New method may speed gene searches.

To geneticists, the final frontier lies literally at our fingertips -- and elsewhere in the body.. Each of our cells holds a vast storehouse of genetic information in some 100,000 genes strung out along 46 chromosomes. Collectively this material forms the human genome.

Using DNA probes - snippets of genetic material that home in on specific segments of the genome - geneticists have explored the genes of people in families affected by various inherited illnesses, seeking the defect that causes their disease. These "linkage studies" have scored important successes, but they remain painstakingly slow to carry out.

Now, a new technique, genomic mismatch scanning ((ELMS), may provide geneticists with a more rapid and precise means of finding genes. The technique uses a series of enzymes to isolate identical stretches of DNA - the thread-like molecule that holds the genetic code from different individuals. Knowing the regions of DNA shared by two related individuals - possibly inherited from a common ancestor- helps geneticists find the particular locations on chromosomes that carry disease genes.

"GMS makes it appear feasible to go after a lot of genetically complex traits that would be ridiculously expensive and laborious, and maybe impossible, to do by any other means;' says Patrick O. Brown of Stanford University Medical Center. Such complex, multi-gene traits include susceptibility to schizophrenia.

Brown and his colleagues describe their use of the technique, which they developed, to study inheritance patterns in yeast in the May issue of NATURE GENETICS. The researchers are now working out the details of how to use GMS on the larger, more complex human genome.

GMS uses a series of enzymes, including several from the DNA-repair machinery of the bacterium Escherichia coli. Researchers break up the chromosomes of two individuals into thousands of fragments, unzip their two mirror-image strands of DNA, and then allow the separated strands to regroup, sometimes as a mixture of strands from two individuals. Then, enzymes eliminate all combinations but those that contain identical genetic information from two individuals. Scientists can use these surviving fragments to identify the DNA that two individuals inherited from a common ancestor

In conventional linkage analysis, researchers use previously mapped reference points on chromosomes, called genetic markers, to narrow the search for a gene to a general region of a chromosome. These markers often pass in identical form from parent to child along with nearby genes. After years of scrutinizing the DNA of related individuals affected by a disease, researchers can find markers that point to the gene's approximate location.

According to Stanley E Nelson, a postdoctoral fellow in Browns laboratory, researchers using conventional linkage analysis may have to check scores of markers, one by one, to track down an inherited trait. "The biggest advantage GMS offers is the ability to scan an entire genome all at once;' says Nelson.

But a formidable obstacle currently blocks widespread use of GMS on human DNA: The human genome contains a great deal of duplicate information. These repetitious DNA segments interfere with the GMS process, hindering its ability to create useful amounts of perfectly matched DNA fragments. The researchers believe they can solve these problems, however, and the results of preliminary experiments using GMS on human DNA are "encouraging:' Brown says.

Dramatic proof of GMS' usefulness may come when scientists use it to track down genes responsible for an inherited disease, comments Jean-Marc Lalouel at the University of Utah in Salt Lake City, Lalouel and his colleagues are working to understand the genetic basis of high blood pressure (SN: 10/10/92, p.230).

"If the [GMS] method could be adapted to the human case, the impact could be very large indeed;' says Stanford geneticist David Botstein.