The Invisible History of the Human Race (36 page)

Then again, you
only
get 50 percent of your DNA from each of your parents. Sometimes people don’t look like either of their parents or other members of their family. Some are tall where their parents are short or dark where their parents and siblings are fair. While appearance can be a persuasive pointer to ancestry, it is not always a reliable one.

Of the studies that have specifically looked for genes implicated in facial structure, most have attempted to determine the cause of an abnormality. In 2012 a group of scientists in the International Visible Trait Genetics Consortium published one of the first genomewide association studies to identify genes that contribute to the face. Led by Manfred Kayser from Erasmus University Medical Center in the Netherlands, the researchers took three-dimensional photographs of more than five thousand people and examined more than two million markers in the genomes of
more than ten thousand Europeans.

The photographs were analyzed for forty-eight different facial characteristics, and the researchers tried to establish connections between the genomes and the different facial traits.
They found five genes that contribute to the shape of the face. For example, the TP63 gene affects the distance between the eyes, while the PAX3 gene contributes to the distance between the eye and the nasion, the place where the nose meets the forehead. The findings suggest that, as with height, many genes contribute to the face’s particular contours and size, each with a relatively small effect. Kayser is optimistic that much of the genetic basis of human facial variation will be discovered.

After the announcement of Kayser’s groundbreaking findings, another team found evidence for the influence of many noncoding segments of
DNA on the structure of the face. Soon after that, another team announced that their study using 3-D photographs of almost six hundred subjects had identified twenty genes that strongly influenced facial structure. Variations in one of these genes’ codes were such useful predictors of facial shape that the team was able to build reasonable approximations of a subject’s face based on his DNA alone. Overall, this kind of work may aid in the
reconstruction of faces from ancient remains and ultimately even be used in
forensic police profiling.

 • • • 

On the ancient meeting ground of Gulkula in Arnhem Land—the northeastern corner of Australia’s Northern Territory—an elder called Gulumbulu demonstrated one way to span the worlds of whitefellas and blackfellas (Australian for white and black people): She was teaching her daughters and granddaughters the old ways while simultaneously sharing them with a large group of tourists—white Australians and visitors from other countries. Gulumbulu was a teacher at Garma, the country’s largest alcohol-free, Aboriginal-driven festival of dance, film, and storytelling. Every day of the festival men and women streaked with white paint and wearing bright red wraps or yellow headbands danced on an open field on the edge of a large forest, which stretched many miles to Kakadu National Park. Huge mounds created by magnetic termites formed gray tombstones among the gum trees, and the woods were full of stinging green ants whose formic acid smelled like citrus. Beyond them an ocher escarpment dropped down to the inviting green Gulf of Carpentaria.

One morning I trudged up an unlit dirt road in the predawn hours with fifty paying tourists. We followed a group of elders to the edge of a cliff and sat quietly until the sun began to rise. This was a “cry for country” for women only, and the elders’ gatekeepers warned, “No photos!” Just before dawn broke, birds began to sing, and the creaky-voiced Aboriginal ladies lifted their voices up as well, lamenting all the land that had been lost. It was sad and eerie and beautiful, until a spat broke out when one tourist furtively tried to take a photo and another crankily told her to stop. Yet another woman raised her voice and cried out with the elders. She was not one of them, and her skin was white. The women around her looked upset: Who was she to join in on the singing?

As we walked back from the morning ceremony, the woman who had sung told me about herself. She grew up in a poor family in New South Wales and was raised mostly by her single mother. When she left school, she sometimes traveled into small towns in the outback. More than once local Aboriginals singled her out from the group she was traveling with and said to her, “You are one of us.” They welcomed her to spend time with them. As far as she knew, she was white, so she always took this to be not much more than a simple act of kindness. Much later she discovered that her mother was indeed half Aboriginal, a fact that had been concealed from her all her life. Years later, when she found herself on the cliff in the dawn light, she felt as if she belonged. The elders were the aunties she had never known, and she cried for her mother and her mother’s father and everything that her family had lost as well.

