New Findings Challenge Beliefs About DNA

Jun 18, 06:36 AM

Current Headlines: By Rick Weiss

WASHINGTON -- 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 Wednesday.

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 massive project involving hundreds of scientists in 11 countries and detailed in 29 papers published Thursday -- confirm growing suspicions that the vast stretches of so-called "junk DNA" flanking hardworking genes are not junk at all. The study goes further, though, 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 physically overlap one another and share common 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.

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 so much the focus of molecular medicine. Complicating the picture further, 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" that was 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."

Perhaps most surprising was how much of the human genome is at work at any given time, the scientists said.

Researchers have long known that only about 2 percent of human DNA is involved in making proteins, the molecular workhorses inside cells. That involves a two-step process in which a stretch of DNA - - a gene -- serves as a template to produce a strand of RNA, which is then used as a template to produce a protein.

Recent studies had shown that some snippets of DNA in between genes also get transcribed into RNA even though they do not go on to make protein. Surprisingly, though, the new work shows that most of a cell's DNA gets transcribed, raising big questions as to what all that RNA is doing.

Some of it may be doing nothing. "It may be like clutter in the attic," Collins said -- noting that clutter might be useful when conditions change and evolution needs new material to work with.

Much of it now seems to be playing crucial roles -- regulating genes, keeping chromosomes properly packaged, or helping to control the spectacularly complicated process of cell division, which is key to life and also is at the root of cancer.

"We are increasingly being forced to pay attention to our non- gene DNA sequences," wrote John Greally, of the Albert Einstein College of Medicine in New York, in a commentary in Thursday's issue of the journal Nature, where one of the new reports is published. The other 28 papers appeared in Thursday's issue of Genome Research.

Greally noted that several recent studies have found that people are more likely to have type 2 diabetes and other diseases if they have small mutations in non-gene parts of their DNA that were thought to be medically irrelevant.

Another aspect of ENCODE had researchers looking at the equivalent 1 percent of the genomes of more than 20 other mammals, and those results are forcing a rethinking of the interplay between genetics and evolution.

The expectation was that many of the most active DNA sequences in humans would be prevalent in other mammals, too, since evolution tends to save and reuse what works best. But more than half of them were not found in other creatures, which suggests they may not actually be that important in people, either, said Ewan Birney of the EMBL-European Bioinformatics Institute in Cambridge, England, a coordinator of the ENCODE effort.

"I think of them as gate crashers at a party," Birney said. "They appeared by chance over evolutionary time ... neither to the organism's benefit nor to its hindrance. That is quite an interesting shift in perspective for many biologists."

Text of fax box follows:

A genome catalog

The findings come from the Encyclopedia of DNA Elements project, nicknamed ENCODE.

ENCODE focused on a representative 1 percent of the genome. Using a variety of experimental and computational approaches, the researchers sought to catalogue absolutely everything going on there.

The 3-year effort was designed as a pilot project to see if it would be practical to study the entire genome in such depth.

So successful was ENCODE that the other 99 percent of the genome is now expected to be studied the same way for just $100 million.

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