Researchers have long known that complex diseases such as cancer and heart disease have genetic components that heavily affect their onset, progression, and response to treatment. But because these conditions involve many different genes interacting with each other as well as with factors in a person’s environment, teasing out these elements has been difficult.
A newly completed map that plots where small genetic differences can exist among people may be a powerful tool for figuring out why some individuals get certain diseases and even for custom designing treatments.
Each person’s DNA is composed of enormous sequences of four building blocks that go by the letters A, T, G, and C. The vast majority of these sequences are the same in all people, but about 0.1 percent of these letters differ from person to person and can affect an individual’s risk of disease or response to drugs.
A common type of variation is a trade of one letter for another, known as a single-nucleotide polymorphism (SNP, pronounced “snip”). Scientists estimate that there are about 10 million locations for SNPs in the approximately 3 billion letters that make up the human genome.
Previous studies have shown that groups of SNPs on chromosomes tend to be inherited within clumps of 10,000 to 20,000 letters, known as haplotypes. Thus, says Peter Donnelly, of the University of Oxford in England, surveying just a small number of SNPs could tell researchers the sequence of many other letters that surround them. Comparing haplotypes in healthy and sick people could help researchers nail down which genes are associated with diseases.
“It’s as if you knew there were a group of five people who always took the same bus to work,” Donnelly explains. “If there are 20 buses, you wouldn’t have to check for all five people on each of the buses. All you’d have to ask is whether ‘Mary’ is on a particular bus because, if she is, then you’d know it’s very likely that the other four people would be there as well.”
Three years ago, several teams of scientists around the world, including one team led by Donnelly, began an effort to map the position of 1 million SNPs in the human genome and to identify haplotypes associated with them. To start their study, known as the International HapMap Project, the researchers extracted DNA from the blood of 296 volunteers from Nigeria, China, Japan, and the United States. Pilot studies had shown that these populations carry the majority of different haplotype variations found in people.
By systematically inspecting SNPs at about every 5,000-letter interval in the volunteers’ DNA, the researchers constructed a detailed map of places where variations typically occur along each of a person’s 46 chromosomes. The completed map is published in the Oct. 27 Nature, and all data from the project are publicly available online (http://www.hapmap.org/). Studies to survey the DNA of volunteers from other populations around the world for additional SNP sites are in the works.
With the newly completed HapMap, “the power of the modern genomic tool kit is breathtaking,” says David Goldstein of Duke University in Durham, N.C., in a commentary that accompanies the Nature article.
“In a few years, we have gone from knowing almost nothing that could be characterized as genomic … to having complete genome sequences for many organisms, and now a nearly complete catalog of the common genetic differences among people,” Goldstein says.
The next challenge for researchers will be to take HapMap’s raw data and translate it into novel, genome-based ways to fight disease.