The Invisible History of the Human Race (38 page)

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 said, 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.

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Millions of people are affected by Mendelian diseases. One birth in every thousand is shaped by a single-gene disorder, of which there are at least ten thousand. Yet as enormous as this number is, Mendelian diseases are considered rare. We have known since Francis Galton, the great innovator, eugenicist, and cousin of Charles Darwin, that not everything we inherit can be explained by a single gene. Now, as the revolution in genomewide association studies enables us to compare the genomes of many people, we know it to be true that
most
genetic effects are caused by more than one gene. Many traits and common diseases cluster in families, so we should be able to find traces of them in the genome, but so far those traces have been elusive. Some rather large factor is missing from the picture.

The great paradox of this last crank of the scientific wheel is that while we have finally affirmed the principle that many genes may contribute to one condition, we still don’t know how all those genes do what they do. Now that we have the technology to establish how much influence any one gene has, it
appears
to be the case that a lot of the time they don’t have that much influence at all.

Take height as an example. In families height appears to be a strongly inherited trait. In addition, genomewide association studies indicate that it is influenced by at least forty different genes. Yet when scientists tried to understand how these genes underlie the pattern of inheritance, they couldn’t work it out. The height genes were found to only explain 5 percent of the difference in height in the population. Clearly, a lot of
something
happens between the genome and the person, but as of now we don’t understand precisely what that is. Geneticists call this the problem of “missing heritability.”

The first explanation, naturally, is other genes. If a condition is the product of many genes, it seems likely that the activity of some genes or pieces of noncoding DNA may affect the actions of others. It may also be the case that some common diseases are shaped by rare mutations that have not yet been tracked down. As advances in medical care keep many more of us alive than hundreds of years ago, rare mutations may be on the increase. The problem of missing heritability must also be due in part to the scope of studies. So far most of the subjects in genomewide studies have been European. As more of the world’s genome is surveyed, the picture will inevitably become more detailed.

Some common disorders or traits may be explained by idiosyncrasies in the structure of the genome: Segments may be inverted or moved to different spots, and there are many varieties of repeats, like the CAG repeat in the huntingtin gene. New mutations underlie some disorders as well. A small percentage of cases of autism are caused by de novo point mutations, which is to say that while the mutations occur in genes, the condition isn’t inherited. In addition to these dark-matter candidates, there is noncoding DNA. When geneticists discover that differences in DNA correlate with differences in health (for example, people with a certain condition have a T in one spot on the genome rather than an A), they have overwhelmingly found that these significant differences occur not in genes but in the noncoding regions of the genome.
Why? They don’t know.

It is also the case that the environment modulates genes, but which elements of the environment exactly? How well you slept as a child? How well you ate? The absence or presence of certain stressors matters too. Did you grow up in a war zone? Did your family live in poverty? Is anyone in your family an addict? What about your family history of disease and its level of education? Were you exposed to a large number of pollutants? Keep in mind that the way the environment shapes genes isn’t through some vague influence: Everything we hear or see or feel or touch is translated into our tissue by the action of biochemicals of some kind, which should be traceable.

The lives that our parents and grandparents lived may also affect the way genetic conditions play out in our bodies. One of the central truths of twentieth-century genetics was that the genome is passed on from parents to child unaffected by the parents’ lives. But it has been discovered in the last ten years that there are crucial exceptions to this rule. Epigenetics tells us that events in your grandfather’s life may have tweaked your genes in particular ways. The classic epigenetics study showed that the DNA of certain adults in the Netherlands was irrevocably sculpted by the experience of their grandparents in a 1944 famine. In cases like this a marker that is not itself a gene is inherited and plays out via the genes. More recent studies have shown complex multigenerational effects. In one, mice were exposed to a traumatic event, which was accompanied by a particular odor. The offspring of the mice, and then their offspring, showed a greater reactivity to the odor than mice whose “grandparents”
did not experience such conditioning. In 2014 the first ancient epigenome, from a four-thousand-year-old man
from Greenland, was published. Shortly after that, drafts of the Neanderthal and Denisovan epigenomes were published. They may open up an entirely new way to compare and contrast our near-relatives and ancestors and to understand the way that they
passed down experiences and predispositions. As yet it’s unclear for how many generations these attachments to our genes might be passed down.