The Invisible History of the Human Race

by Christine Kenneally

  Carroll is part of a much smaller group who have taken the test. “Some people just have to know,” he explained. And he is also part of an even smaller group: scientists who are at risk for Huntington’s who devote their careers to understanding the mutation. He thinks he can make it to forty-nine years of age before serious symptoms start to appear. In the meantime he has work to do.

  Huntington’s may be the prototypical example of a Mendelian disease, but not all single-gene disorders are the same. Indeed, there’s a long list of ways that a single gene can have an impact on health and that a genetic test can change a life.

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  The Samaritans are members of an ancient religious sect who live in the village Kiryat Luza on Mount Gerizim in the West Bank and in a town called Holon in Israel. They have the highest rate of inbreeding in the world.

  In Roman times there were one and half a million Samaritans. According to their history, they descend from the sons of Joseph and lived in the northern kingdom of Israel in the Solomonic period, around 1000 BC. In the early eighth century BC the Assyrians swept through, exiling or supplanting many of the inhabitants, yet somehow the Samaritans were able to remain. When the Israelites returned from exile, they rejected the Samaritans from the tribes of Israel because the Samaritans had adopted some Assyrian customs. Even today, according to geneticist Marcus Feldman, who studied the group, Samaritans are not considered Jews. Yet work carried out by Feldman’s lab has shown that their ancestry is very similar. The genomes of the Samaritans, he said, “seem to be very close to those of other Jewish people after all this time.”

  In the centuries after the Assyrian invasion, one catastrophe after another befell the Samaritans, and in the wake of attacks by Romans, Muslims, and Ottomans, the population progressively shrank. By 1917 there were less than 150 Samaritans left. In the years since then the group has slowly recovered from its extreme bottleneck. As of 2009 there were approximately 750 Samaritans.

  One of the reasons the population has struggled to expand is its higher-than-average risk of certain genetic disorders. For much of the twentieth century Samaritans had relatively high rates of miscarriage, stillbirth, serious disability (such as being deaf or mentally retarded or unable to walk), and infant mortality from degenerative diseases. These health issues are in part a consequence of the community’s commitment to wed only other Samaritans. Marrying a close relative increases the risk of a genetic disorder, because if there are recessive mutations in a larger family group, when both parents come from that group the likelihood that they both carry the recessive mutation is increased. But the Samaritans are unique in their preference to marry not just within their larger group but within their own surname group. There are four surnames in the entire community, which shrinks the genetic pool considerably.

  At least 84 percent of Samaritan marriages take place between first and second cousins. A marriage between first cousins might increase the risk of some conditions, Feldman said. But it is the repeated choice to marry first cousins over many generations that vastly increases the risk of a genetic disorder. Simple math tells us that ten generations ago in anyone’s family tree, 1,024 people coupled up. All 1,024 people are genealogical ancestors, but if they contributed anything at all to the genome of their modern descendants, it was only a small amount of DNA. Reality, though, is often more complicated. The math is correct only as long as no couple in the family tree was related to his or her spouse. When there is repeated marriage between cousins in a small population, the amount of DNA shared by any two spouses increases and the number of genealogical relatives in the tenth generation (as in all others) decreases. As the number of genealogical ancestors shrinks, the chance of inheriting a DNA segment from any one of them increases. While it seems improbable and almost infinitesimally unlikely that any one child would inherit two copies of a mutated gene that has been passed down over multiple generations, when a community prefers endogamous marriage, the odds drop.

  In a marriage of first cousins, for example, the children will have six great-grandparents instead of eight. The children of this first-cousin marriage will have fewer than 1,024 ancestors in the tenth generation. In such a marriage it is necessarily the case that two of the married couple’s four parents are siblings. In a double first-cousin marriage, the children will have four great-grandparents instead of eight. If you repeated the pattern many times over throughout the generations, the size of the ancestral pool would shrink considerably.

  It is extremely unlikely that anyone in the twenty-first century does not have some consanguinity in his or her family within the last three hundred years. Yet according to Feldman, more than half of all human populations today still engage in consanguineous marriage, and up to 10 percent of all humans are in first- or second-cousin marriages.

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  The Ashkenazi population is much larger than that of the Samaritans, but it went through a bottleneck between the tenth and fifteenth centuries after the Ashkenazis had been expelled from France and the Rhineland. Even though it has expanded into a community of ten million people worldwide, it’s thought that all Ashkenazis are at least ninth cousins to one another. The physical legacies they deal with today include Tay-Sachs disease, a recessive, degenerative disorder that is often fatal by four years of age. In the United States typically one in 250 adults carries a recessive copy of the gene. But in Ashkenazi communities that drops to one in every 27 people. There are at least twenty genetic diseases that Ashkenazis are more likely to be afflicted with than many other populations. Their suite of risks, said Feldman, is shaped by the fact that they are a small population with a preference for marrying people within their own communities, and the founder effect.

