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Gene switches once dismissed as ‘junk’ now seen as key to disease

NEW YORK — Among the many mysteries of human biology is why complex diseases like diabetes, high blood pressure, and psychiatric disorders are so difficult to predict and, often, to treat. An equally perplexing puzzle is why one individual gets a disease like cancer or depression, while an identical twin remains perfectly healthy.

Now scientists have discovered a vital clue to unraveling these riddles. The human genome is packed with at least 4 million gene switches that reside in bits of DNA that once were dismissed as junk but that 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.

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The findings are the fruit of an immense federal project, involving 440 scientists from 32 global labs. 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 all. 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 immediate applications for understanding how alterations in the non-gene parts of DNA contribute to human diseases, which may in turn 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 determined 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.’’

links to many ailments

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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 studies over the past decade, scientists found that minor changes in human DNA sequences increase that risk that a person will get those diseases. But those changes were not in genes but in the junk — now often referred to as the dark matter — 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.

And that, said Dr. Bradley Bernstein, an ENCODE researcher at Massachusetts General Hospital, ‘‘is a really big deal. 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. 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.’’

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