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DOE Completes Working Drafts of Human Chromosomes 5, 16, and 19
April 2000
Researchers in the U.S. Department of Energy (DOE) Human Genome Program have achieved "working drafts" of the complete DNA sequences for human chromosomes 5, 16, and 19, thus fulfilling DOE's share of a major goal in the international U.S. Human Genome Project (HGP). All data have been deposited in the human DNA sequence database, GenBank, and are freely available through the Internet. Working drafts for the remaining human chromosomes are expected later this spring from other participants in the international HGP.
These three chromosome drafts were constructed by the DOE Joint Genome Institute (JGI), with data analysis by the Computational Bioinformatics group at Oak Ridge National Laboratory. The JGI is part of a consortium of five major international partners working together to provide by 2003 a high-quality reference sequence for the entire human genome—the ultimate goal of the Human Genome Project.
These newly completed working drafts provide a road map to an estimated 90% of genes on the three chromosomes, offering scientists worldwide an invaluable resource for improving human health and combating disease. Knowledge about genes will increase understanding of how genetics influences the development of disease, help researchers find genes associated with particular diseases, and aid in the development of new pharmaceuticals.
DNA Sequencing
DNA sequencing determines the exact order of the individual chemical building blocks, or bases, that make up the human genome.
DOWNLOADABLE GRAPHIC "DNA: THE MOLECULE OF LIFE"
Even though a draft does contain some gaps and errors, it provides a scaffold for the ultimate entire reference genome sequence and gives researchers advance access to much of the "gold" of the genome—its genes. Scientists believe that a high-quality sequence is critical for recognizing control components of genes that are very important in understanding human biology and such disorders as heart disease, cancer, and diabetes. These complex diseases are thought to be influenced by multiple genes interacting among themselves and with environmental factors.
DOWNLOADABLE GRAPHIC: "FROM DNA TO HUMANS"
Caption: The flow from DNA to protein to cells (interacting with environmental factors) to people (phenotypes).
Genes on Chromosomes 5, 16, and 19
Sequencing and analysis of chromosomes 5, 16, and 19 have enabled researchers to characterize in detail a number of genes associated with diseases. Some specific examples follow.
Chromosome 5. Human chromosomes range in size from about 50 million to 260 million bases. Chromosome 5, with an estimated 194 million bases, represents about 6% of the human genome. Last year, researchers at Lawrence Berkeley National Laboratory discovered two genes on chromosome 5 that contribute to the development of asthma, a complex disease believed to be linked to a number of genes. Asthma affects more than 5% of people in the United States; the number has doubled over the last 15 years and continues to rise. Further work may reveal additional genes or biological pathways linked to asthma and may suggest potential target for drug interventions. Other disease-linked genes on chromosome 5 include those for a type of dwarfism, severe combined immunodeficiency, schizophrenia, colorectal cancer, basal cell carcinoma, deafness, acute myelogenous leukemia, susceptibility to obesity, and atrial septal defect (a heart defect).
DOWNLOADABLE GRAPHIC "HEALTH OR DISEASE? "
Caption: Some DNA variations have no negative effects; others may lead to disease or increased susceptibilities to disease, as well as different reactions to drugs.
DOWNLOADABLE GRAPHIC "GENE CHIPS REVEAL SUSCEPTIBILITIES"
Caption: Gene expression chip.
Chromosome 16.Chromosome 16 contains about 98 million bases, or some 3% of the human genome. Studies have implicated a gene on chromosome 16 in the development of adult polycystic kidney disease (PKD), the most common potentially fatal disease caused by a defect in a single gene. An estimated 5 million people worldwide have PKD (500,000 in the United States), and half require dialysis or a kidney transplant by the age of 60. Knowledge gained through HGP data will pave the way for earlier diagnostic methods and more effective treatments of this disease.
Other major ailments associated with chromosome 16 are inflammatory bowel disease (ulcerative colitis and Crohn disease); breast and prostate cancers; Batten's Disease (a juvenile-onset neurodegenerative disorder); Fanconi anemia (a rare disease characterized by skeletal abnormalities, bone marrow failure, and a predisposition to cancer); and acute nonlymphocytic leukemia.
Chromosome 19. At 60 million bases in length, human chromosome 19 contains about 2% of the human genome, and data suggest that it is particularly gene rich. Important genes that have been the focus of intense study include three involved in the repair of DNA damage caused by exposure to radiation and other environmental pollutants. Studies of DNA-repair genes also may yield insights into the development of cancers, many of which are caused by defects in DNA-repair pathways.
Another important gene family studied on chromosome 19 comprises some 60 genes involved in detoxifying and excreting chemicals foreign to the body. This gene family may influence individual responses to such substances as pollutants and medicines. Other identified chromosome 19 genes are associated with a rare type of migraine, myotonic dystrophy, atherosclerosis, and diabetes mellitus.
DNA Sequencing: A Prelude to Understanding Function
Interpreting the functions of individual genes and other DNA sequences such as those that regulate gene activity is a task that will extend well into this new century. The multidisciplinary teams and resources located at DOE national laboratories are uniquely poised to play prominent roles in these future explorations.
The HGP already has revolutionized biology by providing tools and resources for basic research and has catalyzed the growth of the life sciences and bioengineering industries. Today, researchers worldwide use HGP data and associated analytical technologies to devise creative applications in an expanding array of fields. These fields include agriculture, forensics (identification technologies), environmental cleanup, industrial processes, and generation of new energy resources.
Background on the HGP
The DOE Human Genome Program began as a 1986 initiative by the DOE Biological and Environmental Research Program. The goal was to use newly developed DNA-analysis technologies in fulfilling a longstanding mandate from Congress to assess the health effects of radiation. In 1990, at the request of Congress, DOE and NIH formally began the joint U.S. Human Genome Project, which was expected to cost $3 billion and last 15 years. The collaborative effort aimed to find the estimated 80,000 human genes and determine the sequence of the 3 billion DNA bases that underlie all of human biology and account for its diversity, including disease. The early phase of the U.S. project was characterized by efforts to create the biological, instrumentation, and computing resources necessary for efficient production-scale DNA sequencing. In 1993 remarkable technological progress led to a revised 5-year plan that projected goals through FY 1998. The current plan, published in the October 23, 1998, issue of Science, projects a finishing date of 2003.
For More Information
•Ari Patrinos: 301/903-3251, ari.patrinos@science.doe.gov
•Marvin Frazier: 301/903-5468, marvin.frazier@science.doe.gov
•Human Genome Project Information: www.ornl.gov/hgmis
•Human Genome Project Information Online Media Kit: www.ornl.gov/hgmis/resource/media.shtml
•Joint Genome Institute: www.jgi.doe.gov
•Computational Biosciences: genome.ornl.gov/jgi
