Intricate Toiling Found In Nooks of DNA Once Believed to Stand Idle

The first concerted effort to understand all the inner workings of the DNA molecule is overturning a host of long-held assumptions about the nature of genes and their role in human health and evolution, scientists reported yesterday.

The new perspective reveals DNA to be not just a string of biological code but a dauntingly complex operating system that processes many more kinds of information than previously appreciated.

The findings, from a project involving hundreds of scientists in 11 countries and detailed in 29 papers being published today, confirm growing suspicions that the stretches of "junk DNA" flanking hardworking genes are not junk at all. But the study goes further, indicating for the first time that the vast majority of the 3 billion "letters" of the human genetic code are busily toiling at an array of previously invisible tasks.

The new work also overturns the conventional notion that genes are discrete packets of information arranged like beads on a thread of DNA. Instead, many genes overlap one another and share stretches of molecular code. As with phone lines that carry many voices at once, that arrangement has prompted the evolution of complex switching, splicing and silencing mechanisms -- mostly located between genes -- to sort out the interwoven messages.

The new picture of the inner workings of DNA probably will require some rethinking in the search for genetic patterns that dispose people to diseases such as diabetes, cancer and heart disease, the scientists said, but ultimately the findings are likely to speed the development of ways to prevent and treat a variety of illnesses.

One implication is that many, and perhaps most, genetic diseases come from errors in the DNA between genes rather than within the genes, which have been the focus of molecular medicine.

Complicating the picture, it turns out that genes and the DNA sequences that regulate their activity are often far apart along the six-foot-long strands of DNA intricately packaged inside each cell. How they communicate is still largely a mystery.

Altogether, the new project shows that the simple sequence of DNA letters revealed to great fanfare by the $3 billion Human Genome Project in 2003 was but a skeletal version of the human construction manual. It is the alphabet, but not much more, for a syntactically complicated language of life that scientists are just now beginning to learn.

"There's a lot more going on than we thought," said Francis Collins, director of the National Human Genome Research Institute, the part of the National Institutes of Health that financed most of the $42 million project.

"It's like trying to read and understand a very complicated Chinese novel," said Eric Green, the institute's scientific director. "The take-home message is, 'Oh, my gosh, this is really complicated.' "

The findings come from the Encyclopedia of DNA Elements project, nicknamed Encode. While much of the decades-long effort to understand DNA's role in health and disease has been driven by scientists' interest in particular genes, Encode focused on a representative 1 percent of the genome. Using a variety of experimental and computational approaches, the researchers sought to catalogue everything going on there.

The 3 1/2 -year effort was designed as a pilot project to see whether it would be practical to study the entire genome in such depth and to hasten the development of cheaper tools to do so. Encode was so successful, Collins said, that the remaining 99 percent of the genome is expected to be studied the same way for $100 million.