22 July 2003 12:00 GMT

by Laura Spinney

A common genetic mutation that confers protection against HIV and possibly also multiple sclerosis and type 1 diabetes may have arisen over 1000 years ago in a lost kingdom in what is now Russia, according to an Australian geneticist.

Marc Buhler of the Institute for Immunology and Allergy Research at the University of Sydney thinks that the delta32 deletion mutation in the CCR5 gene is now a target for selection because it protects against certain strains of HIV, but that initially it may have been selected for because carriers survived small pox - a potential killer on the eastern trade routes around 800 AD.

The CCR5-delta32 mutation is particularly common among Ashkenazi Jews, and for that reason has always been thought to have originated in a population of northeastern Europe - where the Ashkenazis last settled en masse.

But not all Ashkenazi populations show this higher incidence-among Ashkenazis from Western Europe, for instance, it occurs with the same frequency as in Caucasian non-Jews. So Buhler set out to measure the mutation's frequency in a group of around 1400 Australian Ashkenazi Jews.

He found that the mutation occurred with a frequency of 15% in this group, compared with 6% in a group of Sephardic Jews and 11% in Caucasian non-Jews. He then genotyped the 26 Ashkenazi Jewish individuals who turned out to be homozygous for the mutation, and measured the degree of recombination that had taken place in the region in which the mutation occurs to come up with an estimate of when the mutation first arose.

To his surprise, his calculations generated an age of 50 generations, or just over 1000 years. The Ashkenazi Jews left Israel around 2000 years ago, settled in and around Germany and were later expelled from their adopted home after the plague of the 14th century, for which they were blamed. After that, they dispersed far and wide.

Since the mutation is not common among the Sephardic Jews who stayed in the Middle East, and since it appears to be older than the Ashkenazis' Germanic period - the last time they were concentrated as a population - Buhler surmises that it had its origins elsewhere.

There were several other pieces to fit into the jigsaw: for instance, the incidence of CCR5-delta32 is relatively high among Scandinavians. "But the real motherlode of the mutation seems to be the Russian, Polish Jewish community," says Buhler.

When he gathered information about his Ashkenazi volunteers' forebears, he found that the frequency of the mutation leapt to 20% in a subgroup whose grandparents came from Russia or Eastern Europe - almost 10% higher than the frequency among Western European Ashkenazis.

Having pored over his history books, Buhler has now come up with an intriguing scenario to accommodate all these findings, which begins with the forgotten kingdom of Khazaria.

Khazaria lay to the east of the Black Sea and to the north of the Silk Road, a region that would now fall into southern Russia. According to Buhler's research, the Khazars were descendants of the Mongol nomads of Central Asia who settled there before the 6th century and fought a protracted war with their Arab neighbors.

He thinks the mutation may have arisen spontaneously among these people, spreading rapidly through the population because carriers were more likely to survive small pox.

"Pox virus uses the [CCR5] receptor signal pathway to tickle a cell from the inside, as if the receptors all around the cell are saying simultaneously, 'move in this direction'," Buhler explains. In other words, the effect of the virus is to confuse the cell.

"Lacking this particular receptor allows the cells to get to the lymph node where they can mount an immune response," he continues. "You may get pocked up with small pox, but you survive."

Since small pox kills around one third to a half of its untreated victims, Buhler says selection would have been very strong for CCR5-delta32 if heterozygotes did indeed avoid death.

After the war with the Arabs, the history gets even more interesting. As a protest against the oppressive forces of Christianity and Islam hemming them in on all sides, upper class Khazars adopted Judaism in the mid-10th century.

Meanwhile, between the 8th and the 10th centuries, Vikings passed by, lured eastwards by the promise of Arab gold.

"The Jewish Khazars had the main block of the mutation," says Buhler, "But a few [Khazar] slaves kidnapped by the Vikings would have been enough for them to take it away as a souvenir."

Khazaria ceased to exist around the 13th century, when it was absorbed by Russia, and from then on the Khazar Jews would have blended with the Ashkenazi ancestors of Buhler's Australian volunteers.

David Heckel, a geneticist at the University of Melbourne, Australia says the findings are fascinating. "In this kind of human population study there are always so many different types of cultural information to be taken into account," he said.

And Haci-Murat Hubey, a computer scientist at Montclair State University in New Jersey, USA who studies linguistics in his spare time, adds a further dimension to the already complex cultural picture. There is now plenty of evidence that the Khazars didn't come from Central Asia at all, he says.

"They weren't descendants of the Mongols," said Hubey. "They were probably related to the Huns. In fact, there is a group called the Kidarite Huns whose name probably derives from Khazar."

Buhler presented his study, which is unpublished, at the International Congress of Genetics in Melbourne at the beginning of July.