Significant step forward in the genome era

In what promises to be a significant step forward in the genome era, the National Human Genome Research Institute (NHGRI) 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 hunters.

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 informed consent.

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 sequencing.

"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 Research.

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, Md.; and Washington University School of Medicine, St. Louis. Assignment of each organism to a specific center or centers will be determined at a later date.

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.