The International HapMap Consortium has published a comprehensive catalog of human genetic variation, an achievement that is already accelerating the search for genes involved in common diseases, such as asthma, diabetes, cancer and heart disease.
In a paper in the Oct. 27 issue of the journal "Nature", 200 researchers from Canada, China, Japan, Nigeria, the United Kingdom and the United States describe the initial results from their public-private effort to chart the patterns of genetic variation that are common in the world's population.
The results provide overwhelming evidence that variation in the human genome is organized into local neighborhoods, called haplotypes, which usually are inherited as intact blocks of information.
At the project's outset in October 2002, the consortium set a goal of creating a human haplotype map, or HapMap, within three years.
The "Nature" paper marks the attainment of that goal with its detailed description of the Phase I HapMap, consisting of 1 million markers of genetic variation, called single nucleotide polymorphisms.
The consortium is also nearing completion of the Phase II HapMap that will contain nearly three times more markers than the initial version and will enable researchers to focus their gene searches on specific regions of the genome.
"This represents a milestone for medical research. Built upon the foundation laid by the human genome sequence, the HapMap provides a powerful new tool for exploring the root causes of common diseases," said David Altshuler, M.D., Ph.D., of The Broad Institute of Harvard and MIT in Cambridge, Mass., who along with Peter Donnelly, Ph.D., of the University of Oxford in England are the paper's corresponding authors.
"Such understanding is required for researchers to develop new and much-needed approaches to prevent, diagnose and treat diseases, such as diabetes, bipolar disorder, cancer and many others."
The HapMap shows the neighborhoods of correlated genetic variation, or haplotypes, across the entire human genome. With these haplotypes defined, HapMap provides an efficient method for choosing "tag SNPs" that captures the genetic variation in each neighborhood with a minimum amount of work.
By using HapMap data to compare the SNP patterns of people affected by a disease with those of unaffected people, researchers can survey genetic variation across the whole genome and identify genetic contributions to common diseases far efficiently than is possible with traditional approaches.
"The HapMap is a phenomenal tool that is making possible research that was impractical, if not unimaginable, only a few years ago," said Yusuke Nakamura, M.D., Ph.D., director of the University of Tokyo's Human Genome Center, as well as leader of the RIKEN SNP Center and the Japanese group working on the HapMap.
"It offers the scientific community an enormous savings, reducing the expense of searching the genome for hereditary factors in common disease by a factor of 10 to 20."
In studies published in March in the journal "Science", scientists used HapMap data to uncover a genetic variation that substantially increases the risk of age-related macular degeneration, the leading cause of severe vision loss in the elderly.
The discovery of this single spelling variant out of the 3 billion letter DNA instruction book for humans, which affects a gene that codes for a protein involved in inflammation, points the way for development of better diagnostic tests and treatments for this debilitating disease.
"Rigorous standards of statistical significance will be needed to avoid a flood of false positive results," they write in their paper.
"We have devoted much effort to making sure this project is done as ethically and transparently as possible. Following the precedent set by the Human Genome Project, we have weighed the ethical, legal and social implications of this research from the outset," said Bartha M. Knoppers, J.D., Ph.D., of the University of Montreal.
"For example, we developed a very careful community engagement and sampling strategy to ensure that participants from all the different population groups could give full informed consent."
"Still, we know our job is far from over and we stand ready to address whatever ethical, legal and social issues may arise in the future."
The HapMap consortium found that genes involved in immune response and neurological processes are more diverse than those for DNA repair, DNA packaging and cell division.
Researchers speculate the difference might be explained by natural selection shaping in the human population in ways that favor increased diversity for genes that influence the body's interactions with the environment, such as those involved in immune response, and that do not favor changes in genes involved in core cellular processes.
"Like the Human Genome Project before it, the key to the International HapMap Project's success lies in the shared vision and hard work of hundreds of researchers from many different nations and many different disciplines," said NHGRI Director Francis S. Collins, M.D., Ph.D., who led the U.S. component of the Human Genome Project and served as the project manager for HapMap.
"Each member of the consortium is to be commended for helping to create this outstanding public resource for exploring the genetic components of human health and disease."
"Our participation in this collaborative effort underscores the private sector's enthusiasm for the HapMap and its potential as a tool for the understanding of disease. The Phase II map will make it even easier for researchers to correlate genetic variation with gene function, which is crucial for developing therapies tailored to each person's genetic make-up," said Kelly A. Frazer, Ph.D., vice president of genomics at Perlegen.