Sacramento Bee, March 19, 2001

Much DNA just "junk" -- or is it?
Human Genome Project spurs new look at mystery material

by Edie Lau, Bee Science Writer

In his most telling experiment, Carl Schmid put 18 mice in a "hot tub" for about a half-hour to induce a feverish stress.

Afterward, the scientist analyzed the animals' genetic material to see how it reacted to the 108-degree heat. One particular segment, he found, increased in volume 40 times.

Did Schmid discover a gene for stress? One might think so, except the piece of genetic material that ballooned is not technically a gene. In fact, it's a segment that historically has been categorized in biology as "junk DNA."

Schmid has long been fascinated by the so-called junk, which makes him a rarity among molecular biologists. But now that a draft of the human genome is completed, scientists realize that more than 90 percent of the genome is not genes but the "junk." And on closer inspection, the junk sequences look like they might tell much more about human evolution and biology than previously thought.

"It certainly says that before we dismiss any part of human DNA as uninteresting, we ought to take a close look at it," said Eric Lander, lead scientist in the government-sponsored Human Genome Project. "It is, after all, a product of 3 billion years of evolution. It may be just a little bit flip for us to decide that there's nothing we can learn from things that evolution produced in 3 billion years of handiwork."

In the past, molecular biologists have been interested primarily in genes -- tidy sequences of DNA that give instructions to the body to make proteins or construct cell machinery. Proteins are the workhorses of the cells, the molecules that conduct the business of life.

The junk sequences don't instruct the body to make proteins, and they have no proven function. But just because no one knows of a function, does that necessarily mean none exists?

"That's the issue," said Schmid, who teaches at the University of California, Davis. "We know there's a lot of DNA that we don't know its function. The fact that we don't know its function doesn't mean it doesn't have a function."

DNA consists of strings of four chemicals known as nucleotides or bases, represented by the letters A,T,C and G. The nucleotides come in twos -- always A's with T's and C's with G's -- which are called base pairs. The human genome consists of 3.2 billion base pairs.

The junk comes in several varieties, the most common of which are repetitive segments. There are short repetitive segments, such as the pieces that Schmid studies, consisting of 272 base pairs; and there are long repetitive segments of 6,000 base pairs. Both segments pop up repeatedly in human DNA, collectively accounting for 20 percent of the entire genome, Schmid said.

Just to complicate things, the repetitive segments aren't completely identical. Schmid said the short ones he studies -- named, inscrutably, "ALU repeats" -- are about 20 percent different from one another. But that's close enough that they're considered the same thing.

The idea that the junk may not be junky hearkens back to the early days of molecular biology. The prevailing view once was that all DNA was useful to the body. Then, two different teams of scientists published commentaries in the journal Nature in 1980 suggesting that some DNA is "selfish" -- that it exists simply for the sake of existing.

Francis Crick, who co-discovered the structure of DNA, and Leslie Orgel, researchers at the Salk Institute for Biological Studies in La Jolla, wrote:

"We & have to account for the vast amount of DNA found in certain species, such as lilies and salamanders, which may amount to as much as 20 times that found in the human genome. It seems totally implausible that the number of radically different genes needed in a salamander is 20 times that in a man. & The conviction has been growing that much of this extra DNA is 'junk.' "

W. Ford Doolittle and Carmen Sapienza of Dalhousie University in Halifax, Nova Scotia, argued that DNA evolved to copy and insert itself randomly throughout the genome, and that its "only function is self-preservation."

The men who popularized the notion of junk DNA believe in it yet. "There are people who still believe that most of the DNA is useful," Orgel said. "I say, 'Fine, go find what it does, and we'll call it something else, but I think you're wasting your time.' "

Doolittle looks upon the repetitive DNA as cellular bureaucracy -- fat and comfortable molecules that hinder efficiency. "If you looked at the bureaucracy of the City of Sacramento," he said by way of analogy, "there are things that are dysfunctional, that are stuck, but they're there. & But they really aren't functional."

Schmid at UC Davis said there may well be junk in our DNA, but he believes the sequence he's studying isn't part of it.

His experiments intriguingly suggest that the "ALU repeats" serve some sort of role helping genes deal with stress. That's because the ALU DNA is converted into RNA -- a working copy of DNA -- when Schmid subjects cells, whether cultured in petri dishes or in live mice, to stress.

If DNA is a library full of instructions, RNA is a carbon copy of those instructions that is read and obeyed by the cell. RNA is DNA in action.

In other words, Schmid's experiments suggest that when the cells are stressed, the ALU springs into action. The question is: What is the action? That's what Schmid is trying to answer.

Other junk sequences are likewise intriguing, said Lander, director of the Center for Genome Research at the Whitehead Institute in Cambridge, Mass.

For example, the body seems to have crafted 50 genes out of junk sequences known as transposons, so named because they are transposable, moving around the genome like text copied and duplicated in a computer file.

It turns out that two of those genes are important to the immune system, Lander said. The transposable sequences probably landed willy-nilly within existing genes, which then evolved into genes that generated antibodies.

The junk sequences also reflect the DNA of bacteria and other organisms that long ago melded with the human genome.

Summing up the work of the Human Genome Project, Lander wrote in a paper published in Nature last month, "It has not escaped our notice that the more we learn about the human genome, the more there is to explore."

That line, he said, applies as much to the junk as to the genes.

Copyright 2001 Sacramento Bee. All rights reserved. International copyright secured. Filel Date: 3.26.01