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NINDS Scientists Develop Strategy To Speed Gene and Brain Research

For release: Thursday, June 20, 1991

Using a novel strategy, scientists at the National Institute of Neurological Disorders and Stroke (NINDS) have isolated key identifying regions of more than 400 genes that work inside the human brain. Their results appear in the June 21 issue of Science .* The scientists say their work should help identify genetic defects that cause brain disease and speed progress of genetics research.

Of all the DNA found coiled inside the nuclei of human cells, only about 3 percent consists of genes, or strips of DNA that hold blueprints for the proteins required for life. Some of these genes are active in all tissues, while others are expressed only in certain parts of the body, such as the heart, liver or brain. The number of genes expressed in the brain may be as many as 30,000 of the body's approximately 50,000-100,000 genes.

Sequencing studies examining the human genome generally sequence all of the DNA found inside each human cell. In the NINDS study, scientists sequenced only partial DNA from genes expressed in the brain, saying their strategy is a valuable advance in gene sequencing.

"If your aim is to sequence the genes, this strategy is fast, efficient and cheap," said J. Craig Venter, Ph.D., chief of the NINDS Receptor Biochemistry and Molecular Biology Section. "Using our strategy," Dr. Venter explained, "we can obtain a unique DNA region that identifies the gene over a very short time and at a cost of about $48 -- a fraction of what sequencing 100 percent of the DNA will eventually cost."

These unique regions, called expressed sequence tags (ESTs), are stretches of sequenced DNA taken from separate genes. Dr. Venter said they offer scientists a shortcut in their genetic research. Much in the same way that police use fingerprints to identify suspects for a crime, scientists can use the tags to identify a gene quickly and efficiently.

"Normally if you sequence DNA from cells, it's very difficult to tell where the genes are," said Dr. Venter. "But if you have tags and know their nucleic acid sequence, you can spot the genes hidden in a long strand of sequence. You can also tell if the gene is expressed in the brain."

Of the 466 tags that were located and sequenced in the study, more than 330 represent new human genes. NINDS scientists found that 48 of these new genes closely matched known genes from other well-studied species, including yeast and fruit flies. They now plan to collaborate with other scientists in uncovering the role of the additional new genes.

Sequenced ESTs could also speed mapping of disease genes that affect the brain, such as the gene for Huntington's disease, Dr. Venter said. "It will help those looking for the cause of genetic disorders," he predicted, "because we can immediately map the ESTs onto the chromosomes."

For example, Dr. Venter explained, if one of the ESTs were to map to the chromosomal region suspected of containing the Huntington's disease gene, then the sequenced brain gene would immediately become a possible candidate for causing the disease. Thus far, NINDS scientists have mapped 46 ESTs to human chromosomes.

Of the estimated 4,000 genetic diseases, one in four affects the brain and nervous system. Besides Huntington's disease, neurogenetic disorders include such diseases as neurofibromatosis, muscular dystrophy, and Alzheimer's disease.

"The identification of ESTs could make a significant contribution to the analysis of human genes," said Elke Jordan, Ph. D., deputy director of the National Institutes of Health National Center for Human Genome Research. "Dr. Venter is one of the first to demonstrate the usefulness of automated commercial sequencers in obtaining large amounts of DNA sequence information."

"ESTs will boost efforts to sequence the human genome," Dr. Venter said, "and work should continue to sequence all of the DNA, since areas that are not expressed genes will also contain important information about health and disease."

Dr. Venter said he and his colleague Mark Adams, Ph.D., will now sequence ESTs for the rest of the expressed brain genes during the next five years -- at a rate of 48 genes each day. "Nobody would have even considered embarking on something this ambitious before--this is the first time sequencing has been done on this scale. It represents a major advance in the rate we gain new information on the brain," Dr. Venter said.

In Dr. Venter's laboratory at the NINDS, DNA sequencing is completely automated: a computer-controlled robot performs the "exacting and tedious" chemical reactions to process the DNA; a computer scans and color codes the DNA base pairs; and the sequences are put back in order using several additional computers. "It requires a lot of equipment that you don't find in most laboratories," Dr. Venter said.

In the study, NINDS scientists working with colleagues at the National Institute of Mental Health took advantage of special collections -- called cDNA libraries -- to narrow their sequencing to expressed genes. These libraries contain genetic material derived from brain tissue by a complex process.

Whenever a gene is read to form a protein, the cell creates a temporary copy, called messenger RNA, with a nucleic acid sequence that nearly mirrors the original DNA. Starting with brain tissue, scientists extract this RNA, then use it to recreate the sequence of the DNA found on the original gene. The recreated DNA is called complementary DNA (cDNA), with each piece of cDNA corresponding to one gene and known as a cDNA clone. By using libraries of many such cDNA clones, NINDS scientists were able to bypass long stretches of DNA that are not used to make messenger RNA and, therefore, are not expressed.

NINDS scientists took more than 600 cDNA clones at random from three libraries, obtained partial sequences with automated techniques and isolated 466 ESTs. The remaining partial sequences were not sufficiently unique to be used as ESTs.

The National Institute of Neurological Disorders and Stroke, one of the 13 National Institutes of Health in Bethesda, Maryland, is the primary supporter of brain and nervous system research in the United States.

*Mark D. Adams, et. al. "Complementary DNA Sequencing: Expressed Sequence Tags and the Human Genome Project." Science, June 21, 1991.

Last Modified August 7, 2009