We tend to associate some features with different kinds of ancestry. In the TV series
African American Lives
, host Henry Louis Gates Jr. discussed the DNA analyses of various guests, like the comedian Chris Rock and actor Don Cheadle. The show’s guests described their family lore about Native American ancestry; relatives had made remarks like “That’s Indian hair” and “You do have high cheekbones.” Similarly, it’s often said that there are only six faces in Ireland. The Y-chromosome data suggests that there is in fact a great deal of genetic overlap in Ireland, but we don’t yet know how much all Irish genomes overlap, and if that might produce similar features. How much of the past is inscribed on our faces?

The Oxford geneticist Sir Walter Bodmer has long been interested in the face: “
The fact that identical twins are so similar in their facial features, and they of course share essentially all their genetic make up, shows us that facial features must be largely genetically determined. The evolution of facial differences together with facial recognition must have been a very important part of the social and cultural evolution of the human species, and it’s most probably connected with belonging and being recognized as a member of a group. The face also, almost certainly, plays an important role in choice of mate.”

Bodmer and his colleagues are currently investigating faces in their study of British regional genetics. He explained, “It is a common observation that there seem to be facial characteristics that are associated with particular regions or countries even when they are basically closely related, such as within Europe. There are, of course, very obvious differences between major ethnic groups, such as Europeans and East Asians.”

But this raises a question: If the genomes of the small British groups weren’t distinctive enough to look different in a medical study, how could they produce different types of faces, even subtly different ones? “Even within Europe there has to have been sexual selection with respect to facial features, and that means, on the whole, picking people who are somewhat similar. I think that’s been a very powerful force during evolution,” Bodmer said. His team is in the process of taking three-dimensional photographs, each with 3,500 points of reference (“a full canvas”), of subjects who participated in the first stage of the study.

In retrospect the woman at the “cry for country” ceremony believes she should have realized she was not actually white, especially because of the way other Aboriginals treated her. Yet no one else in her life had guessed her ancestry. She looks like her mother, who looked like her own father, who was recognizably Aboriginal. Could other Aboriginals tell that she was part Aboriginal because they were Aboriginal themselves?

It turns out that some people are better than others at making judgments about ancestry based on looks. For decades psychologists and anthropologists have investigated a phenomenon called own-race bias. At least forty different experiments have demonstrated that people are better at remembering faces when the face appears to be the same race as their own. This is true no matter what the race of the observer or the observed is. It’s also been shown that people are better at predicting how well they will perform a face-recognition task when the race of the photographed face is thought to be the same as their own, which is to say we overestimate our ability to judge how well we recognize faces from races other than our own. It’s not entirely clear what the mechanism responsible for own-race bias is. One of the most important implications of own-race bias is that in eyewitness situations the testimony of a witness may be considered less reliable if
the accused is of a different race.

Most studies of own-race bias have relied on self-reported race. In 2012 Mark Shriver, an anthropologist at Penn State University who studies the interplay of faces and genes, ran an experiment that investigated the connection between genetic markers of ancestry and the ancestral cues we detect on people’s faces. He asked more than two hundred subjects who lived in New Mexico to assess the component ancestries of fourteen Hispanic faces based on front- and side-view photographs. The genomes of the people in the photographs had been analyzed with respect to their mixture of Native American, European,
African, and East Asian ancestry.

Shriver found that most observers made a better guess at the admixture of the photographed individuals than someone who simply guessed randomly. Still, the guesses were far from perfect, suggesting that, while we have some general ability to detect ancestry, it’s not uniformly reliable. Shriver’s results were consistent with other studies that show the more similar the observer’s ancestry is to the ancestry of the person in the photograph, the better the observer is at guessing the correct family history. The most plausible explanation for this is that the observers had
learned
to interpret the features of faces with which they were most familiar.

