Scientists explore DNA variations to root out diseases

WASHINGTON — Your DNA has the hiccups. It stutters, gags, repeats itself and skips stuff like a nervous teenager giving a speech in school.

Scientists are studying the effects of these irregularities in the human genetic code. Some variations cause disease. Others can help identify criminals, trace ancestors and shed light on the course of evolution.

The human genome — the collection of genes strung along the long ribbon of DNA coiled inside each cell — is turning out to be a lot more complicated than researchers first thought.

It's not a straightforward chain of 3 billion chemical units — labeled A, C, G and T, the four letters of the genetic code — that scientists unveiled at a triumphant White House ceremony on April 14, 2003.

Instead, an individual's genome contains hundreds of segments — some tiny, some as long as 5 million letters — that have been duplicated, reversed, deleted or have switched locations.

Scientists say that these abnormalities, which differ from person to person, are part of what makes an individual, well, individual.

At least 10 percent of your DNA consists of these variations, resulting in a state of ``bewildering complexity,'' said Evan Eichler, a genome expert at the University of Washington in Seattle.

``The human genome is a mess,'' David Collier, a molecular geneticist in London wrote in the British Journal of Psychiatry. ``Not only is it full of apparently redundant, highly repetitive and unstable DNA sequences, but also as much as 5-10 percent of the genome is duplicated.''

For example, in a healthy person's DNA, a trio of letters may be repeated, like a stutter — CAG-CAG-CAG-CAG — up to 36 times without harm. But if CAG is repeated 40 or more times, as happens in some unfortunate people, the extra copies greatly increase the risk of Huntington's disease, an incurable degeneration of brain cells that leads a person to lose control of his body movements and mental facilities over time.

An international team of scientists based in Boston, Toronto and Cambridge, England, has begun a Copy Number Variation Project to create a comprehensive ``atlas'' of all these peculiarities. A preliminary version was published in the journal Nature last year. Work began this fall on a new listing that will be 100 times more detailed.

A ``whole new world has been opened up in genetic variation,'' one of the project's leaders, Charles Lee of Brigham and Women's Hospital in Boston, told Science magazine in September.

If scientists connect a specific CNV to a disease, that eventually could lead to a treatment or cure, they say.

The CNV consortium reported in Nature that it's identified 57 significant copy-number variations associated with lung cancer. Extra copies of certain genes also can produce too much of a protein that's linked to Alzheimer's disease.

Other rearrangements have been implicated in anthrax, the plague, Parkinson's, HIV, autism, Down's syndrome and more.

Diseases caused by duplication ``are more diverse and widespread than previously anticipated,'' Swiss geneticist Bernard Conrad reported in this year's Annual Review of Genomics and Human Genetics. Thousands more may remain to be discovered.

``We've barely scratched the surface,'' said Eric Lander, a leading genome researcher at the Massachusetts Institute of Technology in Cambridge, Mass.

Besides searching for the causes of disease, copy-number variations can be useful in other ways.

Matching copy numbers can be a sophisticated form of ``fingerprint'' to identify a criminal suspect or free a wrongly convicted person.

Many CNVs are inherited, so it's possible to identify a missing parent or child by matching DNA repeats.

Genetic variations also are responsible for the evolution of early humans as well as the more recent development of such characteristics as skin color, lactose tolerance and body hair.

Eichler's team has traced CNVs back 25 million years, before the ancestors of humans and apes diverged. Humans have many more duplications than apes do. Presumably, the extra genes were available to take on new functions, such as language and bipedal walking.

By comparing genomes, ``we are reconstructing 100 million years of human evolutionary history,'' said David Haussler, a biological engineer at the University of California-Santa Cruz.

``DNA contains the ultimate record of evolution,'' Sean Carroll, an evolutionary biologist at the University of Wisconsin in Madison, wrote in his recent book, ''The Making of the Fittest.''


Information on the CNV Project: