WASHINGTON _ A newly discovered gene marker _ identifiedusing a powerful, broadly applicable analytic technique _ mayprovide a potent new tool for tracking the prehistoric path of nativeAmericans from Asia to the New World.

Scientists at Stanford University, in Palo Alto, Calif., reportedMonday in the Proceedings of the National Academy of Sciences thatthe single-point mutation _ in a gene on the Y chromosome knownas DYS199 _ appears to be common to several groups of nativeAmericans who speak different languages.

The paper is titled, "A pre-Columbian Y chromosome-specifictransition and its implications for human evolutionary history."

If subsequent research can identify the same rare mutation in adiscrete Asian population, the scientists believe they would havesolid evidence that they have located the Asian ancestors of nativeAmericans.

Geneticist L. Luca Cavalli-Sforza and his coworkers have calculatedthat the mutation _ from the gene's C allele to the T allele _occurred 30,000 years ago, centuries before the settling of the NewWorld.

By examining the genes of 173 humans and six non-human primatesfrom five continents, the researchers determined the T allele waspresent in more than 90 percent of native South and CentralAmericans, 50 percent of North American Navajos and 67 percent ofthe Eskimos studied. It does not appear in those from outside theAmericas.

The researchers believe mingling between native populations andEuropean settlers is the reason some of the native people testedlacked the tell-tale allele. Further comparisons may ultimately make itpossible to determine how often native Americans intermarried withHispanics after Spanish settlers arrived in the Americas, according tothe report.

"We wanted to reach back thousands of years into human prehistory,"Peter Underhill, a Stanford molecular biologist and the study's leadauthor told BioWorld Today. "That's one reason to use geneticinformation about where we come from and who we're related to. Butwithin a few generations, so much genetic recombination occurs thatit becomes difficult to track markers through generations."

The challenge, Underhill said, is to find markers "that persist overmany generations and that don't get too scrambled by the processesof human recombination."

A Window To The Past

Underhill's mentor and a lead author on the paper, Cavalli-Sforza,has long viewed the Y chromosome as a potential window into thepast because _ even though it represents just a fraction of the humangenome _ it remains virtually intact as it flows through manygenerations of fathers and sons.

"The Y chromosome has some unique advantages," Underwood said."It doesn't undergo recombination, so it tends to preserve rare,chance mutations that happen occasionally and persist over manygenerations."

But those mutations have been tough for researchers to track down.The reason is simple: Polymorphisms on the Y chromosome appearto be few and far between.

"Many people who have looked have walked away because they havenot had the tools, or the energy, or the resources to search enough ofthe Y chromosome to find the variations that are out there," Underhillsaid.

The traditional approach would have required the Stanford team tosequence the genes on the Y chromosome of a number of researchsubjects. Then the researchers would have had to compare thesequences, looking for elusive variations.

"They came up dry," Underhill said.

Given the difficulty and the esoteric nature of the informationobtained, Underhill said, research institutes and investment bankersare reluctant to fund such projects. Before they commit large sums ofmoney, he said, potential backers want to know the work willeventually have some practical application.

They are likely to ask: Why don't you sequence something moreimportant like a disease-causing gene.

So Underhill and Peter Oefner, a Stanford researcher who hasdeveloped extensive expertise using high-performance liquidchromatography, set out to find a new, more efficient, method ofidentifying elusive markers without having to rely solely onsequencing techniques.

`Real Gem' Helps Locate Polymorphisms

"We were driven to try to come up with a method because all theexisting methods of searching DNA for polymorphisms are labor-intensive, time consuming and inefficient," Underhill said. He calledthe result of their collaboration, "the real gem of this paper."

In essence, Underhill said, "We've invented a new method thatmakes it much more practical, much more efficient to find thesepolymorphisms."

The technique, which they call "denaturing high performancechromatography [DHPLC]," is relatively simple. The researcherstake segments of the Y chromosome from two individuals fromdifferent population groups.

They put the fragments into solution and heat the solution to 95degrees. The heat forces the two fragments to separate into fourstrands.

Then the researchers wait for the solution to cool.

If the strands are identical, they will reanneal "to their exact mate,"Underhill said.

But if there is a polymorphism, only two of the four strands willmatch perfectly, and the unmatched pair will exhibit slightly differentchromatographic behavior on high performance liquidchromatography.

"In five minutes you see a separation," he said. "You see a signaturethat tells you within a matter of minutes you've got a hit."

Underhill said that this method could have far-reaching implicationsfor unrelated genetic research.

"If DHPLC is as good as I think it is, what will come of this veryesoteric study of human origins will spill over rapidly into thebroader genetic community."

Ultimately, he said, scientists who are looking for mutations andpolymorphisms for work that is "completely unrelated to humanhistory" will be able to use the technique for such practical projectsas gene mapping and localization and "comparing the genes ofpeople who are affected with a genetic disease with those of peoplewho are not affected."

Stanford has applied to patent the process, but the university plans toallow researchers time to try it out before charging licensing fees. n

-- Steve Sternberg Special To BioWorld Today

(c) 1997 American Health Consultants. All rights reserved.