|Consortium Publishes Phase II Map of Human Genetic
New Map Improves Power to Find Variants Involved in Common Diseases;
Reveals More Signs of Adaptive Evolution
The International HapMap Consortium today published analyses of
its second-generation map of human genetic variation, which contains
three times more markers than the initial version unveiled in 2005.
In two papers in the journal Nature, the consortium describes
how the higher resolution map offers greater power to detect genetic
variants involved in common diseases, explore the structure of
human genetic variation and learn how environmental factors, such
as infectious agents, have shaped the human genome.
Any two humans are more than 99 percent the same at the genetic
level. However, it is important to understand the small fraction
of genetic material that varies among people because it can help
explain individual differences in susceptibility to disease, response
to drugs or reaction to environmental factors. Variation in the
human genome is organized into local neighborhoods, called haplotypes,
that usually are inherited as intact blocks of information. Consequently,
researchers refer to the map of human genetic variation as a haplotype
map, or HapMap.
The International HapMap Consortium is a public-private partnership
of researchers and funding agencies from Canada, China, Japan,
Nigeria, the United Kingdom and the United States. The U.S. component
of the 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.
"Thanks to this consortium's pioneering efforts to map human
genetic variation, we are already seeing a windfall of results
that are shedding new light on the complex genetics of common diseases," said
NHGRI Director Francis S. Collins, M.D., Ph.D. "This new approach
to research, called genome-wide association studies, has recently
uncovered new clues to the genetic factors involved in type 2 diabetes,
cardiovascular disease, prostate cancer, multiple sclerosis and
many other disorders. These results have opened up new avenues
of research, taking us to places we had not imagined in our search
for better ways to diagnose, treat and prevent disease."
The second-generation haplotype map, or Phase II HapMap, contains
more than 3.1 million genetic variants, called single nucleotide
polymorphisms (SNPs) — three times more than the approximately
1 million SNPs contained in the initial version. The more SNPs
that are on the map, the more precisely researchers can focus their
hunts for genetic variants involved in disease. The rapid growth
of genome-wide association studies over the past year and half
has been fueled by the HapMap consortium's decision to make its
SNP datasets immediately available in public databases, even before
the first and the second versions of the map were fully completed.
Researchers around the globe have now associated more than 60
common DNA variants with risk of disease or related traits, with
most of the findings coming in the past nine months. As just one
example, the Wellcome Trust consortium in England looked at 14,000
cases and 3,000 shared controls, finding variants associated with
increased risk of bipolar disorder, coronary artery disease, Crohn's
disease, rheumatoid arthritis, type 1 diabetes and type 2 diabetes.
"We are thrilled that the worldwide scientific community
is taking advantage of this powerful new tool and we anticipate
even more exciting findings in the future. The improved SNP coverage
offered by the Phase II HapMap, along with better statistical methods,
promises to further increase the accuracy and reliability of genome-wide
association studies," said Gil McVean, Ph.D., of the University
of Oxford in England, who co-led the group that analyzed the HapMap
Another analysis leader, Mark Daly, Ph.D., of Massachusetts General
Hospital and the Broad Institute of MIT and Harvard in Cambridge,
Mass., said, "In addition to providing a critical backbone
for standard genome-wide association studies, the Phase II HapMap
identifies additional features of human genetic variation that
will bolster efforts to pinpoint rarer disease mutations."
The Phase II HapMap was produced using the same DNA samples used
in the Phase I HapMap. That DNA came from blood collected from
270 volunteers from four geographically diverse populations: 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, but the samples were labeled by population group.
To provide information on less common variations and to enable
researchers to conduct genome-wide association studies in additional
populations, NHGRI plans to extend the HapMap even further. Among
the populations donating additional DNA samples are: Luhya in Webuye,
Kenya; Maasai in Kinyawa, Kenya; Tuscans in Italy; Gujarati Indian
in Houston; Chinese in metropolitan Denver; people of Mexican ancestry
in Los Angeles; and people of African ancestry in the southwestern
In its overview paper in Nature, the consortium estimates
that the Phase II HapMap captures 25 percent to 35 percent of common
genetic variation in the populations surveyed. The consortium also
confirmed that use of Phase II HapMap data has helped to improve
the coverage of various commercial technologies currently being
used to identify disease-related variants in genome-wide association
studies. Researchers did note, however, that current technologies
tend to provide better coverage in non-African populations than
in African populations because of the greater degree of genetic
variability in African populations.
