A colossal international effort has yielded the first comprehensive look at how our DNA works, an encyclopedia of information that will rewrite the textbooks and offer new insights into the biology of disease.
For one thing, the effort might help explain why complex diseases such as diabetes, high blood pressure and psychiatric disorders are so difficult to predict and, often, to treat.
The findings, reported Wednesday, reveal that the human genome is packed with at least 4 million on-off switches that tell our genes what to do and when. The switches reside in bits of DNA that once were dismissed as “junk” but turn out to play critical roles in controlling how cells, organs and other tissues behave.
The discovery, considered a major medical and scientific breakthrough, has enormous implications for human health because many complex diseases appear to be caused by tiny changes in hundreds of gene switches.
The findings are the fruit of an immense federal project, involving 440 scientists from 32 labs around the world. As they delved into the “junk” — parts of the DNA that are not actual genes containing instructions for proteins — they discovered it is not junk. At least 80 percent of it is active and needed.
The result is an annotated road map of much of this DNA, noting what it is doing and how. It includes the system of switches that, acting like dimmer switches for lights, control which genes are used in a cell and when they are used, and determine, for instance, whether a cell becomes a liver cell or a neuron.
The findings have applications for understanding how alterations in the non-gene parts of DNA contribute to disease, which might lead to new drugs.
They can also help explain how the environment can affect disease risk. In the case of identical twins, small changes in environmental exposure can slightly alter gene switches, with the result that one twin gets a disease and the other does not.
“It’s Google maps,” said Eric Lander, president and founding director of the Broad Institute of Harvard and the Massachusetts Institute of Technology.
Its predecessor, the Human Genome Project, which mapped out the entire sequence of human DNA, “was like getting a picture of Earth from space,” he said. “It doesn’t tell you where the roads are, it doesn’t tell you what traffic is like at what time of the day, it doesn’t tell you where the good restaurants are, or the hospitals or the cities or the rivers.”
The new result “is a stunning resource,” said Lander, who was not involved in the research that produced it but was a leader in the Human Genome Project. “My head explodes at the amount of data.”
Unexpected results
The discoveries were published Wednesday in six papers in the journal Nature and in 24 papers in Genome Research and Genome Biology. In addition, The Journal of Biological Chemistry is publishing six review articles and Science is publishing yet another article.
Human DNA is “a lot more active than we expected, and there are a lot more things happening than we expected,” said Ewan Birney of the European Molecular Biology Laboratory-European Bioinformatics Institute, a lead researcher on the project.
In one of the Nature papers, researchers link the gene switches to a range of human diseases — multiple sclerosis, lupus, rheumatoid arthritis, Crohn’s disease, celiac disease — and even to traits like height.
In large studies over the past decade, scientists found that minor changes in human DNA sequences increase the risk that a person will get those diseases. But those changes were in the junk, now often referred to as the dark matter — they were not changes in genes — and it was not clear what their significance was. The new analysis reveals that a great many of those changes alter gene switches and are highly significant.
“Most of the changes that affect disease don’t lie in the genes themselves; they lie in the switches,” said Michael Snyder, a Stanford University researcher for the project, called ENCODE, for Encyclopedia of DNA Elements.
That, said Dr. Bradley Bernstein, an ENCODE researcher at Massachusetts General Hospital, “is a really big deal.” He added, “I don’t think anyone predicted that would be the case.”
The system is stunningly complex, with lots of redundancies. Just the idea of so many switches was almost incomprehensible, Bernstein said.
“People have trouble digesting the number,” he said. “Why would you need to have a million switches to control 21,000 genes?”
There also is a sort of DNA wiring system that is almost inconceivably intricate.
“It is like opening a wiring closet and seeing a hairball of wires,” said Mark Gerstein, an ENCODE researcher from Yale. “We tried to unravel this hairball and make it interpretable.”
Diving into dark matter
The project began in 2003, as researchers began to appreciate how little they really knew about human DNA. In recent years, some began to find switches in the 99 percent of human DNA that is not genes, but they still could not fully characterize or explain what a vast majority of it was doing.
By the time the National Human Genome Research Institute, part of the National Institutes of Health, embarked on ENCODE, there had been major advances in DNA sequencing and computational biology that made it conceivable to try to understand the dark matter of human DNA.
Even so, the data analysis was daunting — the researchers generated 15 trillion bytes of raw data. Just organizing the researchers and coordinating the work has been an enormous undertaking.
Gerstein, who was one of the project’s leaders, has produced a diagram of the authors with their connections to one another. It looks nearly as complicated as the wiring diagram for the human DNA switches.
Now that part of the work is done, and the hundreds of authors have written their papers.
“There is literally a flotilla of papers,” Gerstein said.
But, he added, more work has yet to be done — there are still parts of the genome that have not been figured out.
The Associated Press contributed to this report.
