|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, which 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 is the next logical step in our understanding of which genes are associated
with particular diseases. This knowledge will ultimately revolutionalize the
way we practice in medicine, particularly "pre-emptive" medicine, where we can
intervene long before patients are stricken with disease," said NIH Director,
Elias A. Zerhouni, M.D.
"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 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 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
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 the 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
(www.hapmap.org), the NIH-funded National
Center for Biotechnology Information’s dbSNP (http://www.ncbi.nlm.nih.gov/SNP/index.html)
and the JSNP Database in Japan (http://snp.ims.u-tokyo.ac.jp/).
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 2.6 million additional SNPs to the HapMap and then 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.
NHGRI is one of 27 institutes and centers at the NIH, an agency of the Department
of Health and Human Services. The NHGRI Division of Extramural Research supports
grants for research and for training and career development at sites nationwide.
Additional information about NHGRI can be found at its Web site, www.genome.gov.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U. S. Department of Health and Human Services. It is the primary Federal
agency for conducting and supporting basic, clinical, and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.