An international team of scientists has published the first complete draft of a map of human genetic variability, known to scientists as the human haplotype map, or HapMap.
By providing researchers with a guide to locations within the human genome where variations in the genetic code occur in significant percentages of human populations, the HapMap pushes biomedical science a large step closer to the era when analysis of patient DNA will provide important guidance to diagnosis and treatment.
“Six years ago, when I first began doing this type of research, every bit of information that we had on common human genetic variations was a treasured resource,” said Raymond D. Miller, Ph.D., research assistant professor of genetics at the School of Medicine.
“That’s what led the organizers of the HapMap project to begin their work — they realized what a great boon a map of variation across the human genome could provide to medical research.”
The HapMap appeared in the Oct. 27 issue of the journal Nature.
Any two unrelated people will have DNA that is about 99.9 percent identical, according to the HapMap project’s home page hapmap.org. However, the remaining 0.1 percent of DNA that differs from person to person — about 15 million of the 15 billion base pairs in human DNA — can make crucial differences in disease risk and the way a person responds to medication.
Miller’s lab was one of four in the United States that contributed to the genotyping work done for the HapMap. Genotyping involved identifying subgroups within larger populations on the basis of shared genetic variations — a “C” instead of an “A” at a given position within their DNA, for example.
Such a one-character change is known as a single nucleotide polymorphism, or SNP. Although the genetic code has four units, such changes generally tend to come in two forms — one group might always have “A” at the given position, while another group always has “C.”
SNPs tend to occur in clusters in a given region of the genetic code. These clusters, known as haplotypes, often get passed from parent to child.
Part of the analytical work of the HapMap project involved identifying “tag” SNPs that could be used to quickly identify the presence of a particular haplotype without analyzing the entire region of DNA.
To make sure their map focused on variations with significant potential to affect human health, the researchers only included SNPs where the less-common form is found in at least 5 percent of the population. Because the frequency of different haplotypes varies in different ethnic groups, scientists analyzed DNA from several different ethnic groups.
“As phase I of the project, we’ve typed about a million such SNPs in samples from each of four groups — Yoruba from Ibadan, Nigeria, Han Chinese from Beijing, Utah residents of northern and western European origins and Japanese from Tokyo,” Miller said.
“As phase II of the project, genotypes from several million more SNPs from each of these groups have been placed in the public domain.”
The completed first draft of the HapMap should make it much more practical for researchers to look for areas in human DNA linked to complex disorders, which are conditions linked to variations in several genes and environmental factors. Such disorders include cancer, diabetes, heart disease and high blood pressure.
The HapMap will also provide valuable support to the new field of pharmacogenetics, which studies how genetic variations can dramatically alter a patient’s response to a medication. Armed with knowledge of these variations, physicians can avoid life-threatening reactions or alter treatment plans to increase the chances of a successful result.
For example, researchers at Washington University and the University of Washington recently determined that variations in a blood-clotting gene can significantly affect the best dosage levels for an anticoagulant drug given after strokes, heart attacks and major surgeries.
Washington University is also home of the first clinical pharmacogenetics trial in the United States, a study that chooses the treatment of colon cancer patients on the basis of genetic variations that affect patients’ responses to medication.
Over the course of the Hap-Map project, Miller’s lab and others worked to improve high-throughput technology that lets scientists quickly identify a person by their individual genotype. As Miller’s lab identified SNPs in the DNA samples, the scientists forwarded them on to a central database at the Cold Spring Harbor Laboratory. The database is publicly available at the HapMap project’s Web site.
Research institutions from the United States, Japan, the United Kingdom, Canada, China and Nigeria participated in the creation of the HapMap.