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International consortium completes map of human genetic variation


New tool speeding the discovery of genes for common diseases

The International HapMap Consortium today published a comprehensive catalog of human genetic variation, a landmark 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, more than 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, that usually are inherited as intact blocks of information.

At the project’s outset in October 2002, the consortium set an ambitious 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 more than 1 million markers of genetic variation, called single nucleotide polymorphisms (SNPs). 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 even more precisely 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. 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, " 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.

Any two unrelated people are 99.9 percent identical at the genetic level. However, it is important to understand the 0.1 percent difference because it can help explain why one person is more susceptible to a disease or responds differently to a drug or an environmental factor than another person.

The HapMap shows the boundaries of 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 capture 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 more 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."

Gene hunters around the world have been quick to recognize the potential of the HapMap, tapping into its publicly available SNP datasets even before the first draft of the map was completed. For example, 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.

Many other discoveries lie on the horizon as the HapMap empowers studies of other common diseases, including diabetes, Alzheimer’s disease, cancer, schizophrenia, asthma, hypertension and heart disease. In fact, more than 70 papers and presentations related to the HapMap are on the program for this week’s meeting of the American Society of Human Genetics in Salt Lake City.

In addition to assisting in the identification of genetic factors involved in disease, the HapMap can help to pinpoint genetic variations that may affect the response of people to medications, toxic substances and environmental factors. Such information can be used to help doctors prescribe the right drug in the right dose for each patient, as well as recommend prevention strategies that take into account individuals’ varying responses to environmental factors, such as diet. Also, the HapMap may be used to find genetic factors that contribute to good health, such as those protecting against infectious diseases or promoting longevity.

Still, the consortium members caution the research community not to jump to conclusions too quickly when using HapMap data to facilitate their genome-wide searches for genes associated with human health and disease. "Rigorous standards of statistical significance will be needed to avoid a flood of false positive results," they write in their paper. To avert such problems, they urge their scientific colleagues to confirm any gene "discovery" by replicating the findings in independent studies that use the same set of SNP markers in different groups of people with the same disease or condition.

Researchers produced the HapMap using DNA from blood samples collected from 269 volunteers from widely distributed geographic regions. Specifically, the samples came from Yoruba in Ibadan, Nigeria; Japanese in Tokyo, Han Chinese in Beijing and Utah residents with ancestry from northern and western Europe. No medical or personal identifying information was obtained from the donors. However, the samples are identified by the population from which they were collected.

"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."

In addition to its intended function as a resource for studies of human health and disease, the Phase I HapMap has yielded fascinating clues into how our species evolved over time and specific forces that were important as the human population spread around the globe.

Genetic diversity in humans is increased by recombination, which is the swapping of DNA from the maternal and paternal lines. It has been recently realized that in humans, most such swapping occurs primarily at a limited number of "hotspots" in the genome. By analyzing the HapMap data, the researchers have produced a genome-wide inventory of where recombination takes place. This will enable more detailed studies of this fundamental property of inheritance, as well as serve to improve the design of genetic studies of disease.

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.

As expected, the vast majority of both rare and common patterns of genetic variation were found in all of the populations studied. However, the consortium did find evidence that a very small subset of human genetic variation may be related to selection pressures related to geographic or environmental factors, such as microorganisms that cause infectious diseases. This evidence appears as significant differences in genetic variation patterns in particular genomic regions among the populations studied. While more follow-up study is needed to explore the differences, researchers say some of the most striking examples merely serve to confirm well-known genetic differences among populations, such as the Duffy blood group, which plays a role in response to malaria, and the lactase gene, which influences the ability to digest milk products.

All in all, across the 1 million SNPs surveyed, researchers found only five exclusive, or "fixed," differences on human’s 22 pairs of non-sex (autosomal) chromosomes between the Yoruba samples and the Japanese and Han Chinese samples; 11 between the Yoruba samples and the samples from Utah residents of northern and western European ancestry; and 21 between the Utah samples and the Japanese and Han Chinese samples.

The International HapMap Consortium is a public-private partnership of scientists and funding agencies from Canada, China, Japan, Nigeria, the United Kingdom and the United States. The U.S. component of the $138 million international project is led by National Human Genome Research Institute (NHGRI) on behalf of the 20 institutes, centers and offices of the National Institutes of Health (NIH) that contributed funding.

"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."

As was the case with all of the data generated by the Human Genome Project, HapMap data are being made swiftly and freely available in public databases. Researchers can access this data through the HapMap Data Coordination Center (, the NIH-funded National Center for Biotechnology Information’s dbSNP ( the JSNP Database in Japan (

Phase II of the HapMap, for which the data has already been generated and analysis is getting underway, will be an even more powerful tool than the Phase I version described in the Nature paper. Taking advantage of the high-throughput genotyping capacity of Perlegen Sciences, Inc., of Mountain View, Calif., Phase II is adding 2.1 million additional SNPs to the HapMap by testing virtually the entire known catalog of human variation on the HapMap samples.

"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.

Geoff Spencer | EurekAlert!
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