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It Turns Out There is No Norm for DNA, Scientists Say

Posted on: Tuesday, 14 March 2006, 06:01 CST

PHILADELPHIA _ It was a nice idea that we're all genetically 99.9 percent identical, but new research says it's not so simple.

The old thinking held that coiled in our cells, we all carry the same instruction book with just a few alternative spellings. But upon closer scrutiny, it appears our DNA is full of long strings of genetic code that are copied sometimes hundreds of times, the number of copies varying wildly from person to person.

And each of us is apparently missing quite a few large chunks of DNA. Other large segments of genetic code are misplaced on their chromosomes or pasted in backward. Not that there's any one designated normal arrangement _ we're all just different.

As this all was becoming clear over the last several years, scientists expressed some surprise that the human genetic code is such a disorganized mess.

"This changes how we think about evolution and, in some respects, disease," says Evan Eichler, a researcher at the University of Washington, Seattle. "That's the part that's exciting."

This newfound variability may help explain not only differences that affect health, but how we and other living things have evolved. Scientists are coming across places in our chromosomes called genetic "hot spots," critical for evolution to continue reshaping the human race.

The first hints of large genetic differences surfaced as scientists completed the Human Genome Project _ an endeavor that created a reference genetic code based on DNA samples from five individuals of various ethnic backgrounds.

We all carry a genetic code that's about three billion characters long, written in the four different chemical building blocks of DNA _ adenine, thymine, cytosine and guanine, abbreviated A, T, C, and G. In the process of reading the code carried by their volunteers, scientists found some areas just couldn't be decoded in a linear way.

"The handwriting was on the wall that the genome was very dynamic," Eichler says. Several years ago, his lab decided to evaluate the accuracy of the genome project's results by comparing the genetic code of a single female volunteer with the "reference" sequence.

They found there were dozens of genes the woman appeared to be missing and others she carried in multiple copies. It's hard to explain how the scientists behind the genome project were able to keep creating this reference with so much inconsistency, says Michael Wigler, a researcher at Cold Spring Harbor Laboratory, on Long Island. It involved a certain amount of compromise, he says.

In 2004, Wigler and his colleagues compared the DNA for 20 healthy volunteers and found 500 genes that can appear in different numbers of copies _ a stretch of DNA that codes for a single protein.

"It did surprise us," he said. "The question is, what impact does this have?"

Some variations are not necessarily going to result in a health problem, he said, but might have subtle influences on risk of heart disease, diabetes, cancer or immune deficiencies.

Last year, scientists found that your odds of getting infected with HIV after an unprotected sexual encounter with someone who has the virus depend partly on how many copies you carry of a gene called CCL3L1.

That finding followed from an earlier discovery that a rare mutation in about 1 percent of Europeans creates profound resistance to HIV _ "like a genetic condom," says Sunil Ahuja of the University of Texas Health Science Center in San Antonio.

Ahuja and colleague Matthew Dolan started looking for more common genetic variants that influence relative HIV resistance, starting with those that control production of a protein called a chemokine. Chemokines offer protection by blocking the portals through which HIV enters the cells it infects.

The gene CCL3L1 orchestrated the production of a chemokine and showed up in varying numbers, some people carrying two copies, some 12 or more. In a group of more than 4,000 people of different HIV status, the scientists found those who carried an above-average number of copies of CCL3L1 were less likely to be infected.

At Cold Spring Harbor Laboratory, Jonathan Sebat is studying autistic children, looking for structural differences in their DNA. He suspects many autistic people carry new genetic changes that aren't carried by their parents, but spring up in the copying of DNA into egg or sperm cells.

Washington's Eichler is looking for similar factors underlying cases of mental retardation, many of which can't be connected to a known genetic or environmental cause.

Eichler also is studying the effect of this larger-scale DNA diversity on evolution by comparing human genetic material with that of the chimpanzee, our closest relative.

In some cases, chimps and humans shared a gene, but humans carried about four copies, chimps 500, he said. In the end, he found so many larger-scale structural differences that he estimates humans and chimps are around 4 percent genetically different, not 1.2 percent, as previously thought.

It turns out that big structural differences in DNA accumulate in certain zones _ rough spots in the genetic code, he said. These so-called evolutionary hot spots may underlie some of the more obvious physical and behavioral differences between us and our primate cousins. Natural selection needs variety, it needs new traits, and to get these, DNA has to be changeable, dynamic.

Eichler calls these variable parts "crucibles of evolution." Since the rise of anatomically modern humanity around 100,000 years ago, we have continued to evolve, especially in our abilities to deal with variable and changing environments. Descendants of those from malaria-prone places often carry genetic resistance in the form of a sickle-cell gene, for example, while those who descend from Northern European dairy farmers acquired enzymes needed to digest milk.

Science is quickly dismantling the false premise behind eugenics _ that there's one perfect human genetic code and that anything deviating from it represents a mistake or defect.

"Part of the strategy of success in humans is our ability to diversify rapidly," Wigler says. Faced with variable food sources and an ever-changing array of disease threats, he said, "you don't want to be a sitting target."

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(c) 2006, The Philadelphia Inquirer.

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