|NHGRI’s Large-Scale Sequencing Research Network Sets Its Sights
on Disease Targets
NHGRI Effort Expands to Include Medical Sequencing
Bethesda, Maryland — In what promises to be a significant
step forward in the genome era, the National Human Genome Research Institute
(NHGRI), one of the National Institutes of Health (NIH), today announced plans
to devote a portion of its large-scale sequencing capacity to efforts aimed at
identifying the genetic roots of specific diseases that have long eluded gene
The National Advisory Council for Human Genome Research (NACHGR) recently approved
a plan for NHGRI's Large-Scale Sequencing Network that, for the first time, includes
a portfolio of "medical sequencing" projects. Projects given the highest priority
will use large-scale sequencing over the next few years to identify the genes
responsible for dozens of relatively rare, single-gene (autosomal Mendelian)
diseases; sequence all of the genes on the X chromosome from affected individuals
to identify those involved in sex-linked diseases; and to survey the range of
variants in genes known to contribute to some common diseases. The launch of
each project will depend on a number of factors, including the strategic selection
of specific diseases and the availability of patient samples with appropriate
In addition to the new focus on medical sequencing, the plan continues NHGRI’s
emphasis on using comparative genomic sequencing analysis to understand the structure
and function of the human genome and the biological processes at work in human
health and disease. The strategy includes a mix of whole genome sequencing, genome
mapping and sequencing of genomic regions chosen for their scientific merits.
Additionally, NACHGR approved the refinement of several existing draft genome
sequences and targeted a group of seven additional non-mammalian organisms for
“Medical sequencing has the potential to make a substantial impact on both
biological and medical research. While many of the genes we will initially be
pursuing are responsible for rare disorders, what we learn from rare disorders
often has profound consequences for our understanding of more common conditions.
Thus we expect the cumulative impact of this acceleration in disease gene discovery
to be profound, as many of the discoveries will shed new light on the biological
pathways involved in human health and disease,” said NHGRI Director Francis S.
Collins, M.D., Ph.D.
The first medical sequencing project, predicted to begin in the next year,
will be a demonstration project to find the genetic variations responsible for
seven rare, autosomal Mendelian disorders. The demonstration project will establish
the best procedures for obtaining quality samples, for determining the minimum
number of affected and control samples needed, and for deciding how the data
will be released to the biomedical research community.
Among the demonstration projects under consideration are those to identify
the genes responsible for the familial forms of atrial fibrillation, a major
risk factor for heart failure and stroke; thoracic aortic aneurysms, which are
life-threatening tears in the major artery of the heart; and dominant restrictive
cardiomyopathy, another heart disorder. By understanding the familial forms of
these diseases, scientists can apply what they learn to uncover the genetic components
underlying the more common types of these heart disorders in the human population.
The other demonstration projects will target the genes for four other rare
disorders: paroxysmal kinesigenic choreoathetosis, a neurological condition;
neovascular inflammatory vitreoretinopathy, a blinding disorder; lymphedema-cholestasis
syndrome, a hereditary disorder causing jaundice and leg swelling; and Joubert
syndrome, a rare brain and physical development disorder.
NHGRI estimates that there are at least 50 to 100 additional projects in the
scientific community that could benefit from the brute force and specialized
tools of large-scale sequencing. In order to make an accurate assessment and
gather community input into this program, NHGRI has issued a Request for Information
to seek additional examples of such diseases from investigators around the world.
The deadline for responses is Nov. 4. NHGRI will also hold an open discussion
on Oct. 28 during the upcoming meeting of the American Society for Human Genetics
in Salt Lake City to seek additional input from the human genetics community.
NHGRI will analyze the input from these sources and determine the ultimate size
of this aspect of medical sequencing as well as the best way to select those
projects that offer the most promise.
Another medical sequencing project will be an effort to identify the genetic
changes that result in diseases known as X-linked disorders. The human genome
consists of 22 matching pairs of chromosome, referred to as autosomal chromosomes,
plus a non-matching pair referred to as the sex chromosomes. The sex chromosomes,
which are called X and Y, determine whether a person is female (XX) or male (XY).
Any defects in genes on the X chromosome are often more apparent in males than
females because the Y chromosome does not carry corresponding genes to compensate.
While researchers have identified the genes responsible for a number of X-linked
disorders, the precise genetic basis for approximately 130 of these disorders
remains to be determined. The study would entail completely sequencing all genes
on the X chromosomes of individuals affected with the disorders, and looking
for variations that consistently correlate with each disorder.
The other medical sequencing project given priority will attempt to characterize
the entire spectrum of variation, both rare and common, in a significant number
of candidate genes for common diseases. Genes known to influence high blood pressure,
cholesterol and body weight will be targeted. Samples would be sequenced from
hundreds to thousands of individuals from existing large cohort studies examining
specific diseases, such as atherosclerosis or diabetes.
As part of the effort to select medical sequencing projects, NHGRI has included
a working group to examine the ethical, legal and social issues relevant to the
new medical sequencing projects. Many of these issues, which include obtaining
informed consent from volunteers who plan to donate samples or who have already
donated samples for other research projects, protecting the privacy of such volunteers,
and understanding when, or how to report clinically relevant results back to
volunteers, are similar to those encountered in much of human genetics research.
The group will also address data release and intellectual property procedures.
