David Altshuler
David Altshuler explains his latest research in front of a robot used for rapid detection of DNA differences in human population samples, in his lab at the Whitehead Center. (Staff photo Jon Chase)

A new discovery could make it much easier to find each person’s genetic risk of getting cancer, heart disease, Alzheimer’s, and other common diseases.

In the last few years, researchers have found more than 2.6 million common variations in human genes, and they believe there may be as many as 10 million such alterations. The key challenge is to sort through all these variations and determine which ones influence the rates of disease. That requires searching among 30,000 or so human genes, which contain a total of 3 billion elements or “letters,” to find variations that each consist of only a single letter. It’s like finding a noodle in a haystack.

Now a group of scientists in Boston has found that these variations, rather than being randomly scattered among individuals, occur in only three to five different patterns. These patterns include all the thousands of possible combinations of variants that exist in any frequency in the entire population of Earth, about 6 billion people. These blocks of variations, known as haplotypes, comprise copies of genes passed without significant change from the first ancestors of the human race.

“Our study is the first to broadly sample the entire genome and to compare the haplotype patterns across populations from Africa, Asia, and Europe,” says David Altshuler, assistant professor of genetics and of medicine at Harvard Medical School and Massachusetts General Hospital. “Once the whole genome is characterized in terms of haplotypes, the amount of work required to map diseases should be decreased by 20- to 50-fold. This should greatly accelerate the search for disease genes.”

“Because [the variations] travel together in large blocks, researchers won’t have to search through every single [variation] in an area of the genome to try to localize the disease gene. Instead, researchers could simply look at a handful of key [variations] that mark a haplotype and track the inheritance of tens or hundreds of other neighboring [variations],” explains Stacey Gabriel of the Whitehead/MIT Center of Genome Research, in Cambridge, Mass.


Genetic Cliff’s Notes

Take any two people at random: you and Martha Stewart or Osama bin Laden. Your genome, their genome, and the genomes of every one else on the planet are 99.9 percent identical; that is, they share the same letters that spell out the basic blueprint of human biology. It’s the other 0.1 percent that accounts for all the diversity in characteristics and personality in the world.

Most of the 0.1 percent plays no role in our fundamental biology, but a few of these variations influence susceptibility to disease. Rare, single mutations, misspellings of the biological code, underlie maladies such as Huntington’s disease, muscular dystrophy, or certain types of breast cancer. Many of these have been identified over the past 20 years. But variants that raise the risk for common ailments like cancer, heart disease, and diabetes remain elusive.

Said another way, our genomes run 3 billion letters long. An estimated 10 million of those letters are candidates for spelling out your, and any other individual’s, risk for disease. Haplotypes are the Cliff’s Notes that make it easy to find these typos in the genome.

Last year, without the help of such Cliff’s Notes, Mark Daly, a fellow at the Whitehead Institute, was searching a particular region of 250,000 letters, looking for genes involved in Crohn’s disease, also known as inflammatory bowel disease. Crohn’s occurs as a result of several mutations, unlike the single gene mutations of Huntington’s or muscular dystrophy.

Daly was startled to find that the variations in the gene region he studied were tightly correlated, with only a few patterns explaining variations in all the people he examined. One of these common patterns increases the risk of Crohn’s disease by two- to six-fold in the general population.

“That was really striking,” Altshuler comments. “Although he was studying the genes of people 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 part of the genome that had been inherited from a single distant ancestor.”

About the same time, Altshuler, Harvard Medical School Assistant Professor Joel Hirschhorn, and their colleagues took a look at genes thought to be associated with Type 2 diabetes. They found that a common single-letter variation in a gene with the awkward name PPAR-gamma increases the risk of diabetes by 30 percent. The variant is carried by 85 percent of the general public.

Other researchers have found the same type of correlation between common genetic typos and Alzheimer’s, deep vein clots, and protection against the AIDS virus. This evidence leads to the conclusion that common diseases may be caused by genetic variants that are themselves common.


Hap-Map gap

The work, however, leaves major questions unanswered. Do correlations like those found by Daly hold only for different groups of Caucasians, or do they occur in the same patterns in the entire population of the world? Are the simple haplotype patterns limited to one region or are they general across the whole human genome?

To answer, Altshuler’s team took 50 random samples of genome regions and studied them closely in 275 people from Europe, Africa and Asia The results were positive, strongly confirming that the book of life, that is the human genome, can be parsed into haplotype chapters, and that reading these chapters will drastically reduce the work of finding which variants are involved in common diseases.

Within haplotype blocks , variations have been passed from generation to generation for tens of thousands of years without significant shuffling. Among Africans, each chapter runs about 11,000 letters long. European and Asian chapters comprise about 22,000 letters. Researchers don’t yet know why there is a difference. But in all cases, haplotype blocks occur in no less than three or more than five patterns.

Gabriel, Daly, Altshuler and colleagues who come from several different institutions worldwide published details of their discovery in the June 21 issue of the journal Science.

But even before publication, the results helped spark an international project to map haplotype blocks, a “Hap-Map” that identifies the different regions of the genome that can be tested for association with the world’s most common diseases. Many of the people who worked on, and are still working on, sequencing the entire human genome will almost certainly participate. “The U.S. government has allocated $32 million for the map project, and funds have been committed by the governments of Canada, China, England, Japan, and Singapore,” according to Altshuler.

“I’m not suggesting that the Hap-Map will be the answer to everyone’s problems,” Altshuler cautions. “But I’m optimistic that it will play a substantial role in identifying the genes underlying diseases, in aiding the prevention of diseases that are preventable and in the development of new treatments for those that are not.”

If successful, identification of common disease genes would find its first use as a screen to detect disease s before they produce pain and other symptoms. Such screening might prolong the lives of people like baseball pitcher Darryl Kile who died last month at age 33 from clogged coronary arteries. Kile’s father died from a heart attack at age 40. Hundreds of thousands of families worldwide have a high risk of death and disability from heart disease, but the specific genetic variations responsible for these risks have yet to be found. By defining their susceptibility early and starting them on aggressive preventive treatment, many people may gain years of more comfortable, productive life.

Haplotype screening also promises to reduce the risk and expense of drugs and diagnostic tests that might not be needed. President George W. Bush underwent a colonoscopy last month to check for precancerous polyps in his colon. It’s an important preventive procedure recommended for all adults more than 50 years of age, but colonoscopy is uncomfortable, expensive, and not free of risk. Susceptibility to colon cancer is highly influenced by inheritance, so gene-based tests might help to reduce the number or frequency of such procedures.

Altshuler makes no such specific claims for the Hap-Map, but he has high hopes that this research will make a positive impact on the treatment of the most common diseases. “The idea that science can change the world in a positive manner started me down this path 16 years ago,” he says. “It took a while for me to find how I might best be able to contribute. Now, I wake up every morning and thank God that I am part of this exciting effort.”