Unfortunate Drift

Ashkenazi Jews--those of Central and Eastern European origin, which includes most American Jews--are prey to a unique set of genetic diseases. The best known is Tay-Sachs, which kills in early infancy, but there are at least nine other inherited disorders that are especially prevalent among Ashkenazim. Why? The pattern of inheritance offers a clue: most of the diseases are caused by recessive genes, meaning that symptoms appear only if two copies of the mutant gene are inherited, one from each parent. One copy does no harm, and might even do some good--which would cause natural selection to spread the mutation through a human population instead of weeding it out. Many researchers believe the Ashkenazi burden has this sort of flip side; they argue, for instance, that the Tay-Sachs gene protects its carriers against tuberculosis, a disease that was endemic in the crowded ghettos of Eastern Europe.  But there has always been an alternative theory, says Stanford population geneticist Neil Risch: mutant genes may have become concentrated in the Ashkenazi population purely by chance or historical accident. Now Risch and his colleagues have found evidence that such genetic drift does indeed underlie the high incidence among Ashkenazim of idiopathic torsion dystonia (ITD), a disease that causes involuntary muscle contractions. The researchers think drift may explain or help explain the other Ashkenazi diseases as well. The mutant genes may have achieved their high frequency, says Risch, not so much because they confer a selective advantage but because they happened to arise among a relatively small number of Jews who produced a large number of descendants.  ITD, however, is a special case--as Risch and his colleagues discovered when they started analyzing its pattern of inheritance in their study group of 59 Ashkenazi families in the United States. Unlike all the other Ashkenazi diseases, they found, ITD isn’t recessive--it’s dominant, meaning that a single copy of the gene is enough to transmit the disease. For reasons unknown, though, it usually doesn’t. Between one in 1,000 and one in 3,000 Ashkenazim carry the ITD gene, Risch estimates, but only 30 percent of them show symptoms--muscles that cramp and twist a part of the body into contorted positions--and only 10 percent have incapacitating ones. The low incidence of disease allows the gene to survive in the population; most of its carriers can still have children. On the other hand, the gene doesn’t seem to confer any type of advantage that would explain why it became so common among Ashkenazi Jews.  Another clue that genetic drift rather than natural selection might explain the spread of ITD is the history of the Ashkenazim. Ashkenazi is a Hebrew term for German. Beginning in the fourteenth century, a wave of German Jews fleeing east to escape persecution established new homes in Eastern Europe. The immigrant Jews generally didn’t marry members of the surrounding communities, and although historical evidence from the period is sketchy, there is some evidence that their initial population was small. If so, it was an ideal candidate for a type of genetic drift known as the founder effect: when a small group of immigrants founds a new population, isolated from others, whatever mutations the founders happen to have, good or bad, will necessarily be more concentrated in that new, smaller population than they were in the old, larger one the founders came from.  That’s just what happened with ITD, says Risch. He and his colleagues have found that a single genetic mutation is responsible for most cases of the disease, and they have traced it to its source. They did so by showing that 90 percent of the families in their study had an identical pattern of genetic markers--recognizable bits of noncoding DNA-- flanking the ITD gene on chromosome 9. Since chromosomes swap pieces of DNA each time a sex cell is formed by meiosis, marker patterns tend to get scrambled over time. That 90 percent of the families still had identical markers showed they had all inherited the same mutation--and also that the mutation had arisen in a single individual fairly recently.  Knowing the rate at which chromosomes swap DNA, Risch could estimate when the original ITD mutation occurred: around 1650, plus or minus a century or two--but probably after the Ashkenazi Jews migrated to Eastern Europe. When Risch started asking the people in his study about their grandparents and great-grandparents, he found that more than two- thirds of the oldest ITD carriers who could be traced hailed from Lithuania and Belorussia. The most likely scenario, Risch concludes, is that the progenitor of the ITD mutation lived in one of those two places some 350 years ago. That person’s descendants spread the mutation to other parts of what came to be known as the Jewish Pale of Settlement--a region that included Poland, the Ukraine, and parts of Russia. (From the late eighteenth century on, Jews living under the Russian czar were confined to the Pale.) In the late nineteenth century, Jews fleeing pogroms in Eastern Europe carried the mutation to other parts of the world, including the United States.  By 1900 there were 5 million Jews living in the Pale of Settlement; in spite of repeated persecutions, the population had grown explosively since at least 1765, when the earliest reliable census put it at 560,000. Extrapolating that growth rate backward in time, Risch estimates that in the mid-seventeenth century, when the ITD mutation most likely appeared, the Ashkenazi population in the Pale was around 100,000. The mutation’s initial frequency, then, would have been around one in 100,000. How could the frequency have risen to at least one in 3,000 among today’s Ashkenazim?  The answer, Risch thinks, is a second type of genetic drift. In the seventeenth century and later, he says, not all Ashkenazi Jews left equal numbers of children. Family genealogies suggest that the more affluent classes--business and community leaders as well as scholars and rabbis, who were considered desirable marriage partners--had between four and nine children who reached adulthood. In contrast, poorer Jewish families, who were more subject to overcrowding and thus more at risk from epidemics, left fewer surviving descendants. Risch thinks the original ITD mutation just happened to arise in an affluent family, and that it spread rapidly because the affluent Jews tended to marry one another and to have many children. ITD is so common among the Ashkenazim today, he argues, because most of the world’s 11 million Ashkenazim are descended from just a few thousand people who lived in the Pale of Settlement in the seventeenth century.  What about the other Ashkenazi diseases? They are all recessive, which means natural selection could more easily have influenced their frequency. Typically only 1 percent or so of the carriers of a rare recessive mutation get sick (because they have two copies of the mutated gene), compared with 30 percent of the carriers of ITD. As a result, even a small selective advantage might be enough to spread a recessive mutation through the population. Risch points out that natural selection and genetic drift could have worked together to spread the Ashkenazi diseases; the two are not mutually exclusive. But he also thinks further studies will show that most or all of the diseases are, like ITD, of recent origin--too recent for the slow grind of evolution to be the main reason they have achieved such high frequency.  There is another population, Risch points out, whose history makes for an instructive comparison with the Ashkenazim. The French Canadians have Tay-Sachs also--a different mutation, but almost at the same frequency as the Ashkenazim, he says. I’ve never heard anybody arguing that Tay-Sachs gives them an advantage against tuberculosis in crowded ghettos! In fact, the French Canadians are well known for having their own, unique genetic diseases. Their demography is remarkably similar to that of the Ashkenazi Jews--there are currently about 5 million French Canadians who are descended from a relatively small founder population, in the thousands or tens of thousands, dating to 300 or 400 years ago.  And in Eastern Europe, tuberculosis was quite common in non-Jews also, and you don’t see them with these genetic diseases. But our study confirms that the conditions for the operation of genetic drift existed there. You would expect it to apply not just to the ITD gene but to others also. If Risch turns out to be right, the diseases that plague the Ashkenazim will no longer be seen as an example of the cruel beauty of evolution. They’ll just be an example of bad luck.