 • • • 

Human skin color is another important case study in the way that genes shape traits. An inherited trait, the many varieties of skin color have emerged in a surprising way from the intersection between environment and behavior in the last hundred thousand years. When humans left Africa and began to live in the Northern Hemisphere, the color of their skin became lighter. This has long been attributed to natural selection and the need for skin to make vitamin D. As the details of human genetic history are being uncovered, some changes look more like a case of
relaxed
selection rather than natural selection. Many genes are involved in skin pigmentation; the MC1R gene (melanocortin 1 receptor) is critical in the production of melanin, which darkens the skin. In Africa today at least eleven different mutations to MC1R have been identified, but eight of these are so-called synonymous mutations, which do not actually affect the related amino acid in the protein structure or the protein’s function. The fact that most of the African MC1R mutations are synonymous means that what the gene does is critical in that particular context. Outside of Africa MC1R has undergone many more mutations, and many of them do have an effect on melanin production. So what has been hard won by positive selection in the bright light of Africa—strict genetic control of dark skin that protects against damage from strong ultraviolet radiation—disappears when it no longer affects survival. Outside Africa it appears there are many ways to turn white. The nonsynonymous mutations to MC1R are diverse and vary from region to region, but most lead to the same result: reduced melanin production. Some mutations merely alter the function of MC1R, while others completely shut it down. The red hair and freckles of many people in the British Isles
results from just such a mutation.

Skin pigmentation is affected by more than genes. It may even be that lighter skin was inherited from Neanderthals, as regions of the genome that contribute to skin color show influence from the Neanderthal genome. Yet change did not happen only in the distant past. There is evidence from ancient DNA that lighter skin, hair, and eye pigmentation was strongly selected for in Europe in just the last five thousand years. The change could have resulted from the greater success of people who were able to process more vitamin D, or it could have resulted from sexual selection, where people with lighter pigmentation were more successful in reproduction.

There is much to be learned about how DNA shapes traits and how traits then shape our experience of the world, either because of our abilities or because of the way people treat us. One of the most crucial aspects of this nexus is the way that genes affect our well-being, either by predisposing us to disease or by protecting us from it. As with everything else to do with DNA, the forces of fate and randomness play a huge role in people’s health, and as always the family is often the crucible of this drama.

The laws of genetics apply even if you refuse to learn them.

—Alison Plowden

W
hen Jeff Carroll was sixteen he dropped out of high school. At twenty he joined the army and was posted to Europe. He served in Germany for a year, and on his first trip home for Christmas, his father told him that his mother was showing signs of Huntington’s disease, a condition that Jeff had never heard of. Huntington’s is the cruelest diagnosis. Patients slowly lose control of their bodies, as well as their memories and their ability to think. They may undergo personality changes too, often becoming aggressive toward their loved ones. The degeneration is slow and relentless, unfolding over the course of years. Although Cindy Carroll was in her midforties when her body started to jerk without warning and she forgot one of her best friends’ names, she lived for many years afterward.

After his father told him about the diagnosis, Jeff went back to his life in the service and later enrolled in an army biology course. When he returned to civilian life, he completed an undergraduate degree in biology and began working toward a PhD in a lab studying Huntington’s. During this period he got married, and in the last year of his mother’s life he and his wife had twins.

By that stage Cindy Carroll’s body was so constantly overcome with the uncontrolled jerking and writhing, called chorea, that is typical of the disease that all her nursing home could do was place her on floor mats and hope she wouldn’t hurt herself. The night she died, Jeff brought his baby son to her, carefully placing him in the crook of his mother’s neck. It had been years since Cindy had shown any sign that she recognized her son, but when the baby nestled in to her, she was briefly still and seemed at peace. Her respite probably lasted only a minute, Jeff said, but to him it felt like hours.

After his mother’s death Carroll told a reporter that the worst thing about the disease was not the fact that it is fatal but that it “destroys your personality and turns you into an object of horror for your family.” Yet that is not the end of it. Huntington’s disease is hereditary, and when people talk about things like destiny and genetics and whether it is wise or not to know how you will die, Huntington’s is often what they have in mind. Cindy Carroll died in 2006, six years after her own mother, who was also a Huntington’s sufferer. When Cindy was first diagnosed, Jeff and his siblings learned that because of the way the Huntington’s mutation works, they had a 50 percent chance of developing the disease themselves.

