HARVARD GAZETTE ARCHIVES

David Altshuler, a member of the Broad Institute and associate professor of genetics at Harvard Medical School and Massachusetts General Hospital, is among the scientists who have just published the HapMap, the largest catalog of common disease-related genetic changes ever assembled. (Staff photos Jon Chase/Harvard News Office)

The genes that everyone inherits contain coded information that influences which diseases any individual is most at risk of getting. Countless studies show that small variations in genes play a major role in a host of common maladies that produce untold suffering and premature death. However, progress in tying these variations to specific maladies has been slow.

On Oct. 26, the Broad Institute of Harvard and Massachusetts Institute of Technology (MIT) announced publication of the largest catalog of common disease-related genetic changes ever assembled. It was prepared by an international group of 200 researchers from Canada, China, Japan, Nigeria, the United Kingdom, and the United States.

The catalog "is a powerful new tool for exploring the root causes of common diseases," says David Altshuler, a member of the Broad Institute and associate professor of genetics at Harvard Medical School and Massachusetts General Hospital. "Such understanding is required for us to develop new and much needed approaches to prevent, diagnose, and treat many diseases."

Previous studies show that any two unrelated people possess sets of about 25,000 genes that are 99.9 percent identical at the most basic level. In other words, your genes are roughly the same as those of Osama bin Laden, Martha Stewart, and Michael Jackson. Only 0.1 percent of the variable units in human genes account for all the inherited diversity in our looks, bodies, and behaviors.

But that 0.1 percent includes some 10 million small changes that make it more or less likely that any person will get one or more of the common diseases. They could explain why one person gets bipolar depression and others do not, why one medication successfully treats high blood pressure in one person but produces devastating side effects in another.

David Altshuler (left), Mark Daly, and Stacy Gabriel discuss a HapMap section that shows patterns of genetic changes for common ailments that are the same in unrelated people worldwide.

Happiness is a HapMap

Finding those 10 million "dings" in the code of life would not be possible were it not for the recently completed human genome project, which mapped out the sequence of DNA, the stuff of which genes are made. That sequence contains 3 billion units. Think of them as the letters that spell out the plan of your life. The 10 million variants involve misspellings that increase your risks of common diseases.

To find which variations are associated with which diseases, researchers would have to examine the full 3 billion-lettered genomes of a large number of people with, say, type 2 diabetes, and then see how their genes differ from those without that ailment. High costs and the limits of technology make this approach impractical, especially because common diseases stem from variations in not just one but many genes. (Only rarer diseases, such as Huntington's disease, multiple dystrophy, and cystic fibrosis, arise from mutations of only one or a pair of genes.)

However, just when all was looking bleak, one of Altshuler's colleagues, Mark Daly, made a terrific discovery. He found that human gene variations are not scattered all over the genome map but are clustered in blocks. Find one variation and it serves as a tag to identify a whole series of misspellings associated with a disease. (See http://www.news.harvard.edu/gazette/2002/07.18/01-gene.html)

"That was really striking," Altshuler said at the time. "Although [Daly] was studying the genes of people [with inflammatory bowel disease] from different families, the same specific region was seen over and over. It was like finding a whole city of unrelated people in which the disease could be traced to a single variant in their genomes."

These local gene neighborhoods are inherited as intact blocks of variations known as haplotypes. This discovery helped launch a three-year, $138 million international effort to map the patterns of human disease called, appropriately enough, the HapMap Consortium. (See http://www.news.harvard.edu/gazette/2005/10.27/01-hapmap.html)

The scientists checked genetic variants in 269 volunteers from different races, 90 from the United States, 90 from Nigeria, and 89 from China and Japan. They found more than 1 million changes, grouped into haplotypes that have been passed down through families for tens of thousands of years. They appear in the first edition of the HapMap, now available to all researchers and published in the Oct. 27 issue of the science journal Nature.

In the same issue, two researchers from Duke University note that it took them two years to find a haplotype that is the target of a drug used to treat epilepsy. "Today," they write, "the same job can be accomplished in minutes using the HapMap data."

Impact on evolution

The happy mappers already are nearing completion of a second edition of the HapMap, which they say will catalog nearly three times more variants. Meanwhile, around the world, researchers are applying the data that are now available to a large range of common diseases. Broad (pronounced "brode") Institute scientists are organizing investigations of diabetes, cancer, and mental illnesses. One of them will focus on bipolar disorder, a problem that used to be called manic depression. Another will attempt to identify which genes raise the risk of diabetes.

In Britain, the Wellcome Trust plans to use the HapMap to explore high blood pressure, heart disease, rheumatic arthritis, and other problems. A Japanese research team has announced that it will use the data to study no fewer than 47 diseases.

Another type of investigation propelled forward by HapMap involves identification of genes important to our evolution. "When a genetic change or mutation improves the fitness of those who inherit it, a record is left in the DNA," Altshuler explains. "HapMap makes it possible to search for such records, and to see which genes matter in the evolution of our species." To date, researchers have identified 14 places in our genome that show evidence of having changed under pressure of natural selection.

Altshuler highlights two of them. One explains our ability to drink milk and eat dairy foods into adulthood, foods that all other mammals become unable to digest after weaning. Another gene change, seen mainly in Africans, provides protection against malaria, albeit at the cost of a high risk of sickle-cell anemia.

Although elated at the results so far, HapMap teams agree that much additional work must be done to expand and confirm their findings. Nevertheless, they agree with Altshuler that a new era has begun in which scientists will unveil important factors in human evolution and find new ways to diagnose, treat, and prevent human disease.