Building on that success, Eichler's group has begun examining the connection between structural variation and a range of more common diseases. "The million dollar question is: What is the genetic basis of diseases like diabetes, hypertension, and high cholesterol levels?" he says. "We know there is a genetic factor, but what is the role of single base pair changes versus structural changes?"

To answer that question, Eichler and a group of colleagues known as the Human Genome Structural Variation Working Group have decided to get a better fix on where the structural variation in our genome occurs. The freezer in the basement of Eichler's laboratory containing the DNA of G248 is one of 62 freezers scattered around the United States, each containing the DNA of a single individual. The working group will compare each donor's DNA with the reference sequence from the Human Genome Project, looking for locations where the DNA doesn't line up. Wherever they find a discrepancy, they'll sequence the DNA to identify the differences.

Understanding human disease is the main objective, but Eichler wants to know something else. Why did variable regions of our genome evolve, and what purpose do they serve?

Eichler's hypothesis is that structural variation is a way for our genomes to remain fluid and adaptable. As our ancestors encountered new environments and new circumstances, continual rearrangement of their DNA would have generated lots of evolutionary experiments. In fact, initial comparisons have shown that humans and other primates have much more structural variation than do other mammals. Eichler speculates that the unique abilities of primates—our elaborate social structures and communication abilities—may be related to the amount of structural variation in our genomes. "Maybe the cost of having these new abilities is the possibility of disease caused by genes that allow us to adapt to the right environments at the right time," he says.

The discovery of structural variation has shattered the image of the human genome as an inert and largely stable object. Instead, there are as many human genomes as there are humans, and each unique assemblage of DNA has its own strengths and weaknesses. "My wife and I had a baby just two months ago, and I joke with her that it's amazing that any of us ever comes out normal, knowing what we know now," Eichler says. "But I think the right answer is that none of us is normal. And that's an enlightening feeling, to realize that no one has the perfect genome."

		To be completely accurate, the Human Genome Project should have been called the "Half-of-a-Composite-Human Genome Project" because the DNA sequenced came from a single set of chromosomes drawn from several donors. Our cells contain two copies of every chromosome, with one copy coming from our mothers and one from our fathers. Therefore, the structural variation carried in our parents' chromosomes is passed down to us—making for a lot of variation in our own cells. Recently, a team of researchers that included J. Craig Venter and Stephen Scherer compared the chromosome pairs in Venter's DNA. They found much more structural variation between his chromosomes than most geneticists expected. Forty-four percent of the genes on Venter's chromosomes differ from the corresponding genes on the other member of the chromosome pair. And three-fourths of the total variable DNA content between chromosome pairs arises from structural variants, with one-fourth coming from changes in individual DNA letters. —S.O.

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