Feb. 13, 2001 Philadelphia, PA – As the "working draft" of the human genome is officially published today, scientists are unveiling powerful tools to make the crucial data more useful to medical researchers. One team, the BAC Resource Consortium, led by a researcher at The Children’s Hospital of Philadelphia, announced today that it has used large segments of DNA to connect the genome’s sequence data to cytogenetic landmarks – the microscopic patterns of light and dark bands seen on human chromosomes.
With the help of this new resource, researchers studying a disease associated with detectable defects on a chromosome can identify the precise DNA segment involved, then order normal copies of the segment for further analysis in their own laboratories. This resource will enable researchers to identify the genes that are defective in genetic diseases, including cancer.
"Our project helps to make human genome data usable by guiding scientists to specific DNA segments needed for their research," says Vivian G. Cheung, M.D., a researcher in the Division of Neurology at The Children’s Hospital of Philadelphia and an assistant professor of Pediatrics at the University of Pennsylvania School of Medicine. Dr. Cheung is the lead author of a paper about the BAC Resource Consortium in the Feb. 15 special issue of the journal Nature, which contains the official publication of the draft of the human genome, along with many related papers. Other major collaborating institutions in the federally funded consortium include the Roswell Park Cancer Institute (represented by Dr. Norma Nowak) and the Fred Hutchinson Cancer Research Center (represented by Dr. Barbara J. Trask).
The completion of the working draft of the human genome was announced in June 2000 at a White House ceremony, well in advance of this week’s formal publication of the data in Nature by the International Human Genome Sequencing Consortium. Heralded as the compilation of the "Book of Life," the working draft is a listing of the 3 billion DNA base pairs that carry genetic instructions in the human chromosomes. The finished version of the sequence is projected to be completed in 2003. In the meantime, scientists throughout the world have been applying the data to gene identification, disease research and drug discovery.
The BAC Resource is a tool to bridge the gap between two levels of genetic knowledge. One level is the genome sequence: the detailed, ordered listing of the chemical bases adenine, guanine, cytosine and thymine, which are the four members of the genetic alphabet, often simply abbreviated as A, G, C and T. The other level is cytogenetic, found in the patterns of dark and light bands visible on human chromosomes. "Our Consortium has produced the first comprehensive integration of cytogenetic and sequence maps for the whole human genome by identifying a library of DNA segments that contain landmarks for both maps," said Dr. Cheung.
Identifying Abnormal Genes Researchers investigating cancers, developmental disorders and multisystem genetic diseases often directly observe abnormal band patterns and other microscopic aberrations in a patient’s chromosomes. In addition, laboratory tools such as fluorescent tags may detect a translocation, an abnormal exchange of DNA between chromosomes. However, understanding the molecular details of many diseases has not kept pace with the discovery of chromosome abnormalities.
The BAC Resource Consortium aims to hasten discovery of molecular changes occurring in specific diseases. By referring to the BAC Resource database, publicly accessible on the Internet, scientists can identify DNA sequences underlying particular locations on chromosomes. The scientists can then obtain those specific segments of DNA, called bacterial artificial chromosome (BAC) clones. The BAC Resource links chromosome landmarks to 8,890 such clones, each of which is available to researchers at low cost through several sources.
As an example of the resource’s usefulness, the BAC Consortium took DNA from a patient with mental retardation and developmental disorders. Knowing the location on the chromosome of abnormal structures, the researchers used their map to pinpoint the associated DNA segment. Analyzing the DNA clone, they were then able to narrow their search to specific candidate genes that may be responsible for the patient’s disorder. "Identifying abnormal genes that are responsible for a disease is a first step toward eventually designing treatments to restore normal function," said Dr. Cheung.
Islands of DNA In addition to providing a resource for scientists focusing on particular diseases, the BAC Resource helped other researchers to produce a physical map of the human genome. "Because our clones are highly accurate islands of DNA sequences throughout the genome, they provided anchors for researchers doing the sequencing to check their results when assembling the genome sequence," said Dr. Cheung, who co-authored another paper in the special issue of Nature reporting on the assembly of a whole-genome physical map.
In addition to Dr. Cheung, members of The Children’s Hospital of Philadelphia staff who were among the co-authors of the BAC Consortium paper were lab manager Alan Bruzel, Ph.D., database manager Michael Morley and project manager Sandya Narasimhan. Other contributors from Children’s Hospital were Melissa Arcaro and Teresa Weber, both technicians, and computer programmer Josh Burdick. The research at Children’s Hospital was supported by grants from the National Institutes of Health and the Merck Genome Research Institute.
Founded in 1855 as the nation's first pediatric hospital, The Children’s Hospital of Philadelphia is ranked today as the best pediatric hospital in the nation by a comprehensive Child Magazine survey. Its pediatric research program is among the largest in the country, ranking second in National Institutes of Health funding.
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