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| Vol. 22, No. 15 |
| August 15, 2000 |
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Discovering Baylor's Human Genome Sequencing Center by KRISTINA VAN ARSDEL Texas Medical Center News
Staff at Baylor College of Medicine's Human Genome Sequencing Center recently took time out to celebrate completing the "working draft" of the human genome with colleagues ... but not for long. The 220 employees have a job to finish, one that could change the way diseases are detected and treated in the future. "This is the beginning of the beginning," says Dr. Steve Scherer, assistant professor of molecular and human genetics and the center's director of mapping. "Much more work needs to be done." Dr. Scherer makes the analogy of an incomplete library to describe the working draft. "It's like checking out books in a library, only some of the books right now may be missing chapters," he says. The Human Genome Sequencing Center will be responsible for "filling in the gaps" on chromosome 3, home to, among others, the SCLC1 gene and the MLH1 gene associated with types of lung and colon cancer respectively; chromosome 12, including the gene for the metabolic disorder phenylketonuria, or PKU, and a portion of the X chromosome. "We have discovered there are fewer genes than we probably thought initially," says Dr. Scherer. "As a result, the genes that are there may code for multiple proteins. This means that regulation becomes more important since there are fewer genes doing several tasks."
Simply filling in those areas in between genetic markers on the working draft does not do justice to the complex work under way at the center. Dr. Richard Gibbs, the center's director, describes the final phase as putting together a puzzle with missing pieces. Only this is not just one puzzle. He says this is more like 40,000 puzzles and not all of the puzzle pieces are in their respective boxes. To further complicate matters, some puzzles are overlapping where they should not be while others should be connected. Dr. Gibbs extends the metaphor by adding that when the puzzles are finished, they are not pictures of concrete objects such as a house. These are abstract pictures that require interpretation. In scientific terms, the human genome is the collective name for the 80,000 genes in each cell of the human body. The genes are located on the cell's 23 chromosome pairs - one set comes from the mother and the other set from the father - to form a unique genetic makeup. Genes provide instructions for the cell, determining how the cell will function and reproduce. This genetic recipe is encoded in a "language" known as deoxyribonucleic acid or DNA, structured as a double-helix ladder. Broken down into its parts, DNA consists of four chemical bases - adenine (A), thymine (T), cytosine (C) and guanine (G). When these 3 billion bases are strung together, they direct the building of a protein. The protein product is instrumental in helping the cell perform its function. The goals of the Human Genome Project are to identify all of the genes and determine the order or "sequence" of the bases, thus, cracking the code to the cell's genetic instructions. The first phase involved a shotgun approach to determine genetic markers. This phase, completed two years ahead of its intended schedule, resulted in the "working draft." Now, researchers are faced with the task of determining the exact order of the chemical bases and putting all of the work into a finished, high-quality form. Accomplishing this involves several steps. Scientists first break down the genome into manageable pieces for research (about 150,000 bases each). The strips of DNA chosen for sequencing are cloned; the collection of cloned DNA is known as a library. The clone DNA then undergoes the sequencing process in which each of the base types (A, T, C and G) is assigned a color code. The bases are then separated and identified by their colors. The information is transferred to a computer where the data is analyzed and the clone is put back together again. The work is divided among professionals and automated means, such as robots. Dr. Gibbs attributes the early completion of the working draft to the integration of technology, which made the process more efficient. He says he hopes the Baylor center can continue to increase its production of sequenced DNA bases in this final phase. While sequencing the human genome is a major undertaking at the center, it is not the only project under way there. Scientists are also studying other genome models, which they hope will provide further insight into the human genome based on the similarities and differences they uncover. "We are more related to each other and other species than we probably thought," says Dr. Scherer. The Baylor center is currently involved in the Berkeley Drosophila Genome Project to map and sequence the genome of the Drosophila melanogaster, the fruit fly. The group announced the completion of the genetic map of the fly in the March 24 edition of Science and efforts are now focused on closing any gaps left in the genome. What do we, as humans, have in common with the fruit fly? Scientists are using the fruit fly model because it contains some of the same genes, proteins and chemical pathways found in the human genome. In addition, the fruit fly reproduces every two to three days, which allows researchers to confirm theories about hereditary diseases and the way in which they are past from parent to offspring. More closely related to the human genome are those of the mouse and rat. Baylor's Human Genome Sequencing Center is presently involved in mapping the genome of the mouse and may soon begin working on the rat genome. "The mouse model is useful because you find similar parts that have been conserved by evolution," says Dr. Gibbs. The scientists will look at those similarities - and differences - to gain a better understanding of the human genome. A third model, that of the social amoeba Dictyostelium discoideum, is also on the Baylor center's list. The amoeba contains 34 million bases in its genome and the efforts to decipher it are being conducted collaboratively with other centers. The project is funded by the National Institutes of Health, through the National Institute for Child Health and Human Development. The applications that could result from such work on comparative models and the Human Genome Project are vast. Due for completion in 2003, the 50th anniversary of Watson and Crick's discovery of the double helix structure of DNA, the completed human genome will offer scientists an incredible resource. The wealth of information available could one day bring about new ways to detect, treat and even prevent disease at the molecular level. For example, Dr. Gibbs says his group is currently working with Dr. Judith Margolin, a pediatric oncologist at Texas Children's Hospital, to understand what happens when the white cell population is overtaken in children with acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML). He also cites work with Dr. Heather Goodman in the department of psychiatry and behavioral sciences at Baylor to locate a gene associated with schizophrenia. "This is where the Human Genome Project comes into its own," says Dr. Gibbs. "It acts as a net that will catch all of the fish and then allow us to look through them one at a time."
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