Progress, and Applications
of the Human Genome Project
Sponsored by the U.S. Department of Energy Human Genome Program
Human Genome News Archive Edition
Human Genome News, January-March 1996; 7(5)
STS-Based Map Represents Halfway Point to 100-kb Human Genome Project Goal
In December 1995, a team led by scientists at the Whitehead Institute Massachusetts Instituteof Technology (MIT) Center for Genome Research and Genethon presented the most detailed physical map of the human genome yet published. The new map which contains more than 15,000 STS DNA markers spaced an average of 199 kb apart, covers almost 95% of the entire genome. Previously, the highest-resolution whole-genome physical map, a clone-based effort reported last fall in a special supplement toNature, covered about 75% of the genome and involved about 2500 STSs.
Reported in the December 22, 1995, issue of Science (270, 1945-54), this latest achievement brings within close range the short-term Human Genome Project goal of a 100-kb whole-genome map requiring about 30,000 STSs. The map project required 2.5 years and involved a Whitehead-MIT team averaging 16 researchers in mapping, 3 in sequencing, and 5 in data management and computational analysis. Although originally slated for 1998, map completion by Whitehead-MIT and other groups is expected by the end of this year.
Detailed genome maps and improved technology will drastically reduce the time needed to localize and clone disease genes and also enable researchers to determine the complete sequence of all human DNA the ultimate goal of the Human Genome Project.
The new map is based on STSs DNA markers that can be used in various physical and genetic mapping techniques to provide a common link for integrating and comparing different types of genome maps. Another advantage of STS-based maps is their accessibility. Stored electronically in publicly available databases, STSs are easily accessible to researchers, who can obtain any mapped chromosomal region by PCR-based clone screening for particular STS markers.
Detecting and placing STSs on the 3 maps required over 15 million PCR analyses. Eric Lander, director of the Whitehead-MIT genome center, and Thomas Hudson, leader of the mapping team, credit their success to a strong, early commitment to laboratory automation. The team spent the first 1.5 years of the project developing automated robots, designing mathematical pooling schemes to reduce the number of tests required to localize markers, and generating a bar-coding system like that used in supermarkets to accurately identify and track samples. The researchers also adapted camera technologies from the aerospace industry to read PCR test results directly into the computer database and created computer programs to check data automatically and design new sets of experiments based on existing results.
The resulting Genomatron, built in collaboration with Intelligent Automation Systems, enabled scientists to run 300,000 PCR reactions/day compared with 6000/day in 1993.
Combined Genome View
The new map is a combination of three independent maps that were joined to produce an integrated map with different levels of detail. Efforts by the Whitehead-MIT team included (1) construction of an STS-content map consisting of 10,000 STSs screened in the CEPH YAC library and depicting marker order over a range of about 1 Mb; (2) assembly of a radiation hybrid (RH) map consisting of roughly 6200 markers enabling STSs to be mapped up to about 10 Mb; and (3) incorporation of the 5200-loci Genethon genetic linkage map allowing STS mapping over distances up to 30 Mb (Dib et al., Nature 380, 149-54 (March 14, 1996).
Each type of map has advantages. Genetic and RH maps help determine the long-range order of STS landmarks, and STS-content maps are best suited for estimates of fine-structure order. "Integration of the three strategies allowed us to check and recheck the accuracy of our data, producing a detailed product with a high level of precision," said Hudson, who coauthored the Science article with Lander, Lincoln D. Stein, and others.
The combined map makes much of the human genome accessible to the entire community, Hudson continued. "The wonderful feature of an STS-based map is that any scientist can find a specific location in the human genome by setting up the appropriate PCR assay," he said. "All the information necessary to locate an STS from our map is freely available by computer through our World Wide Web site. In one recent week we had 67,000 accesses to that site."
Scaffold for Sequencing
The Science article authors state that this STS-based map also presents a practical scaffold for initiating large-scale sequencing. STS maps are useful for production sequencing, they note, because the markers are anchored in the genome. Improved libraries can be substituted easily as they become available, and efforts can focus on regions of any size, instead of entire chromosomes. "Generating the complete sequence of human DNA is the most exciting adventure in modern science," says Lander. "In the 19th century, chemists defined the periodic table of elements, and it forever changed the practice of chemistry. Sequencing the human genome will have the same impact on human biology and medicine. It will give us a new understanding of human development and a broad array of new tools for fighting human disease."
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