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Surprising variations discovered in human genomes

5 min read

Unexpected DNA losses and gains found

Charles Lee and John
Standing on a spiral staircase inspired by the helical structure of DNA, Charles Lee (right) and John Iafrate discuss the surprising gaps they found in the human genome. The gaps may explain some of the differences in human nature, as well as to identify people who are prone to certain diseases, including cancer. (Staff photo Stephanie Mitchell/Harvard News Office)

Contrary to expectations, a startling number of large variations have been found in the human genome. The genetic blueprints for humans were thought to be 99.9 percent similar, but researchers at Harvard Medical School and the University of Toronto in Canada have accidentally discovered large chunks of missing or added DNA in normal, healthy people.

“We were extraordinarily surprised to see that some people have so much more or less DNA,” says Charles Lee, a geneticist and assistant professor at Harvard. “We’re very excited about this. It could explain differences in human nature, and help us to identify people who are more prone to certain diseases.”

Working at Brigham and Women’s Hospital in Boston, Lee and his colleagues were comparing genomes of a group of unrelated people. The idea is to establish a template with which to compare the genomes of patients. Any differences found in patients might be related to specific diseases.

“We expected to see flat lines when we matched the genomes of healthy people, denoting a lack of difference at various regions throughout the human genome,” Lee recalls. “But we kept seeing blips. At first, we thought this was simply static in our equipment. But the same blips kept showing up in different people.”

About this time, Lee was invited to give a talk at the University of Toronto. In the talk, he didn’t mention what he’d found because he was not sure what it meant. But the variations came up during a conversation with Stephen Scherer and his colleagues at The Hospital for Sick Children in Toronto. They admitted that they were seeing similar blips.

The two groups decided to collaborate by pooling the blip data they had on different sets of patients. “It turned out to be a very fruitful collaboration,” Lee comments. “It is helping us to understand a new aspect of the human genome that was not appreciated before.”

Health effects

The researchers looked at 55 healthy, unrelated individuals and found an amazing total of 255 regions with relatively large gains or losses in their DNA. Our genomes boast some 3 billion units, or base pairs, and these deletions and additions each consist of tens to hundreds of thousands of base pairs. Every person checked has an average of more than 12 such regions.

Some experts speculate that these variations could be responsible for differences in intelligence, behavior, and predisposition to certain diseases.

Lee is not ready to go that far, but he notes that half of the regions of variation are associated with genes. (The 3 billion base pairs comprise an estimated 32,000 genes.) The differences in DNA could affect the activity of their associated genes in ways that impact both human nature and health.

For example, a common variation overlaps genes that involve a protein secreted by the pancreas to aid digestion. If one person had 24 copies of this gene and another had 10, it might mean that, at age 60 or 70 years, the first person would be more prone to pancreatic cancer than the second.

There are other overlaps of these variations with genes “currently associated with known diseases,” points out John Iafrate, a Harvard pathologist and principal participant in the study. No details of how a glut or scarcity of DNA might alter their functions are available yet, but genes do play a major role in who we are and how we react to our environment. “It’s just too early to tell,” says Lee. “More research is required to better understand how to use this information to improve human health,” Iafrate adds.

Opening a treasure chest

Lee compares the discovery to opening up a treasure chest containing precious jewels of new information. “After the initial shock of opening the box,” he says, “we have begun to look at each item carefully.”

One interesting bauble is the fact that 13 of the variable regions occur within gaps in the genome. Because of all the publicity about mapping the human genome, many people believe that the complete sequence of 3 billion base pairs is known. That’s not so. The precise number of human genes is not even known. There’s no telling what will be found in the gaps.

To share their treasure, the Harvard-Toronto collaboration makes the details of their discovery available to the public in the Genome Variation Database ( A scientific report on the findings also appears in the September issue of Nature Genetics.

“We resisted the temptation to hold onto the data and use it for our own research,” Lee says. “We decided it needs to be available to all and continually updated so that researchers around the world can benefit from it and build on it. Mysteries will be solved faster with more people working on them.”

For instance, researchers all over the world are tying to map the genes of the lowly zebrafish, who develops a blood system and tumors in ways similar to humans. Lee noted that his laboratory is developing tools for studying the zerbrafish that are similar to those he uses for the human genome. He hopes the increased understanding of the dynamics of the human genome will uncover zerbrafish aberrations that are related to human diseases.

“The discovery that the human genome is more dynamic than we thought should have a wide ripple effect on medical diagnoses and outcomes,” Lee believes. It may also help scientists to better understand the nature of humanity.