  The founding fathers and mothers of a population may have enormous influence on their descendants. Consider: The founders of a small group are just a random sampling of their original population. The sample may be a small-scale representation of the diversity in the original population or, more likely, it may be a tiny subset of the genomes in the population they left behind. If one of the founding group has a recessive mutation, and it’s customary to marry within the group, it’s likely that with a few generations, distant cousins who are both carrying a copy of the same mutation will marry. Tay-Sachs disease results from a mutation on the HEXA gene, and it’s thought that the founder who introduced it into the Ashkenazi population lived during the fifteenth-century bottleneck.

  Disorders like Tay-Sachs, Gaucher’s disease, and Bloom syndrome are genetic risks for the Ashkenazis, but they are not exclusive to them. Other populations are also at higher risk for some of these disorders—or for conditions that the Ashkenazis themselves tend not to get. The Irish, French Canadians, and Cajuns also have a higher incidence of Tay-Sachs disease than do other groups. None of these groups practiced cousin marriage, but they were small populations in which the locals, as a matter of course, preferred to marry people who were like them or who lived close to them. Curiously, a genetic disorder shared by two or more populations doesn’t necessarily imply shared ancestry for those populations. While it is often the case that a particular mutation on a gene may have a dire consequence and a different mutation to the same gene have no apparent consequence at all, sometimes the same disease results from different mutations to the same gene. French Canadians, for example, carry a different HEXA mutation than the Ashkenazis, one that has been traced to a carrier in the seventeenth century.

  Cajuns, however, do carry the same mutation as most of the Tay-Sachs-affected people in the Ashkenazi population. Until the nineteenth century Cajuns were relatively isolated, and there was a high degree of marriage within extended families. Even in the twentieth century many families stayed in the same areas for generations, and some of the signs that individuals there might be related, like common surnames, were lost in time.

  In the late nineties Iota, a small town in Louisiana, experienced a disturbing spike in Tay-Sachs diagnoses.
Within a period of months four cases of Tay-Sachs disease were brought to the attention of New Orleans clinician and geneticist Emmanuel Shapira. When more cases followed, Shapira began to try to trace the recessive gene. He visited Iota and, after taking 230 blood samples, found that the percentage of carriers of the Tay-Sachs mutation was twice that of the Jewish population. Where had it come from? Shapira and his colleagues examined the pedigree of seven Cajun families affected by Tay-Sachs, all of whom lived within seventy miles of one another. Most of the families were found to share common ancestors: a couple who immigrated to Louisiana from France in the early 1700s. Of the seven families in the study, five were traced directly to the couple; the other two were traced to individuals with the same name who lived around the same time. It’s likely that they too were related, but a definitive connection to the original couple could not be established. It’s not known whether the eighteenth-century couple was Jewish or not, but some commenters have speculated that they must have been.

  The common ancestry in the families suggests that multiple copies of the same segment of DNA, which happened to contain the mutated HEXA gene, came from one person who lived around three hundred years ago. The mutation was copied and recopied within the Cajun community, whose members by the late twentieth century no longer knew if or how they were related to one another. Indeed, they weren’t related in the way we normally think of it. They possibly didn’t have much other DNA in common at all, only the fateful HEXA segment. But of all the parents in the entire Cajun family tree, that one couple played a uniquely important role in their lives.

  Why after hundreds of years of isolation did so many young adults each carrying a single copy of the recessive gene unwittingly pair up? In fact, it’s likely that previous generations also did so, and indeed, once the extended families of the afflicted children learned about their condition, a number of them recalled similar cases in previous generations where an otherwise normal infant stopped thriving, began to degenerate, and eventually died by the age of four. Locals used to call the condition “lazy baby disease.”

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  A community’s experience of its genome will be shaped not only by its genome, but by the technology it has access to. Unsurprisingly, the Samaritans’ experience of their own genome and genetic information is significantly different from that of people in the Huntington’s community. Once individuals with the huntingtin mutation, a disorder of just one copy of a gene, learn their diagnosis, there is nothing they can do to change it. In the case of the Samaritans, who typically face recessive disorders, which require two copies of a gene to be mutated, steps can be taken. While there are no cures for the genetic disorders that afflict them, the adult carriers of recessive genes are not affected, so their focus is on prevention in the next generation. Samaritans actively seek information about the genomes of potential offspring. They now take part in both premarital and prenatal testing, and even though one in every five pregnancies is abnormal, they can determine which embryos carry two copies of the same mutation and choose to terminate. In this way they change neither their genome nor their cultural practices, yet testing ensures that only nonaffected children are born.

  As well as genetic testing, a small group of Samaritans have used specialist agencies to find wives from outside the sect. In the last decade a number of young Ukrainian women have been recruited to marry Samaritans, bringing with them entirely new genomes in order to maintain the three-thousand-year-old culture. Still, many Samaritans remain committed to marrying within their families. “I’m against marrying women outside our community,” one Samaritan told a Reuters reporter in 2009. Speaking of his sons, he said, “If they don’t find a wife, my sister has three daughters, and my cousin has three daughters.” He added, “Of course, we’d have them tested genetically first.”

