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Ancient DNA may hold clue to HIV resistance

Usually DNA analysis tells a story of the future or recent past. In hospitals, genetic tests reveal patients’ risk for disease and in court rooms it helps solve crimes. But for students of history, DNA can also unlock the door to the distant past.

One unorthodox research team, comprised of Danish biochemists and archeologists, is analyzing genetic material from ancient bones to solve the mystery of why many Northern Europeans are resistant to HIV.

The 32D mutation increases in frequency with distance from the Mediterranean. The plague began in Sicily and spread north to hit Scandinavia around 1350.

Biochemist Jesper Eugen-Olsen leads a team at Copenhagen’s Hvidovre Hospital that investigates the disease mechanisms of HIV. But he also has an abiding interest in history. He has worked for years with a genetic mutation that confers immunity to HIV. To delve into the history of this mutation, Eugen-Olsen teamed up with archeologist and carbon-dating expert Kaare Lund Rasmussen, of the Danish National Museum.

This mutation—called 32D—is a deletion of 32 DNA bases in a gene encoding CCR5, a protein that allows HIV to enter cells. Two copies of the mutation confer complete protection against HIV. A single copy confers only partial protection. Individuals inheriting only one copy of the mutation can become infected, but they stay symptom free considerably longer than those with no mutations of the CCR5 gene.

"It always puzzled scientists in the field that the mutation never occurs in Asian or African populations, but only among European Caucasians," Eugen-Olsen says. Within Europe, the mutation shows a characteristic gradient, with an extremely high prevalence in the North tapering off towards the Mediterranean. So while only eight of 100 Southern Italians carries a copy of 32D, one in every four Danes has it.

From its distribution, most scientists agree that 32D emerged in Northern Europe. Because 32D is identical in all carriers, the mutation probably arose in one person, an ancestor to all those who now carry the mutation. But when did that ancestor live? For the mutation to be widespread in the Danish population, it must have arisen long before the known advent of HIV. In order to have spread so successfully, it must at some point have provided its carriers with a selective advantage, Eugen-Olsen reasons. "Most likely it conferred immunity to one or more epidemics that selectively wiped out people with a normal CCR5 gene."

One hypothesis holds that this epidemic was the bubonic plague of the Middle Ages, which killed a third of Europe’s population. According to this hypothesis, 32D would have protected carriers against plague.

The Danes doubt this conclusion. "Examining the history of the plague made us dispute this," says Rasmussen. The Black Death began in Sicily and spread north to hit Scandinavia around 1350. This course would predict that the prevalence of 32D should be higher in the south, just the opposite of its observed prevalence. Furthermore, molecular evidence remains inconclusive. Using two different molecular methods for dating mutations, two American teams have analyzed human DNA attempting to determine when 32D first arose. But their estimates vary widely. One group came up with a figure of 700 years and the other with 2,000.

Eugen-Olsen and Rasmussen are taking an alternative route. Building on the assumption that 32-D arose in Scandinavia, they are trying to nail down the time of its explosive spread by examining DNA from bones found in Denmark and dating from the period between the last ice age (around 8,000 BC) and 1950.

In particular, the scientists have their eyes on a Mesolithic period of massive cultural change, between 1,800 and 2,600 BC. Archeological evidence shows that the shift dramatically changed weapons, ornamentation, farming methods and burial customs. Archeologists call the new culture the Single Grave Culture, and have speculated that massive migrations brought on the change.

The Danish team is the first to suggest instead that one or more epidemics caused the cultural change. According to Rasmussen, an epidemic decimating the stone age population could explain the archeological observations as well as the distribution of 32-D. "There is support in the fact that the distribution of the Single Grave Culture in Northern and Middle Europe matches that of the high prevalence of 32D."

Although still a work in progress, the Danish project is already turning up evidence against the reigning Black Death hypothesis. After extracting DNA from some 50 ancient bone tissue samples, the researchers have identified the mutation in specimens predating the middle ages. "Using simple statistics, this tells us that the mutation was highly prevalent in Denmark before the bubonic plague," says Eugen-Olsen.

If the complete DNA analysis supports his theory of Mesolithic epidemics, Eugen-Olsen hopes to identify those microbes that might have been responsible. In what he calls a fishing expedition, the group will grow immune cells from the blood of people with and without the 32D mutation, then challenge the cells with a range of human pathogens. "Microbes that kill normal cells but leave cells from mutation carriers unharmed are candidates," says Eugen-Olsen. "And hopefully, archeological findings of the period may provide further clues and evidence."

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J. Eugen-Olsen, J., Møller-Jensen, A. & Nielsen, J.O. Afspejles forhistoriske epidemier i danskernes genetiske variabilitet og i nutidens hiv-patogenese? (Are pre-historic epidemics mirrored in the genetic variability of the Danes and in the present time hiv-pathogenesis?). J Danish Med Assoc 160/52, 7585-7588 (December 21, 1998).

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