|Researchers Produce First Sequence Map Of Large-Scale
Structural Variation in Human Genome
Map Will Boost Efforts to Explore Role of Structural Variants
A nationwide team of researchers, funded in part by the National
Human Genome Research Institute (NHGRI), part of the National Institutes
of Health (NIH), has produced the first sequence-based map of large-scale
structural variation across the human genome. The work, published
today in the journal Nature, provides a starting point
to examine how such DNA variation contributes to human health and
Other recently created maps, such as the HapMap, have catalogued
the patterns of small-scale variations in the genome that involve
single DNA letters, or bases. However, the scientific community
has been eagerly awaiting the creation of additional types of maps
in light of findings that larger scale differences account for
a great deal of the common genetic variation among individuals
and between populations, and may account for a significant fraction
of disease. While previous work has identified structural variation
in the human genome, a sequence-based map provides much finer resolution
and location information.
Large-scale structural variations are differences in the genome
among people that range from a few thousand to a few million DNA
bases. Some are gains or losses of stretches of genome sequence.
Others appear as re-arrangements of stretches of sequence. Already,
some structural variations have been linked to individual differences
in susceptibility to the human immunodeficiency virus (HIV), risk
of coronary heart disease, as well as to schizophrenia and autism.
Researchers hope the new map will open the door to uncovering the
functions of structural variants in even more conditions.
"It is important that we understand how changes in the human
genome, both small and large, contribute to individual differences
in susceptibility to diseases," said Francis Collins, M.D.,
Ph.D. "This map is a valuable starting point for researchers
studying the normal patterns of structural variation and how differences
in those patterns affect human health."
Researchers constructed the structural variation map by partially
sequencing the genomes of eight people: four people of African
descent, two of Asian descent and two of European descent. The
samples were collected as part of the International HapMap Project.
No medical or personal identifying information was obtained from
the donors, but the samples were labeled by population group.
Sequence data were collected from each end of roughly 1 million
random small pieces of DNA from each individual’s genome. These
end sequences were compared to the reference sequence of the human
genome completed in 2003. Where precise matches did not occur,
the scientists inferred that there was a structural difference
between the volunteer’s sample and the reference sequence of the
In addition to revealing new variations, the map also provides
a more detailed look at the locations of nearly 1,700 structural
variations — half of which had not been previously described.
About half of the structural variations were found in at least
two of the eight genomes analyzed. The work also uncovered 525
new regions of large-scale structural variation in the human genome.
The large-scale differences came in many forms, including deletions
and out-of-place insertions of long stretches of DNA. Almost half
of the new variations consist of differences in how many copies
individuals have of a certain gene, which researchers refer to
as a copy number variant.
"The structural variation map will give us a much better
picture of genetic variation between each individual, and help
us better understand these areas of the genome that are prone to
large-scale changes over time," said Evan Eichler, Ph.D.,
of the University of Washington, who led the research.
Sequence data from the structural variation map are publicly available
through the NIH’s National Center for Biotechnology Information
Trace Archive, www.ncbi.nlm.nih.gov/Traces.
Mapping data are also freely available from the University of Washington, http://hgsv.washington.edu.
In addition to Eichler and his colleagues at the University of
Washington, the project included researchers at Agencourt Bioscience
Corp., Beverly, Mass.; Agilent Technologies, Santa Clara, Calif.;
Washington University School of Medicine, St. Louis; Division of
Intramural Research, NHGRI, Bethesda, Md.; the University of Wisconsin,
Madison; the Broad Institute of MIT and Harvard, Cambridge, Mass.;
and Illumina, Inc., San Diego.
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 www.nih.gov.