In addition to the new focus on medical sequencing, NHGRI is continuing its
ongoing effort to sequence other organisms’ genomes, with the aim of deepening
our understanding of human biology and evolution. Since the human genome and
that of other mammalian and non-mammalian genomes have all evolved from a common
ancestor, scientists can use the genome sequences of the non-mammalian animals
to learn more about how, when and why the genomes of humans and other mammals
came to be composed of certain DNA sequences. Such studies also provide new insights
into the function of those sequences, the organization of genomes, and expand
our understanding of the biological basis of certain infectious diseases.
NHGRI has selected seven non-mammalian organisms or groups of organisms for
the next round of sequencing. Three of the organisms have been targeted for “high-quality
draft” sequencing. They are: the green anole lizard (Anolis carolinensis), zebra
finch (Taeniopygia guttata) and body louse (Pediculus humanus). Researchers will
also construct physical genetic maps and do some targeted genomic sequencing
of two sandflies (Lutzomyia longipalpis and Phlebotomus papatasi), and will obtain
a low coverage sequence of the Africanized honey bee (Apis mellifera scutellata)
for comparison with the honey bee genome sequence. Finally, the genomes of 100
bacteria cultured from the normal human gut will be sequenced.
"We are continuing to focus on those organisms that will reveal the greatest
amount of information about the major biological innovations that have occurred
throughout evolution, with emphasis on learning more about our own genome. Genomic
information from a wide array of species is proving useful in many areas of biomedical
research," said Mark S. Guyer, Ph.D., director of NHGRI's Division of Extramural
The green anole lizard will be the first reptile to have its genome sequenced.
Sequencing this reptile will provide a valuable comparison to the chicken, human
and other mammalian genomes. The green anole lizard is also a well-established
experimental model for neurobiology, endocrinology and reproduction.
Selected for physical mapping earlier this year, the zebra finch will now be
sequenced to a high-quality draft. The zebra finch was chosen because it is a
major model system for understanding brain development, learning and memory.
Because it is related to the chicken, whose genome has already been sequenced,
it will be possible to leverage the chicken genome to get more insight from the
zebra finch genome sequence.
The body louse, which possesses the smallest measured insect genome, is a vector
for Rickettsia prowazekii, a category B bioterrorism agent that causes typhus.
The two sand flies targeted for sequencing are major vectors of leishmaniasis,
a parasitic disease responsible for disfiguring skin lesions and damage to the
spleen, liver and bone marrow. It is estimated that 12 million people are infected
worldwide and that this disease causes more than 60,000 deaths each year. In
fact, approximately 1,200 soldiers deployed during the Gulf War have contracted
the skin lesions caused by leishmaniasis. Sequencing the genomes of the sandflies
will give researchers a better understanding of this disease and possibly aid
the development of vaccines.
The human gut microbiome project represents an exciting new research area for
NHGRI, which, except for the bacterium E. coli, has focused its large-scale sequencing
program on higher organisms rather than bacteria. But there are more bacterial
cells in the human gut than there are human cells in the entire human body. Furthermore,
human gut microbes have a profound effect on many human physiological processes,
such as digestion and drug metabolism, and play a vital role in disease susceptibility.
Sequencing the genomes of these 100 microorganisms found in the human gut, which
represent a significant, but unknown fraction of all microbes in the human gut,
is expected to provide a much more complete picture of this aspect of human biology
than has ever been available previously. It is hoped this new information could
lead to improved diagnostic tools for monitoring human health.
The latest NHGRI sequencing plan will also support the refinement of the rat,
chicken and dog genomes. All are important model organisms, and their genomes
are used to identify features that are similar, or conserved, among the genomes
of the human and other mammals. Sequences that have been conserved throughout
evolution often reveal important functional regions of the human genome. To learn
more about the field of comparative genomic analysis, go to: www.genome.gov/10005835.
Sequencing efforts will be carried out by the NHGRI-supported Large-Scale Sequencing
Research Network, which consists of five centers: Agencourt Bioscience Corp.,
Beverly, Mass.; Baylor College of Medicine, Houston; the Broad Institute of MIT
and Harvard, Cambridge, Mass.; the J. Craig Venter Science Institute, Rockville,
Maryland; and Washington University School of Medicine, St. Louis. Assignment
of each organism to a specific center or centers will be determined at a later
NHGRI's process for selecting sequencing targets begins with three working
groups comprised of experts from across the research community. Each of the working
groups is responsible for developing a proposal for a set of genomes to sequence
that would advance knowledge in one of three important scientific areas: to identify
areas in genetic research where the application of high-throughput sequencing
resources would rapidly lead to significant medical advances, understanding the
human genome and understanding the evolutionary biology of genomes. A coordinating
committee then reviews the working groups' proposals, helping to fine-tune the
suggestions and integrate them into an overarching set of scientific priorities.
The recommendations of the coordinating committee are reviewed and approved by
NHGRI's advisory council, which in turn forwards its recommendations to NHGRI
leadership. For more on the selection process, go to: www.genome.gov/Sequencing/OrganismSelection.
The genomes of a number of organisms have been or are being sequenced by the
large-scale sequencing capacity developed by the Human Genome Project. A complete
list of organisms and their sequencing status can be viewed at www.genome.gov/10002154.
High-resolution photos of many of the organisms being sequenced in the Large-Scale
Sequencing Program are available at: www.genome.gov/10005141.
NHGRI is one of the 27 institutes and centers at 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.