In 1993 researchers identified the genetic mutation that causes the disease. The discovery made an enormous difference to the likelihood that a cure would be found, and it led to the development of a test that can determine if someone will develop the disease. Before the test existed, the children of Huntington’s patients could only watch the suffering of their family members and wait anxiously to see if they developed symptoms, asking themselves whenever they dropped something if it was clumsiness or Huntington’s. Now the test brings grim certainty: If candidates have the mutation, they will develop the disease. Yet more than 80 percent of the people who could take the test do not.

Jeff always knew he wanted to be tested, but it wasn’t until 2003 that he started the process. On July 31, 2003, he and his wife met with a physician to get the results. The physician told Carroll that he was positive for the mutation.

 • • • 

Descriptions of a disease that sounds like Huntington’s can be found in writings that date from the Middle Ages. The uncontrolled twitches and swooping, circular, constant motion of the Huntington’s sufferer were first described as a dance in the 1500s. Later observers drew closer to understanding the condition and in the nineteenth century finally connected the affliction in one person to a similar condition in one of his parents. In 1872 the young physician George Huntington was the first person to clearly describe the illness as hereditary and degenerative, with an onset typically taking place in the afflicted in their thirties. “Those who pass their fortieth year without symptoms,” he wrote, “are seldom attacked.”

Almost two hundred years later the science of Huntington’s was forever changed by Nancy Wexler, a thirty-three-year-old New York–based neuropsychologist whose mother was diagnosed with the disease in 1968. “It was as if some mad puppeteer was in control of her body,” Wexler wrote. In 1979 Wexler traveled to a small town on Lake Maracaibo in Venezuela to visit the largest Huntington’s family in the world. Since the 1950s the people who dwelled in the town by the vast and ancient lake had been known in the medical literature for their extraordinary one-in-ten chance of developing Huntington’s, which they
called
el mal
or “the bad.”

Wexler founded the U.S.–Venezuela Collaborative Research Project and for several decades traveled to the region every year, studying pedigrees and sampling blood. She worked out that the villagers of Lake Maracaibo had seen more than eighteen thousand cases of Huntington’s in the span of ten generations. There are a few stories about when, and with whom, Huntington’s began in Lake Maracaibo. Some say the first cases were children of a woman called Maria Concepcion who lived in the early 1800s. Concepcion had ten children, and it’s thought that their father may have passed on the mutation. Genealogical work has traced tens of thousands of cases of Huntington’s to Concepcion’s pedigree. Another story, probably apocryphal, is attributed to a physician who diagnosed the villagers’ condition as Huntington’s in the 1950s and wrote that the locals told him that sometime between 1862 and 1877 a ship’s priest named Antonio Justo Doria left his ship and decided to live by the lake. He married and had children, and later in his life he was seen “walking with some
strange movements, like dancing.” Currently one thousand locals have the disease, and around five thousand are known to carry the mutation for it. On a 2010 visit Wexler encountered a single large family in which both parents and ten of their fourteen children had Huntington’s.

In 1983 Wexler’s team got close to the gene when they found a marker that was closely linked to it. In 1993 they finally identified the “huntingtin” gene, as well as the mutation that caused the disease. Because the Huntington’s mutation is dominant, you only need one mutated copy from either parent to develop the disease. As categorical as the disease is—you either have it, or you do not—the genetic underpinnings of Huntington’s are oddly not so exact. Huntingtin contains a repeated sequence of the letters CAG. In normal copies of the gene, CAG is repeated around seventeen times, and it can be repeated up to twenty-six times with no obvious consequence. However, if the CAG sequence is repeated more than forty times, the carrier of that gene will develop the disease. When Carroll was tested, he found out that he had forty-two CAG repeats.

While forty repeats is a definitive threshold, the CAG repeats have an odd additive effect as well, which people in the community call the “gray area”: If you have between thirty-five and thirty-nine CAG repeats, you will get the disease, but it won’t strike until your seventies or later.

