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Human Genome Yields Up More Secrets

By E.J. Mundell
HealthDay Reporter
Wednesday, June 13, 2007 12:00 AM

WEDNESDAY, June 13 (HealthDay News) -- In what's being hailed as a milestone in human genetics research, an international consortium of scientists announced Wednesday new data that could revolutionize how scientists study health and disease.

An exhaustive look at only 1 percent of the human genome produced two major findings: a vast amount of seemingly useless genes formerly called "junk DNA" may, in fact, be crucial to regulatory processes governing cells; and "epigenetic" factors outside of genes are probably big players behind many diseases.

The results of the Encyclopedia of DNA Elements (ENCODE) Project, published in the June 14 issue ofNature, are "moving us into a deeper understanding of how life works and how, sometimes, things go wrong and disease occurs," Dr. Francis Collins, director of the U.S. National Human Genome Research Institute, told reporters at a morning news conference.

The completion of the Human Genome Project in April 2003 was an historic achievement, resulting in a catalog of more than 30,000 genes that make up the species' genetic blueprint. Those genes are comprised of 3 billion individual nucleotides -- labeled A, C, G, or T -- which combine to form genetic code. All of this is packed and bound into chromosomes as material collectively called chromatin.

"This script is written in this apparently simple alphabet with just four letters, but somehow carries within it all of the instructions necessary to take a single-cell embryo and turn it into a very complex biological entity called a human being," said Collins, whose institute is the major source of funding for the $41 million project.

It is one thing to map the whole genome on the "macro" level, the experts noted. But what the ENCODE team -- 35 groups from 80 organizations worldwide -- is seeking to do is examine, in much more detail, just 1 percent of the genome.

About half of this 1 percent involves areas that were known by scientists to influence gene replication and protein coding to make the building blocks of life. The other half was a random sample meant to include other aspects of the genome, including so-called "junk DNA."

"When they first sequenced the genome, [scientists] were surprised at how little DNA was involved in protein coding regions," explained Ewan Birney of the European Bioinformatics Institute in Hinxton, England.

Birney, who headed up the two-and-a-half year analysis of the ENCODE data, noted that just 1.5 percent of the "letters" in the genome actually make cellular proteins. So, his team wondered, what was the other 98.5 percent doing?

"People rather dismissively called the rest of it 'junk DNA,' " he said. But the ENCODE data suggest that this genetic material is, in fact, very active.

"One of the big surprises is that the regions between genes seem to be alive, not only with regulatory regions -- which we suspected -- but also there's a lot of [gene] transcription," Birney said. Transcription is the process whereby DNA transcribes its information into usable proteins.

The researchers also discovered another, less obvious purpose to a lot of genetic material. They noticed that up to 70 percent of "functional regions" in the genomes of both humans and other mammals were what Birney called "neutral." These neutral genetic blips popped up frequently and didn't help or hinder the organism, in terms of activities needed to sustain life.

But Collins and other experts believe the neutral regions may, in fact, be key players in evolution and disease, swinging into action occasionally and triggering either helpful or harmful changes.

"It's like clutter in the attic," Collins said. "It's not the kind of clutter that you would get rid of without consequences, however, because you might need it."

"Most of the time the human genome is operating on the 'first and second floor,' with maybe 5 percent of the genome doing whatever needs to be done in terms of daily activities," Collins added. "But over evolutionary time, a much larger fraction of the genome -- this stuff up in the attic -- becomes important. In fact, it's probably responsible for getting us where we are in terms of [our] complexity. It's still there, waiting for natural selection to call upon it."

ENCODE is also revealing that epigenetics -- factors that modify the function of DNA but don't change its sequence -- are a major player in disease.

For example, a team at the University of Virginia has found that the degree to which DNA is bound within the chromosome's chromatin structure strongly influences whether that gene can express, or produce, a protein.

While smaller studies have hinted at that before, "this genome-wide survey really shows that these factors are beautifully coordinated," lead researcher Dr. Anindya Dutta, a professor of molecular genetics at the university, toldHealthDay. "Portions of the chromosome that are lightly packed are replicated early, and they also have the highest amount of gene expression."

That means that a too-loose or too-tight "packing" can cause changes in how a gene functions, much like a mutation would. The ENCODE survey found that, "in cancer cells, this happens in 20 percent of our genes," Dutta noted.

Indeed, revelations from ENCODE should, in the long run, greatly enhance research into a variety of diseases, the experts said. The findings come on the heels of a major study, released last week inNature, in which British scientists substantially increased the number of genes implicated in such common diseases as bipolar disorder, diabetes, heart disease and rheumatoid arthritis.

In many cases, the new complexity arising from ENCODE means that "it will take us a bit longer to sort out exactly what is the mechanism of disease risk," Collins said. "We will have some work to do to figure out exactly how [a genetic aberration] works and what is the consequence."

The results announced Wednesday, he added, are merely those of a pilot project. "We aim to scale this up in the not-too-distant future and apply these same approaches to the entire human genome," he said.

And, Collins noted, "I think that we are all, regardless of our philosophical perspective, rather awed by what we are seeing."

A host of related articles on the ENCODE project were also published Wednesday in the June issue ofGenome Research.

More information

For more on the human genome, visit the U.S. National Human Genome Research Institute.

SOURCES: June 13, 2007, news conference,Nature, including Francis Collins, M.D., Ph.D., director, U.S. National Human Genome Research Institute, Bethesda, Md., and Ewan Birney, Ph.D., head, genome annotation, European Molecular Biology Laboratory's European Bioinformatics Institute, Hinxton, England; Anindya Dutta, M.D., professor, biochemistry and molecular genetics, University of Virginia, Charlottesville

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