The overview paper also reports that the Phase II HapMap has provided
new insights into the structure of human genetic variation. One
new finding was the surprising extent of recent common ancestry
found in all of the population groups. Taking advantage of the
map's increased resolution, the researchers identified stretches
of identical DNA between pairs of donor chromosomes and then compared
these stretches both within and across individuals. Their analysis
showed that 10 to 30 percent of the DNA segments analyzed in each
population showed shared regions indicating descent from a common
ancestor within 10 to 100 generations.
In addition, the new map enabled researchers to quantify more
precisely the rates of shuffling, or recombination, seen among
different gene classes in the human genome. In their overview paper,
researchers report that recombination rates vary more than six-fold
among different gene classes. The highest rates of recombination
were found among genes involved in the body's immune defense, while
the lowest rates appear among genes for chaperones, which are proteins
that play a crucial role in making sure other proteins are folded
properly. In general, genes that code for proteins associated with
the surface of cells and external functions, such as signaling,
were found to be more prone to recombination than those that code
for proteins internal to cells.
While the reasons for the varying recombination rates remain to
be determined, the findings pose interesting evolutionary questions.
In their paper, researchers suggest that one explanation may be
that some recombinations in areas of the genome that affect responses
to infectious agents or other environmental pressures may be selected
for because they provide a survival advantage.
A related study appearing in the same issue of Nature describes
how the enhanced map can help pinpoint pivotal changes in the human
genome that arose in recent history. These changes, now common
among various populations worldwide, became prevalent through natural
selection — meaning they were somehow beneficial to human
health. Although these DNA variants may still be important, their
biological significance remains largely unknown.
Using the Phase II HapMap data, a team led by researchers at the
Broad Institute of MIT and Harvard identified hundreds of genomic
regions that carry the hallmarks of recent positive natural selection.
These regions are large, often extending for millions of nucleotides
and including multiple genes. Thus, the researchers developed a
set of computational guidelines to help locate the single letter
changes that formed the focal points for evolutionary change.
The work uncovered several intriguing genetic variations that
could provide novel insights into the biological forces underlying
natural selection in humans. Two differences, which are common
primarily in Asian populations, lie within the EDAR and EDA2R genes.
In humans, these genes function together to form hair follicles
and sweat glands, as well as other structures.
The researchers also identified DNA variations in African populations
that may be linked to resistance to Lassa fever, a viral infection
common in Western Africa. These changes lie in two genes, LARGE and DMD,
which are involved in viral entry into cells. The findings help
underscore one of the study’s key themes — that multiple
genes, acting together in the same biological process, often show
signs of positive selection, both in humans and other organisms.
Integrating these data may bolster efforts to understand the biological
consequences of human genetic variation.
"Human history and the genome have been dramatically shaped
by environmental factors, diet and infectious disease," said
co-first author Pardis Sabeti, Ph.D., who is a postdoctoral fellow
at the Broad Institute of MIT and Harvard. "The gene variants
identified in our study open new windows on these evolutionary
forces and provide a launching point for future biological studies
of human adaptation."
The effort to build the improved HapMap relied heavily on the
high-throughput genotyping capacity of Perlegen Sciences, Inc.,
of Mountain View, Calif. The firm tested virtually the entire known
catalog of human SNP variation on the HapMap samples, as well as
contributed some of its own resources to make the map possible.
"The Phase II HapMap is truly an example of a public-private
collaboration at its best. It's wonderful that everyone pulled
together to create this improved map, which is a priceless tool
for all researchers seeking to use genomic information to improve
human health, be they in government, academia or industry," said
Kelly A. Frazer, Ph.D., formerly vice president of genomics at
Perlegen and now director of genomic biology at Scripps Genomic
Medicine Program, in La Jolla, Calif.
Researchers can access the Phase II map data through the HapMap
Data Coordination Center (www.hapmap.org),
the NIH-funded National Center for Biotechnology Information's
and the JSNP Database in Japan (http://snp.ims.u-tokyo.ac.jp).
NHGRI is one of 27 institutes and centers at NIH, an agency of
the Department of Health and Human Services. NHGRI's Division of
Extramural Research supports grants for research and for training
and career development. For more, visit 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 www.nih.gov.