Survivors of the Black Death, which ravaged Europe in the 14th century, apparently bequeathed to their descendants the ability to resist infection by the AIDS virus, modern history's most lethal disease.
That is the conclusion of a team of scientists studying a rare genetic mutation that confers on its carriers protection against the human immunodeficiency virus (HIV), which causes AIDS.
Although the origin of the mutation is obscure, it appears to have suddenly become relatively common among white Europeans about 700 years ago. That increase suggests something must have occurred about that time to favor greatly the survival of people carrying the mutation. In fact, such an event is known to have existed - the epidemic of bubonic plague that swept out of Asia and into Europe in 1346.
"The chance of this gene randomly drifting up (to its current frequency among white Europeans) is unlikely," said Stephen O'Brien, a molecular biologist at the National Cancer Institute who headed the research team. "In fact, it's impossible. There had to have been something going on that jacked it up."
The Black Death was one of the cataclysmic events of recorded history. A bacterial disease spread by rats and fleas, it killed between one-quarter and one-third of Europe's population between 1347 and 1350. In some places (notably Florence, Marseille, France, and other crowded Mediterranean cities), more than half the inhabitants are believed to have died, although accurate records are scant.
Plague struck in waves
Several waves of the disease followed the initial one, and the continent's population did not reach its pre-epidemic size for 100 years. By then, much of feudalism's distinct economic features had been crippled or swept away, and the modern period had begun.
Just as bubonic plague permanently altered the structure of Western society, so it appears to have altered the genetic endowment of Westerners, or at least some of them.
The mechanism by which this might have occurred is fairly straightforward.
All genetic mutations arise by chance. Some are harmful and disappear quickly because people carrying them die before they can have children and pass on the mutation. Some are neutral, neither immediately harmful nor immediately beneficial. They spread through a population but never become very common.
However, if by chance a neutral mutation carries a hidden benefit, such as the ability to resist a fatal infection, things can change dramatically when the infection shows up for the first time.
People lacking the mutation will have a greater chance of dying than people carrying it. When the epidemic is over, the "population frequency" of the mutation will be higher than before. Perhaps 10 percent to 20 percent of all people will carry it.
O'Brien, his colleagues, J. Claiborne Stephens and Michael Dean, and their collaborators, believe such a scenario explains the relative commonness of a mutation called "CCR5-delta 32."
The mutation occurs in the gene for CCR5, a receptor on the surface of immune system cells called macrophages. The AIDS virus uses the CCR5 receptor as a molecular "docking bay," permitting it to land on, attach to and infect the cells.
People devoid of the receptor (a condition that occurs when someone inherits the mutant gene from both parents) are essentially immune to HIV infection. People with one mutant and one normal version have fewer than normal numbers of CCR5 receptors on their macrophages. They can be infected with HIV, but if that happens, they tend to have a longer, more indolent course of the disease than people with two normal CCR5 genes.
Frequency of gene
Slightly more than 10 percent of whites of European origin carry either one or two copies of the mutation. It's most common among Swedes, among whom 14 percent of people have it. The mutation becomes less common as one moves south and east from Northern Europe, declining to 4.5 percent among Greeks and 2 percent among Central Asians. It is absent in East Asians, Africans and American Indians.
Like the AIDS virus, the bacterium responsible for bubonic plague also attacks macrophages. Yersinia pestis binds to their membranes and injects toxins into their interiors, disabling the cells' crucial role in marshaling the body's immune response. What is currently unknown is whether the bacterium uses the CCR5 receptor in doing this.
"We're going to try to put this to the test," said Stanley Falkow, a Stanford University microbiologist.
He and O'Brien's team plan to take cells from people with normal CCR5 genes, and from people with one or two copies of the gene, mix them with Y. pestis, and see if there is a difference in the number of cells that become infected.
O'Brien and his collaborators estimated the date of the CCR5 mutation's "expansion" by determining what fraction of contemporary carriers have identical versions of the gene, and what fraction have versions containing slight variations in the DNA sequence. Those changes creep in at a relatively constant rate over time. Consequently, the number observed can be used as a molecular "clock" to determine the age of the ancestral mutation.
The paper outlining their hypothesis appears in this month's American Journal of Human Genetics.