NINDS Scientists Isolate Segments Of DNA Sequence That Identify More Than 2,300 Brain Genes

For release: Wednesday, February 12, 1992

Using a novel strategy, scientists from the National Institute of Neurological Disorders and Stroke have isolated segments of DNA sequence that uniquely identify more than 2,300 brain genes. The recent data, combined with data from 347 segments sequenced earlier by NINDS scientists, doubles the total number of human genes identified by sequencing, scientists report in the February 13 issue of Nature .

The scientists say the DNA segments (called expressed sequence tags or ESTs) may speed the progress of genetics research. "These expressed sequence tags are rapidly expanding the information scientists have about human genes. They will accelerate identification of certain disease genes by providing scientists a shortcut to pinpointing genes amid long stretches of chromosome DNA," said J. Craig Venter, Ph.D., the NINDS scientist leading the gene-sequencing project.

More than 1,900 of the 2,375 tags isolated and sequenced in the study represent "new" human genes that were previously unknown, Venter said. Of these, only about 200 tags were identified by their similarity to previously known genes. For example, Venter explained, several ESTs apparently represent human brain genes that are "close cousins" to genes found in fruit flies, where they are known to play a role in development. In addition, some of the newly found genes were identified by their similarity to genes isolated from bacteria, yeast and such plants as rice and barley.

Venter and his colleagues, including Mark Adams, Ph.D., Anthony Kervalage, Ph.D., and Chris Fields, Ph.D., have made all of the sequences from new tags and the corresponding clones available to other scientists through public sources, including GenBank, a computer database, and the American Type Culture Collection. Venter's team has also created a computer database that cross-references much of what is known about the tags. Reports from this database are available free, via computer, to all scientists.

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.

In studies to sequence the human genome, scientists typically decode a strip of DNA from the chromosomes within the cell's nucleus to get an ordered string of nucleic acid letters, or sequence. This sequence is comprehensive and includes a small proportion of code from genes located within a large amount of other genetic code, most of which has unknown function. In the NINDS study, however, scientists sequenced key regions of DNA only from genes known to be expressed in the brain. These ESTs are unique to each gene.

One of the major initial goals of the Human Genome Project is to identify and map all 50,000-100,000 human genes along the cell's chromosomes, so that scientists can locate and decipher the more than 5,000 genes that cause human disease. "ESTs will complement, even accelerate, this effort," Venter said. "Mapping ESTs to the chromosomes will provide markers of where expressed genes lie within a given stretch of chromosomal DNA. Combining our efforts with those to map the human genome should enable scientists to identify disease genes more quickly and thus help open the door for new diagnostic and treatment strategies."

ESTs could also help identify genetic defects that cause brain disease, such as the gene for Huntington's disease, Venter said. "It will help those looking for the cause of brain disease, because mapping ESTs will tell them where expressed brain genes are located." For example, he 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 likely candidate for causing the disease.

Of the estimated 5,000 human genetic diseases, one in four affects the brain and nervous system. Besides Huntington's disease, neurogenetic disorders include such diseases as Alzheimer's disease, other forms of dementia, and neurofibromatosis.

Venter said his team will now sequence ESTs for the rest of the expressed brain genes during the next 2 to 5 years — at a rate of 168 genes each working 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," Venter said.

In their ongoing project, NINDS scientists take 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" in the cell to form a protein, the cell creates a temporary copy, called messenger RNA (mRNA), with a nucleic acid sequence that nearly mirrors the original DNA. Starting with brain tissue, scientists extract this mRNA, then use it to recreate the sequence of the DNA found on the original gene. The recreated DNA is called complementary DNA (cDNA). Each piece of cDNA that corresponds to one gene is 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.

The NINDS, one of the 13 National Institutes of Health in Bethesda, Maryland, is the leading supporter of brain and nervous system research in the United States.

Date Last Modified: Tuesday, March 08, 2005

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