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Genetics and Genomics Timeline
J. Craig Venter (1946-) describes a fast new approach to gene discovery using Expressed Sequence Tags (ESTs)

Shortly after the Human Genome Project got underway in 1990, J. Craig Venter, then with the National Institutes of Health (NIH), demonstrated a novel method to accelerate gene discovery. At the time, relatively few human genes had been identified and physically mapped to the genome. But molecules called Expressed Sequence Tags (ESTs) offered an efficient way to find genes and explore their functions. In addition, ESTs demonstrated the speed, accuracy and promise of automated sequencing technology.

J. Craig Venter
The EST concept arose from the development of complementary DNA (cDNA). When a gene is expressed, its unique sequence of bases is transcribed onto messenger RNA (mRNA). These molecules, which serve as templates for protein synthesis, can be captured from the various tissues in which they are found. Although fragile and transient, mRNA molecules can be translated into sturdier complementary DNA (cDNA). By 1990 researchers had recourse to "libraries" of such cDNA molecules. ESTs are cloned segments of cDNA molecules that have been partly sequenced—usually several hundred bases from both ends. These sequenced ends could, in theory, provide information about the location and function of the entire gene they represent.

At the NIH's National Institute of Neurological Disorders and Stroke (NIDS), Venter and his colleagues were well-placed to appreciate the potential value of ESTs. Venter had spent a decade working on a few genes, and he was disposed to improve current strategies for gene discovery. With that aim, he initiated a pilot project with ESTs created using automatic sequencing. The results, published in Science in 1991, exceeded expectations.

ESTs could identify new genes. Over 600 ESTs made from cDNA drawn from brain tissue were compared for similarities with known genes. Some were matches, but 230 ESTs represented previously undiscovered and uncharacterized genes.

ESTs could be used to help map known genes to chromosomes. Venter and his colleagues readily mapped 46 ESTs to human chromosomes. In this way, ESTs promised to become a powerful tool to search for families of genes and genes implicated in heritable disorders.

ESTs showed the accuracy of automated sequencing technology. Comparing some 90 matches between ESTs and already sequenced genes, the automatic sequencing machine (Applied Biosystems 373A) was found to have an accuracy rate of 97.7 percent.

Although controversial when first introduced, ESTs were soon widely employed both in public and private sector research. They proved economical and versatile, used not only for rapid identification of new genes, but also for analyzing gene expression, gene families, and possible disease-causing mutations.

ESTs could also facilitate an overview of the whole genetic repertoire of an organism, and in this way helped establish the important discipline of comparative genomics. EST databases were established for various animals, plants, and even fungi. In 1995, in a landmark supplement to Nature, the Venter team described some 170,00 ESTs that could be used to identify over 87,000 cDNA sequences from various tissues in the human body—over 80 percent of which were previously unknown.

Adams, M.D. et al. Complementary DNA sequencing: "expressed sequence tags" and the human genome project. Science 252, 1651-1656 (June 21, 1991).
Adams, M.D. et al. Initial assessment of human gene diversity and expression patterns based upon 83 million nucleotides of cDNA sequence. Nature 377 (Suppl.): 3-174. (September 28, 1995).

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