In the history of biology, two little animals loom large.
In the early 1900s, scientists began studying Drosophila melanogaster, the common fruit fly. Research on these fast-breeding insects revealed that genes lie on chromosomes, which turned out to be true for other animals, including us. For more than a century, scientists have continued to glean clues from the lowly fly to other mysteries of biology, like why we sleep and how heart disease develops.
In the 1960s, another unassuming animal joined biology’s pantheon: a tiny worm called Caenorhabditis elegans. Biologist Sydney Brenner realized that its body, made up of just a couple of thousand cells, offered a singular opportunity to learn how a single egg gives rise to a complete animal. Today, many scientists are studying the worm for clues to how our own brains are wired and why we age.
Now the two species are providing even deeper insights in biology. A team of hundreds of scientists has exhaustively recorded the choreography of their genes as the animals develop from eggs to adults.
“It’s not just this gene or that gene,” said Robert Waterston, a geneticist at the University of Washington who is among the scientists working on the project, called modENCODE. “We can get a picture of the whole.”
Waterston and his colleagues published overviews of the modENCODE results in five papers last week in Nature. In their initial analysis, they find a striking similarity between the choreography of genes in flies and worms and that of our own DNA. Exploring that similarity may provide scientists with new insights into genetic disorders and diseases like cancer.
In 1998, Waterston and a large group of fellow scientists cataloged all 19,000 protein-coding genes in C. elegans, along with a rough guide to the rest of its DNA. In 2000, researchers did the same for D. melanogaster. These two efforts were a huge help to scientists studying the biology of the animals. But these efforts revealed little about what the genes actually do in an organism. It was as if they had inventoried all the instruments in an orchestra but weren’t able to see the sheet music.
A gene contains information that a cell can use to make a particular molecule. But an animal may only use a given gene at a particular time in its life, or in a particular organ.
Cellular DNA is coiled around spool-like molecules called histones. When DNA is tucked away, gene-reading molecules cannot reach it. By adding certain compounds, known as histone marks, to the histones, a cell opens up a stretch of DNA.
When a gene is exposed this way, a protein called a transcription factor latches onto it, recruiting other molecules to “read” it and produce a new protein or RNA molecule. Sometimes, a single transcription factor may switch on dozens of other genes. And sometimes, those genes encode transcription factors of their own, enabling a cell to produce hundreds of kinds of molecules at once.
The modENCODE team took on an enormous task: to create a detailed picture of this molecular dance. For the past five years, hundreds of biologists have been recording DNA activity in flies and worms, and systematically comparing the results to what they see in humans.
To study genes in humans, the scientists focused on a wide variety of cells, like neurons, blood cells and liver cells. In the experiments on flies and worms, the scientists examined the entire bodies of the animals as they matured from eggs.
The scientists cataloged the parts of the genome that cells were using. They also mapped the histone marks and located the transcription factors latching onto the DNA. Because the scientists used the same methods to gather data from all three species, they were able to compare them on a scale never before attempted.
Flies, worms and humans come from distant branches on the evolutionary tree. The last common ancestor lived 700 million years ago. Despite the tremendous differences among the three species, the modENCODE team found some striking parallels in the workings of their DNA.
In all three, it turned out, many genes tended to turn on and off in the same pattern, following an predictable rhythm. All told, the researchers found 16 such sets of genes, each containing hundreds of genes working together. While it’s not clear yet what these genes are doing in all three species, the scientists did observe that a dozen clusters were especially active at some stages of development in the worm and the fly. They may be essential for transforming an egg into an adult animal.
The scientists also found that histone marks control DNA in much the same way in all three species. If certain marks were present around a gene, the scientists usually could predict how active it was, whether fly, worm or human.
“The neat thing is that it works — it really works well,” Mark Gerstein of Yale University, a modENCODE team member, said of the group’s predictive model.
Transcription factors grabbed onto genes in a dizzyingly complex pattern, the biologists learned. Different factors switched on the same genes in different cells and at different stages of development. Yet underneath the complexity, all three species follow a lot of the same rules for regulating their genes.
“A lot of the basic principles are the same,” said Michael Snyder, a geneticist at Stanford University and a member of the modENCODE team.
For example, the scientists found that many transcription factors work in a distinctive pattern. A gene — call it gene A — encodes a transcription factor that switches on genes B and C. Gene B encodes a factor that also switches on gene C.
This pattern, known as a feed-forward loop, may be especially useful for fast, reliable changes in gene activity, such as when a stem cell turns irreversibly into a blood cell. “You set up a system that says, ‘Go!’” Snyder said.
All the results of the modENCODE experiments are now available online. “The potential of such data is enormous,” said Alexander Stark, a genomicist at the Research Institute of Molecular Pathology in Austria who was not involved in modENCODE.
But Stark cautioned that the data still left much to be explained about how genes work in animals. Histone marks, for example, don’t always work as the scientists expect, leaving a gene silent when it should be active.
By improving their understanding of histones and other controls on genes, scientists may be able to gain clues to the causes of diseases. Traditionally, scientists have examined mutations to genes to find the sources of many diseases. But an increasing number of studies show that even if a gene is normal, it can cause harm if its activity is abnormal.
“If they’re not active, or if they’re hyperactive, in a cell, maybe that’s driving a disease,” Snyder said.
The similarities revealed by the modENCODE project mean that experiments on flies and worms could tell us a lot about how the cacophony of our genes leads to diseases.