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In addition to being a landmark in biology, the sequencing of the human genome has been a top-flight engineering achievement. A single DNA sequencing machine now can produce over 330,000 bases (units of genetic information) per day, more than could be managed by a hundred scientists in a a year and a half of work less than a decade ago, when the Human Genome Project began. In the November IEEE Spectrum, contributing editor John Hodgson explains the achievements in automation that enabled scientists to read the over 3 billion bases that form the instruction book for building and operating a human being.
At a basic level, DNA sequencing calls for the preparation and replication of relatively short segments of DNA, the creation of matching copies, each of them one base longer than the next, the identification of the last base in each segment, and the ordering of the identified bases. At almost every step, technological developments have accelerated the pace of discovery. Robots shift genetic material from station to station with speed and accuracy, sequencing machines using multiple capillaries filled with polymer gel have increased throughput to an astonishing volume while reducing sequencing error, and DNA assembly computer systems have been constructed that recently set in order a 120-million-base genome in less than a week's worth of calculations. Hodgson writes that without significant advances in automation the Human Genome Project would have been at least twice and perhaps five times as costly as it has been.
Several technologies central to sequencing DNA were on the drawing board when the project started in the early 1990s, but only one of them, capillary gel electrophoresis, came through in time to make a major contribution. This technique starts with several copies of a segment of DNA, each copy one base longer than the next and each tagged with a fluorescent dye that color-codes the last base in the segment. The DNA copies are sorted according to length as an electric field drives them down a polymer gel-filled capillary. The gel slows longer pieces more than shorter pieces. A laser scans the DNA as it exits the capillary, causing the attached dye to glow. A sensor detects the glow and signals a computer, which determines the identity of the base by the color of the glow.
Several key computer programs put the various pieces of sequenced DNA in the order in which they are found in the human genome. The most important are Phred, Phrap, and Consed. The first determines the accuracy of the sequencing machines, the second puts the strings of DNA sequence in the order they are found in the human genome, and the third determines what gaps need to be filled in the sequence. Celera Genomics of Rockville, Md. uses a more powerful computer program to string together whole genomes at once, Hodgson explains.
Contacts: John Hodgson, 44 181 691 5941, [email protected]; Samuel K. Moore, 212 419 7921, [email protected].
For faxed copies of the complete article ["Gene sequencing's Industrial Revolution," by John Hodgson, IEEE Spectrum, November 2000, pp. 36-42] or to arrange an interview, contact: Nancy T. Hantman, 212 419 7561, [email protected].
URL: http://www.spectrum.ieee.org
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