  Such serious engagement with genetic testing has become prevalent in the larger Jewish population over the last twenty years. In Israel genetic screening and counseling are a normal part of the culture. Everyone is screened for fragile X syndrome, and other tests are offered free to at-risk couples. Mutations leading to rare but devastating genetic disorders are still being discovered as well. In 2012 the mutation causing progressive cerebro-cerebellar atrophy, a fatal degenerative childhood disorder, was identified and the Israeli government moved to test for it as part of a larger battery of tests.

  I asked Marcus Feldman, who is himself Ashkenazi, if he was worried about having children. “Not at all,” he said. “Once you get past second cousins, the danger of producing genetic diseases drops to numbers that are very small.”

  The risk is “significant enough that one would probably want to do some prenatal testing,” he explained. “But I don’t think people do a routine Blooms disease test because although these diseases pop up in the Ashkenazi community, they are very, very rare even among Ashkenazi.”

  In the United States organizations like Dor Yeshorim in the ultraorthodox Jewish community carry out premarital testing. If results reveal that both individuals in a couple are carriers for the same recessive condition, then approval is not given for marriage. Dor Yeshorim and programs like it are so successful that there are now fewer cases of Tay-Sachs disease in their communities than in non-Jewish ones. In the United States and Canada cases of Tay-Sachs have been reduced in the Jewish community by more than 90 percent since 2000. Here is a clear case where genetic risk factors have become decoupled from cultural risk factors, and the culture has adapted so as to diminish the genetic risk. Currently public-health information and genetic testing in the Cajun community are less developed. Many twenty-first-century descendants of the original French Louisiana couple and other local families with a different history may still carry the Tay-Sachs mutation but not be aware of it, and they may yet have children who are afflicted. Or, if they happen to marry someone who is not a carrier, they will not have to know their own status or deal with Tay-Sachs.

  In other communities that carry the legacy of founding genomes or cousin marriage, targeted screening programs exist. Many countries, including Canada, Cyprus, and Iran, have screening programs for beta thalassemia, a blood disorder that severely impacts development and may require a carrier to have lifelong blood transfusions. The countries differ in whether testing is voluntary or mandatory, prenatal or antenatal, and in what kind of counseling is offered. Couples in Cyprus must be tested and issued a certificate if they wish to marry in the Cypriot Orthodox Church. In Cyprus, and possibly Canada and Bahrain, the incidence of beta thalassemia has dropped near 90 percent. In other countries, such as India, little or no progress has been made.

  The issue of marriage and genetic testing can be extremely culturally sensitive. There was much controversy in recent years when it was announced that a Pakistani community of two million people in Bradford, England, had a one-hundred-times greater frequency of genetic disease than the general population. The community had married within its clan for many generations before immigration and continues to prefer marriage between first cousins. Now one in ten of its children develops a recessive disorder or dies in infancy. In an interview on a British television program a local doctor estimated that while other hospitals would normally see 20 to 30 cases of a recessive disorder a year, the Bradford hospital sees around 140 cases. The British government has declined to address the public-health issues in Bradford in any systematic way, and there is much anxiety about criticizing cultural practices that are relatively new to the country. Some insist that first-cousin marriage is not a government issue; other medical and political figures are debating ways to address it.

  Alan Bittles, one of the world’s experts on consanguinity and author of Consanguinity in Context, became interested in the subject when he visited Bangalore to do research in the 1970s. At dinner with his professor, the man introduced his family to Bittles. He said, “This is my wife and she is my niece.” Bittles also met the couple’s children. “They were bright attractive kids,” Bittles sai
d, and it made him wonder about the dire warnings that the medical community of the time attached to consanguinity. The vast majority of first cousin marriages do not have children with birth defects, he explained. Fundamentally, what matters is not just the consanguinity but the size of the group, how many children they have, the degree to which the group’s ancestors were isolated, and in many cases, socioeconomic factors like maternal education and maternal age. There are many varieties of consanguinity as well, each with their own impact on the genome of children. Uncle-niece marriage, which is very common in Bangalore, for instance, is twice as inbred as first cousin marriage. For this reason, consanguinity is best considered as a “spectrum”—it depends on how many identical segments of DNA both parents have inherited from a common ancestor.

  Any population, no matter how large or small, may have a greater predisposition to some disorders than to others. While the populations of western Europe and West Africa can hardly be considered isolated, they are still home to large ancestral groupings of genomes that may affect their carriers’ lives. One in two thousand western-European births is affected by cystic fibrosis, whereas the condition is rare in Africans. West Africans, on the other hand, must deal with sickle-cell anemia in one of six hundred births, but the condition rarely appears in European populations.

  The amount of shared DNA within a population isn’t affected just by cultural choice or bottlenecks from medieval or colonial times. Even today we are shaped by an event that began sixty thousand years ago: the out-of-Africa journey. When humans left Africa and migrated all over the world, they passed through a series of bottlenecks as one population settled and expanded and then a small group broke off and moved on and founded another population. Brenna Henn, a colleague of Marcus Feldman, led a study that found that for every population bottleneck there was a decrease in genetic variation and an increase in deleterious mutations in the genome. Currently Feldman and Henn are investigating whether these impact the health of individuals today.