The researchers selected species from all over the world–from Africa, Asia, the Americas, and the Pacific Islands. Some species are widespread and feed on a range of foods, whereas others are more limited. For instance, one species lives only on the Seychelles islands off the east coast of Africa and eats only one kind of fruit.

In one of the papers, a team led by Manolis Kellis, a computational biologist at MIT, compared the 12 sequences in order to identify all the functional elements in the fruit-fly genome. These include not only genes that code for proteins, but also sequences that help regulate gene expression by, for instance, encoding small RNA molecules that bind to other parts of the genome. To find these elements, researchers typically look for sequences that are common, and therefore highly conserved, among different genomes. “The basic premise of comparative genomics is that if something is conserved over millions of years in a dozen species, it’s likely to do something useful,” says Kellis.

But Kellis and his colleagues were also seeking an alternative strategy. They figured that by looking only for sequences that have remained roughly the same, they would miss a large number of functional elements. For instance, protein-coding genes can undergo extensive changes and yet retain their critical functions.

By looking at all 12 genomes, the team found that each type of functional element changes in characteristic ways over time, and those patterns of change serve as evolutionary signatures. For instance, a series of three-letter DNA sequences in which the first two letters are always conserved but the third one changes is likely to be a protein-coding gene, says Kellis. So the researchers designed computer algorithms to mine the sequence data and find the evolutionary signatures for each type of functional element. “This allowed us to find things that we would never have expected to find just by looking at a single genome,” says Kellis.

Kellis’s team found thousands of previously unidentified functional elements, including 150 protein-coding genes and more than a hundred microRNA genes. (MicroRNAs are short segments of RNA that silence genes by binding to specific sites in the genome.) The researchers also found that some genes, during their translation into proteins, ignore certain instructions and, as a result, acquire bits of protein encoded by other genes. “This is an entirely new mechanism,” says Kellis, adding that his group has since found evidence of this mechanism in the human genome as well.

The second Nature paper describes research led by Andrew Clark, a population geneticist at Cornell University, who looked at known genes to see how they vary from one species to another and how they evolve, acquiring new functions as species adapt to their changing environments. Genes involved in the immune system, for instance, appear to evolve more rapidly than genes in the rest of the genome. The same was true for genes that regulate insecticide resistance.

Taste and smell receptor genes also undergo frequent changes. When the researchers compared species of flies that are generalists with those that have more specialized food preferences, they found that the specialists lose genes for different taste receptors at a much higher rate than the generalists do. “How you smell the world influences how you eat, and this will tell us an enormous amount about how genes that encode for smell and taste influence behavior,” says Vosshall.

The studies of the 12 fruit-fly genomes will no doubt help scientists better understand the human genome, says Kellis. Not only do fruit flies and humans have so many genes in common, but now researchers have a systematic way of interpreting genomes that could lead to the discovery of entirely new kinds of functional elements, he says.