The HapMap provokes such excitement in the medical community largely because the hunt for disease-causing genes has hit a stone wall. Despite successes in finding the genetic culprits for some rare and deadly disorders, such as cystic fibrosis and Huntington’s disease, which are caused by lone genes, researchers have had a difficult time finding the genes behind common diseases, like schizophrenia, diabetes, hypertension, and alcoholism. Geneticists suspect that some combination of dozens or even hundreds of genes contributes to each of these disorders. Tracking down a single rogue gene is already like hunting for a needle in a haystack. But understanding how patterns of variations among individuals and populations correlate with common diseases is “fantastically more complex,” says College of London’s Goldstein.
The discovery of the haplotype blocks gives medical researchers a useful way to navigate this mind-boggling complexity. The evidence, says Daly, suggests that, in fact, most of the human genome consists of these blocks, which vary from 10,000 to around 50,000 letters in length. It is a structure that neatly organizes the three billion letters in the genome and one that “doesn’t necessarily have to be the way it is,” says Daly.
Those pushing the HapMap believe the orderly, blocklike structure of the genome is more a reflection of history than of any biological function. They suspect that most variations in single DNA letters date back many tens of thousands of years and have been inherited intact generation after generation, along with neighboring stretches of DNA. This explains why only a few common versions of each block are likely to be found, since humans share a limited set of ancestors. It also suggests that comparing the patterns of genetic variation found in different parts of the world can provide a remarkable history of human migration over those tens of thousand of years.
Not all geneticists, however, buy it. Some argue that much of the science behind the haplotype project remains speculative. Numerous questions still swirl around the blocklike structure, maintains Kenneth Kidd, a geneticist at Yale University School of Medicine in New Haven, CT. Doubts remain about how to define the boundaries and, even, how widespread the blocks are throughout the genome, says Kidd. What’s more, he contends, the HapMap’s premise that there are consistent patterns of genetic variation around the world is likely wrong and that there will be “tremendous” differences. “There are likely to be few universal blocks,” he says. The haplotype map, he adds, “is being touted as great for all populations, but I don’t think it will be.”
There are also doubts about whether the HapMap is even looking for the right genetic culprits. William Thilly, an MIT geneticist, says that for numerous conditions known to be caused by mutations in a single gene, there are dozens to hundreds of different mutations in that gene that have been found to cause the same disease. Thilly argues that genetic risks for common diseases are caused by a “spectrum” of relatively rare mutations scattered over unknown genes throughout the genome. He points out that many common diseases afflict diverse populations that display markedly different haplotypes. In other words, the HapMap’s effort to detail common patterns in genetic differences and link those differences to diseases is largely a wild-goose chase.