The Invisible History of the Human Race (37 page)

Carroll put in long, hard hours on the drug, but once it reached the point of testing, he found he wasn’t motivated by the careful, plodding work of safety trials. “I got off my high horse,” he explained. “You get humbled by therapeutic development, you realize you’re not that important. This is a team effort and I didn’t have to be the guy at the pointy end of the pipeline. I could decide what I wanted to do with my life.”

Carroll is now working on Huntington’s and metabolism because he became fascinated by “the remaining mysteries.” For example, even though the huntingtin gene is expressed everywhere, the places in the body where it is expressed more aren’t the ones that are most damaged in the course of disease. While most research examines the effect of huntingtin on the brain, because it so obviously and dramatically degenerates, Carroll is fascinated by changes in the liver and pancreas and other tissues caused by the mutant gene. “If you have cirrhosis of your liver, you get profound neurological symptoms.” In some respects, neural imaging in these cases looks a lot like those of Huntington’s disease. “So you don’t have to just have brain degeneration that causes a brain disease; you can have peripheral dysfunction that causes brain dysfunction.”

He is also exploring the problem of Huntington’s and food. “It’s well known among caretakers and caregivers that Huntington patients eat a ton,” Carroll said. Some Huntington’s sufferers consume as much as five thousand calories a day just to maintain weight. “They’re hyperphagic, and yet they lose weight,” he said. Many of them die of starvation, but, as Carroll explained, “Nobody knows why.”

Carroll also started a Web site called HDBuzz with a colleague, Huntington’s clinician Ed Wild. Both men were concerned about the amount of misinformation and hype about Huntington’s in the press, and they were struck too by the fact that while affected families desperately needed up-to-date information about research on the disease, Huntington’s also desperately needed affected families to help them with their studies. The site helps the two connect.

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When Carroll discovered he carried the huntingtin mutation, he decided he would never have children and risk passing the mutation on, but he changed his mind in the early 2000s when scientists came up with a method to ensure that the child of someone with a mutated huntingtin gene would never inherit that copy. In fact, two methods were developed. Doctors can test a fetus early in pregnancy and terminate it if it carries the mutation. They can also conduct a preimplantation genetic diagnosis. Using either a couple’s egg and sperm or a donor’s, doctors can create and test embryos for the mutated gene and then implant a noncarrier using
in vitro fertilization. Jeff and his wife, Megan, were in the first generation of couples to use the second method, and after one try they conceived nonidentical twins who do not carry the huntingtin mutation.

It used to be the case that most people started families before they knew they had the disease. Often they had children before they themselves began to display symptoms, and sometimes even before their own parents developed symptoms. There was also a great deal of secrecy about having the disease, a tendency to hide a diagnosis or not discuss it. In some cases the symptoms were thought to be caused by something else, like alcoholism.

Despite the availability of testing, at least half of the population at risk for Huntington’s disease still has children without making use of the new technologies. Even some of the people who have prenatal testing for Huntington’s still have a profound reluctance to learn their own status. Couples who try preimplantation genetic diagnosis may even conceive a child and choose not to find out if the parent at risk has the mutation.

Deciding whether to find out one’s genetic status is a hugely divisive and painful issue within families and the Huntington’s community, but the desire to conceal information from oneself is a fraught position, especially when other people are affected by the same genes and the same knowledge. In one Huntington’s family a young woman was discouraged from taking the test by her mother, who did not want to know if she herself carried the mutation. The daughter eventually distanced herself from her mother, took the test, and discovered she was positive.

Silencing the mutation will put an end not just to the disease but to all the associated issues around disclosure. Until that happens, though, the issue remains extraordinarily stressful. Many adults who are at risk for Huntington’s and who have not taken the test worry that if they receive a positive result, employers may learn of their condition or, worse, insurers will. Although various organizations lobby to prevent genetic discrimination, it’s unclear how policy will progress, as the science changes so rapidly (more on insurance issues in the epilogue). Mostly, though, it seems to be the case that at-risk adults are traumatized and weary from looking after afflicted family members, and they feel terrible anxiety at the prospect of developing the disease themselves. The time just before people receive a formal diagnosis of Huntington’s is a critical period for suicide. Even those who are negative for the mutation may be haunted by survivor’s guilt. For most it is better to imagine that they do not have the mutation than to seek the knowledge that they don’t and risk finding out that they do.

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.