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, September 1990; 2(3)
Achievement of some of the 5-year goals of the U.S. Human Genome Project relies heavily on the use of the new sequence tagged site (STS) strategy for mapping. The following specific goals make use of this strategy:
What are STSs and Why Are They So Important to the Project?
An STS is a short DNA sequence that uniquely identifies a mapped gene or other marker. The order and spacing of these sequences compose an STS map. A year ago, a new mapping strategy using STSs was enthusiastically received by the scientific community because it promised to solve some of mapping's thorniest problems by providing mappers with a common language and a system of landmarks. The STS approach was made possible by development of the polymerase chain reaction (PCR), which allows rapid production of multiple copies of a specific DNA fragment, for example, an STS fragment.
STSs Will Aid Integration of Diverse Mapping Data
A major challenge in generating a complete physical map has been the difficulty in comparing directly the results obtained by different mapping methods and in combining maps constructed by different techniques into a consistent whole. Cosmids, yeast artificial chromosomes and other recombinant DNAs are being used to produce physical maps as libraries of ordered clones. STSs are expected to be invaluable in solving the problem of combining data from different kinds of recombinant DNAs. For more information on mapping, see the article How Will the STS Strategy Be Used in Mapping?
How Will STSs Facilitate Mapping?
If physical mapping of human chromosomes is to be achieved within 5 years, continuity of physical mapping data over long stretches of DNA is necessary. With STSs, laboratories would use whatever mapping techniques they choose; however, results would always be reported in terms of the STS markers (i.e., in the same language). Therefore, each mapped element (individual clone, contig, or sequenced region) would be defined by a unique STS-a short DNA sequence that has been shown to occur only once in the genome. A crude map of the entire genome, showing the order and spacing of STSs, could then be constructed.
Because almost all mapping methods use cloned DNA segments as landmarks, establishing an STS would require the investigator to determine a short sequence of DNA that defines the landmark. These sequences can be used to synthesize two PCR primers. The primers can then be combined with genomic DNA and DNA polymerase to produce millions of copies of the STS target DNA sequence in a few hours. The PCR-amplified DNA is thus available in sufficient quantity to be characterized further by hybridization, electrophoresis, or sequencing.
Sequence information generated in this way could be recalled easily and, once reported to a database, would be available to other investigators. With the STS sequence stored electronically, there would be no need to obtain a probe or any other reagents from the original investigator. No longer would it be necessary to exchange and store hundreds of thousands of clones for full-scale sequencing of the human genome-a significant saving of money, effort, and time. By providing a common language and common landmarks for mapping, STSs will allow genetic and physical maps to be cross-referenced.
Additional benefits include the following:
Joint Mapping Working Group
An established standard for reporting data will be necessary to make the STS concept usable. Toward this end, the Joint Mapping Working Group met in March at Los Alamos National Laboratory (LANL) to develop a working standard of STSs for the Human Genome Project. They tentatively agreed that STSs would be reported as pairs of oligonucleotide primers that have been tested and shown to produce a PCR product that identifies a single band in a Southern blot with total DNA from a human male. Several experimental projects are already under way to test the practicality of the proposed standard. As experience is gained in generating and using STSs, this standard may be modified, especially as technology changes.
The working group also stated that a primer pair that meets a less stringent standard (e.g., one that amplifies a single sequence but does not identify a single Southern band when tested on genomic DNA) might still be useful under some circumstances.
This article was compiled from information drawn from Understanding Our Genetic Inheritance, the U.S. Human Genome Project: The First Five Years, FY 1991-1995; Science 245: 1434-35, 1438-40 (September 29, 1989); and Science 248: 805 (May 18, 1990). HGMIS wishes to thank Maynard Olson and Eric Green (Washington University School of Medicine) for reviewing this article prior to publication.
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