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Large-Scale Differences Discovered in DNA of Healthy People

By Kate Ruder

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Human Genome

Ever since the human genome was sequenced in 2001, scientists interested in medicine have focused on small, sometimes single letter differences in people’s DNA.

Now, seemingly all of a sudden, two groups of scientists working independently have discovered that healthy people have huge chunks of DNA that are repeated over and over, for no known reason, and also huge chunks of DNA that are missing, also for no known reason.

These research shows that there are places where a whole chapter has been duplicated or deleted. --David Altshuler
“If the human genome is a book, then most genetic methods have focused on variations that swap a single letter in the book for an alternative,” says David Altshuler of the Broad Institute in Cambridge, Massachusetts.

“This research shows that there are places where a whole chapter has been duplicated or deleted,” he says.

The chunks of DNA are hundreds of thousands of letters of genetic code long, and they contain genes, meaning that some people have more copies of a gene than others. The researchers speculate that these extra or missing copies of genes could affect susceptibility to disease.

To do one study, researchers from Harvard and University of Toronto, Canada, teamed up. Charles Lee of Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts, was using DNA microarrays to analyze DNA of patients with developmental disorders.

But then something peculiar happened. When Lee looked at DNA from healthy people as a reference, he was astonished to discover that their genomes had chunks of DNA missing or chunks of DNA that were repeated over and over again.

“I was very surprised,” says Lee. “There were large gains and losses of DNA in the genomes of healthy individuals.”

Around the same time, Lee traveled to Canada to give a lecture at the University of Toronto, where he had coffee with Toronto scientist Stephen Scherer, who mentioned that he had been seeing odd, large-scale differences in the genomes of healthy people.

“We were seeing the same thing,” says Lee. “I figured I’d also better reveal our research findings so that we could benefit by combining our data,” which they later did.

On average, they found 12 chunks of DNA that were missing or repeated in the 39 healthy people included in the study. Their research is published online in the journal Nature Genetics.

In another study, Michael Wigler of Cold Spring Harbor Laboratory, New York, and his colleagues analyzed the genomes of 20 healthy people and identified, on average, 11 stretches of DNA that are either missing or repeated; these stretches were usually more than 400,000 letters of genetic code.

“I wasn’t surprised that there were these differences,” says Wigler. “We were surprised to see them in such numbers. And it was surprising how large they were.”

Wigler and his colleagues published their findings last month in the journal Science, and they are now working on a larger study that includes 300 people.

The stretches of DNA contained genes associated with leukemia, drug resistance in breast cancer, and even “normal” characteristics such as body weight and how much food you eat.

“Thus, a relationship between [these regions] and susceptibility to health problems such as neurological disease, cancer, and obesity is an intriguing possibility,” the authors write in their paper.

Both groups of researchers say that further work is needed to being to determine the effect of these differences on healthy people. And both groups say that their respective findings demonstrate a largely ignored source of variation in the human genome.

Scientists working on the International HapMap agree. The HapMap is a $120 million, international project to catalog genetic variation in the human population in order to identify genes that cause disease or susceptibility to drugs. The HapMap does not currently include the type of large-scale variation in the genome found by Lee, Scherer, and Wigler.

Both groups are eager to meet with Altshuler, a leader in the HapMap project, to talk about how their data could be integrated into the HapMap.

“The goal of the International HapMap Project is to create a resource to support genetic association studies in the human population,” says Altshuler. “In my opinion, given this important new knowledge, it is a no-brainer that data on large-scale variation should be collected on the same DNA samples being used for the HapMap Project.”

Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525-528 (July 23, 2004).
Iafrate, A.J. et al. Detection of large-scale variation in the human genome. Published online in Nature Genetics August 1, 2004.

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