EVOLUTIONARY GENOMICS:
Fruit Fly Blitz Shows the Power of Comparative Genomics

To the uninitiated, one fruit fly is like any other--all equally pesky and deserving a good swat. But in reality, these insects are quite diverse, with species that differ from each other, genetically speaking, more than a platypus differs from a primate. A consortium of about 250 researchers harnessed this diversity and in a blast of reports this week demonstrated the analytical power of comparative genomics.

The group has sequenced 10 genomes from different fruit fly species; combining these with existing DNA data, they have done a 12-way comparison to track the evolution of genes, regulatory regions, entire pathways, and cellular processes. Having these patterns in hand makes it easier to spot similar features in the genomes of other species, including humans, researchers report in more than 40 research papers in the 8 November issue of Nature and in other journals.

"This work has really increased the sophistication of what we can learn from comparative sequence analysis," says genomicist Elliott H. Margulies of the National Human Genome Research Institute (NHGRI) in Bethesda, Maryland. As project co-leader Michael Eisen of Lawrence Berkeley National Laboratory in California points out, the comparison "allows you to map where [genetic] changes occur along the tree, and that allows you to study the process of evolution, not just the product."

Drosophila melanogaster, the lab standard, has powered genetics studies for almost a century. In 2000, its genome became the second animal genome sequenced, but partly because it was one-of-a-kind, it was hard to decipher. Subsequent comparisons between the human and mouse genomes and, in 2003, between the genomes of four yeast species drove home the value of comparative genomics. Immediately, Drosophila enthusiasts appealed to NHGRI to support an even larger multispecies comparison in fruit flies.

NHGRI approved a plan to look at 12 Drosophila species that diverged between a half-million and 60 million years ago. Each has its own lifestyle and geographic distribution--and each has a distinct evolutionary relatedness to D. melanogaster. The genomes proved quite varied, ranging in size from 130 million to 364 million bases, with 13,683 to 17,325 genes. The amount of DNA taken up by transposable elements, or repeated regions of DNA, varied by an order of magnitude, the consort ium reports in the 8 November issue of Nature.

From this material, the researchers pieced together evolutionary stories. Probing a biological pathway as it changes from one species to the next "lets you see where there's evolutionary pressure driving the change," says Andrew Clark of Cornell University. His group looked at the impact of pathogens. They examined the repertoire of genes involved in recognizing microbes, signaling an invader's presence, and producing toxins to thwart attacks--245 genes in D. melanogaster alone and 1200 across the 12 species.

Fruit flies galore. By sequencing Drosophila species of varying degrees of relatedness, genomicists have learned much more about genome structure and evolution. SOURCE: ADAPTED FROM A. STARK ET AL., NATURE (19 OCTOBER 2007); ILLUSTRATIONS: S. L. MARTIN, UNIVERSITY OF TEXAS PUBLICATION, NO. 4313 (1 APRIL 1943) AND NO. 4445 (1 DECEMBER 1944)

The evolutionary analyses yielded surprises as well. For example, Clark's team found that a new gene called drosomycin, which codes for an antifungal compound, appears only in D. melanogaster and its close relatives. There are no clues, however, as to how this gene came to be. Another surprise came from the species D. willistoni: It doesn't seem to have genes to make proteins containing selenium--proteins that researchers had thought were common to all animals.

Manolis Kellis of the Broad Institute in Cambridge, Massachusetts, led an assessment of how each type of gene or regulatory region changed--or didn't change--from one species to the next, revealing specific evolutionary patterns, or signatures. Kellis and others have incorporated those telltale patterns into software to look for the same patterns in other species to pinpoint each type of DNA. "This allows us to assign function" to some regions "through computation alone," says Margulies.

Based on a common pattern of insertions, deletions, base usage, and substitutions, Kellis and his colleagues detected 192 undiscovered protein-coding genes as well as 150 that do not follow standard rules. Typically, proteincoding genes have a "stop" sequence that signals the end of the gene. But in these 150 cases, protein-coding sequences extended beyond the "stop." "It's always a little humbling that the assumptions we are taught in school do not apply across all genes," says Ewan Birney of the EMBL European Bioinformatics Institute in Hinxton, U.K.

With these new tools, which are particularly useful for recognizing regulatory DNA, Kellis and his colleagues have pieced together a fruit fly gene regulatory network that incorporates 81 microRNAs and 67 transcription factors. "The methodology and principles are absolutely general, and they are applicable to any genome," says Kellis. Others say that the model still needs refining to reconcile it with experimental results. But geneticist Rama Singh of McMaster University in Hamilton, Canada, is quite pleased with this beginning. Because many fruit fly and human genes are equivalent, the network "is going to tell us a lot about humans," he predicts.

The analysis bodes well for the utility of bird, marsupial, and reptile sequences in analyzing the human genome. It also argues for sequencing and comparing all the primates, says Birney: "The take-home message is that there are a lot of clear wins from doing this sort of evolutionary genomics."

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