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Landmark Study Prompts Rethink of Genetic Code

The most detailed probe yet into the workings of the human genome has led scientists to conclude that a cornerstone concept about the chemical code for life is badly flawed. The ground-breaking study, published in more than two dozen papers in journals on both sides of the Atlantic, takes a small percentage of the genome to pieces to draw up a "parts list," identifying the biological role of every component.

For the international team of investigators, the four-year project was the computer-equivalent of passing a fine-toothed comb through a mountain of raw data. Reporting in the British journal Nature and the US journal Genome Research on Thursday, they suggest that an established theory about the genome should be consigned to history. Under this view, the genome is rather like a ribbon studded with some 22,000 "nuggets" in the form of genes, which make proteins, the essential stuff of life.

Genes -- deemed so valuable that some discoverers of them have been prompted to file patents over them for commercial gain -- amount to only around a twentieth, or even less, of the genetic code. In between the genes and the sequences known to regulate their activity are long, tedious stretches that appear to do nothing.

The term for them is "junk" DNA, reflecting the presumption that they are merely driftwood from our evolutionary past and have no biological function. But the work by the ENCODE (ENCyclopaedia of DNA Elements) consortium implies that this nuggets-and-dross concept of DNA should be, well, junked.

The genome turns out to a highly complex, interwoven machine with very few inactive stretches, the researchers report. Genes, it transpires, are just one of many types of DNA sequences that have a functional role. And "junk" DNA turns out to have an essential role in regulating the protein-making business. Previously written off as silent, it emerges as a singer with its own discreet voice, part of a vast, interac ting molecular choir.

"The majority of the genome is copied, or transcribed, into RNA, which is the active molecule in our cells, relaying information from the archival DNA to the cellular machinery," said Tim Hubbard of the Wellcome Trust Sanger Institute, a British research group that was part of the team. "This is a remarkable finding, since most prior research suggested only a fraction of the genome was transcribed."

Francis Collins, director of the US National Human Genome Research Institute (NHGRI), which coralled 35 scientific groups from around the world into the ENCODE project, said the scientific community "will need to rethink some long-held views about what genes are and what they do." "(...) This could have significant implications for efforts to identify the DNA sequences involved in many human diseases," he said. Another rethink is in offing about how the genome has evolved, said Collins.

Until now, researchers had thought that the pressure to survive would relentlessly sculpt the human genome, leaving it with a slim, efficient core of genes that are essential for biological function. But the ENCODE consortium were surprised to find that the genome appears to be stuffed with functional elements that offer no identifiable benefits in terms of survival or reproduction.

The researchers speculate that there is a point behind this survival of the evolutionary cull. Humans could share with other animals a large pool of functional elements -- a "warehouse" stuffed with a variety of tools on which each species can draw, enabling it to adapt according to its environmental niche.

The ENCODE endeavour flows from the Human Genome Project, which concluded in April 2003 with the publication of a polished draft of the human genetic code. But having the draft is not the same as knowing what is in it or how it works. And this is essential for unlocking knowledge about our evolutionary odyssey, just as it is needed for engineering new treatments for inherited disease.

The collaborative study focussed on 44 strategically chosen targets which together account for about one percent of the genome, or about 30 million of the three billion "rungs" in the DNA double-helix ladder. The data is being placed in the public domain to help medical and other research.


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