Geneticists map what makes us different

An international team of scientists announced yesterday that it has completed an ambitious map of all the common variations in the human genetic code, an advance that could accelerate the search for the genes behind a wide range of diseases.

The three-year, $138 million project scanned the DNA of 269 volunteers on three continents and found deep patterns in the seemingly random genetic variations that make one person different from another. Human DNA, they found, comes in distinct blocks, each of which can be identified by looking at only a few locations, the way a person might be able to identify a familiar quilt by examining just a handful of its cloth panels. This will greatly reduce the number of the 3 billion units of human DNA that must be checked, and allow scientists to find elusive genetic variations that cause disease.

This advance, announced yesterday by a consortium called the International HapMap Project, marks a major milestone in the quest to understand human afflictions and why people respond differently to drugs. It may also lead to new insights about human evolution, historic migrations of populations, and race.

Genetics is a powerful tool that enables biologists to study the root causes of disease, but most of the disease genes found so far are single genes linked to rare diseases. The new map should make it possible to find groups of genes that are believed to be involved in many common diseases -- genes that individually play a more subtle role and are thus harder to identify.

''This is a profound step forward," said Secretary of Health and Human Services Michael O. Leavitt, speaking at a news conference in Salt Lake City, during a meeting of the American Society of Human Genetics.

The HapMap, which is described in today's issue of the journal Nature, is a follow-up to the Human Genome Project, and an attempt to make it more useful for medical research. The Human Genome Project is a catalogue of the DNA all people share, while the new project is a map of just the DNA segments that make each person different.

Scientists cautioned that the utility of the new map would not be clear until it was widely applied, because the map catalogues common variations, and it is not known how important a role these play in diseases. And even where the map succeeds in tying genes to disease, it could still take years or even decades to find new treatments, said Dr. David Altshuler, one of the leaders of the project and a scientist at the Massachusetts General Hospital.

But the work has generated tremendous excitement, and institutions around the world have begun ambitious studies of a wide variety of diseases using rough drafts of the HapMap. The British charity the Wellcome Trust recently announced that it will use the HapMap to tackle eight diseases, including coronary heart disease, hypertension, and rheumatoid arthritis. In Japan, another team has said it will study up to 47 diseases. In the Boston area, a center of the new research, the Broad Institute of Harvard and MIT is organizing studies, with thousands of volunteers, to investigate diabetes and cancer, as well as psychiatric and other illnesses, according to Altshuler, who directs the Broad's program in medical and population genetics.

One of the first efforts underway at the Broad is a multimillion dollar investigation of bipolar disorder, a disease that causes patients to cycle unpredictably between periods of depression, manic behavior, and relative normalcy. More than 2 million Americans suffer from the illness, according to government statistics, and studies show it has genetic causes. There are treatments that can help, but there is no cure.

Francesca Dodd, 67, is still haunted by the memories of her mother, who had bipolar disorder at a time when even less could be done to help. Dodd said her mother suffered debilitating depressions and once fell into a catatonic state while Francesca's baby brother was breastfeeding. At other times, Dodd said, her mother would fly into manic furies that could last for weeks -- picking fights, belittling friends and strangers, wailing about germs and dark plots around her.

Dodd has been diagnosed with bipolar disorder, too, and her DNA will be used in the Broad study. ''I hope it will help the next generation," she said.

Bipolar disorder is like many of the diseases that researchers want to study using the HapMap: They tend to run in families, but scientists have not been able to find the genes involved because their tools have not been sensitive enough.

The HapMap is an attempt to tackle this problem. In the nucleus of every human cell is a long strand of DNA, made up of some 3 billion units. Each unit is one of four types of molecule -- labeled by scientists with the letter A, T, G, or C. The 3 billion units are known collectively as the genome.

Each person differs from someone else by, on average, 3 million of these units, but every time two people are compared, it is a different set of 3 million. To find all those differences, scientists had feared they would need to determine the full genome, all 3 billion units, of every volunteer in a study, which would be too expensive using current technology.

But then researchers began to notice consistent patterns in the DNA of different individuals that suggested a shortcut, said Mark Daly, a scientist at Mass. General and the Broad who was one of the first to discover the patterns. They found that DNA can be thought of as a series of sections, called ''haplotype blocks." Each block comes in only a handful of variations, and each person has just one of the variations. (Each of these variations is known as a haplotype, which is why the map is known as the HapMap.)

To determine which block a person has, researchers have only to look at one spot where the block varieties are different, giving them a ''tag" that identifies the block. The HapMap project, which was funded by an international consortium that includes the US government, has located some 3.8 million of these tags, the scientists said. The volunteers in the study came from the United States, Nigeria, China, and Japan.

To study a disease such as bipolar disorder, researchers need the DNA from large numbers of volunteers with the disease, said Dr. Pamela Sklar, who is leading the Broad study of bipolar disorder along with Dr. Jordan Smoller, both of whom are scientists at Mass. General. The researchers will check the DNA of the patients at tag locations identified in the HapMap, and see if any of the tags appear more or less often than in the general population. If a pattern emerges and is confirmed, the team will look more closely to see what genes are located near the tags, Sklar said. The same type of study could be done to see whether there are genetic reasons why some people respond well to certain medications and others do not.

All of this, in turn, could provide clues to the biological origins of bipolar disorder, which today is an utter mystery.

''We don't even know what parts of the brain are involved," said Sklar.

This ignorance makes it difficult to look for cures, or to treat patients at all. The lack of a definitive medical test for bipolar disorder has added to the difficulty Dodd has had in accepting her diagnosis. Bipolar patients know when they are depressed, but they typically have trouble recognizing their own manic behavior and often resist treatment, according to Dr. Gary Sachs, who is Dodd's psychiatrist and is also a Mass. General scientist leading a large, government funded study of bipolar disorder that collected the patient DNA that will be used by Sklar.

Dodd said that she is not sure whether she has had a manic episode. But she does remember times when she has felt euphoria and superhuman confidence, typical symptoms of mania. And Dodd tells of intense shopping trips for used books, old clocks, and other memorabilia in which she regaled sales people with her life story.

Sklar said that it is the patients who motivate her, even though she does not know what the research will reveal.

''How could we not do this study?" she said.

Gareth Cook can be reached at cook@globe.com.