If you have between twenty-six and thirty-four repeats, you will not develop Huntington’s yourself, but there’s a small chance that, if the gene you pass on mutates further, you may have a child who does. Even though Huntington’s is so strongly hereditary, Carroll explained that 10 percent of the new cases every year occur in families where there is no history of it. Initially people suggested that such instances might be cases of adoption or illegitimacy, but that was shown not to be true.

Huntington’s usually appears in its sufferers between thirty and fifty years of age, but in rare cases children may also display symptoms of the disease. Often people with Huntington’s develop symptoms around the same time their parent did. But there’s a tendency too for it to appear a bit earlier if the mutation was inherited from the father. Wexler showed that the more repeats someone has, the earlier he will get the disease. The highest recorded number of CAG repeats on a huntingtin gene was near one hundred, a mutation carried by a boy whose symptoms began when he was two years old.

 • • • 

Huntington’s may be the starkest model we have for reflecting on biology and fate. It’s a Mendelian disease, which means that the condition arises from a single gene.

Huntington’s also has deep resonance for how we think about all DNA. While so much knowledge has been steadily acquired in the realm of genetics over the last century and a half, and so much brilliance has blazed in the field in the last twenty years, there is still more dark matter in this particular universe than not. “
We just learned the alphabet,” observed Carroll, “and we were claiming we could write Shakespeare, and it’s a long way from here to there.”

The scientific and citizen community that has formed around Huntington’s disease is by now a highly educated one. The discovery of the gene had enormous consequences not only for Huntington’s disease but for all genetics. The genetic test for the mutation was the first offered for a genetic disease that appears in adulthood. Some of the techniques developed to identify huntingtin were later utilized to sequence the human genome. Still, despite their intimacy with even the smallest molecules that affect the gene, there is a long list of incredibly basic questions to which scientists do not yet have the answer.

Scientists, for example, are baffled by what happens to someone who has two copies of the mutated huntingtin gene. It’s an extremely rare occurrence, but sometimes a man with Huntington’s and a woman with Huntington’s will have a child. That child will have a 75 percent chance of inheriting one mutated copy of the gene and a 25 percent chance of inheriting both. Yet despite the fact that more repeats on a single mutated copy means Huntington’s symptoms have an earlier onset, somehow people with two mutated copies of the gene do not develop a more severe set of symptoms than people with just one copy.

When Carroll gives a presentation about Huntington’s, he sometimes shows his audience a picture of slime mold, because slime mold has a huntingtin gene too. If a creature as simple as mold has a gene that humans also carry, then we can assume that a shared ancestor, an entity that lived millions and millions of years ago, had it as well—which means that all the creatures on the great evolutionary tree between mold and humans likely have it too. Any gene that is conserved in the genomes of many creatures is maintained because it has a very basic and very important function. The Hox genes, for example, are shared by all vertebrates and control their basic body plan, a central spine from which limbs project on both sides (in comparison to, for example, the blobby, spineless jellyfish). Yet scientists do not know what the function of huntingtin is in humans.

The significance of the huntingtin gene is demonstrated quite vividly by slime mold. When researchers turned off the gene in mold, it became sick. But remarkably, the huntingtin gene in mold and the huntingtin gene in humans are so similar that, when researchers put a healthy human huntingtin gene into the sick slime mold, it got better.

Not only is the huntingtin gene extraordinary for its spread across species, but its reach within the body is amazing too. Typically genes produce proteins in particular cells but not in others. It’s also generally true that genes produce proteins for a particular period of time but then stop doing so: They are turned on and off in the normal course of development. Huntingtin, by contrast, is one of the rare genes that is expressed in all tissues all the time. The protein the gene expresses is also called huntingtin, and it can be found in the cells of the heart and the lungs, in the blood and in the brain, and in the bones. Yet scientists still don’t know what the protein actually does. “It’s not super dynamic,” explained Carroll. “It doesn’t seem to change its expression levels in response to signals, which a lot of other genes do. It’s like a housekeeping thing, it’s always there.”

 • • • 

Carroll is a tall, clean-cut, strawberry blond who looks as if he still trains with the army. When he is introduced at conferences, presenters joke about how handsome he is. (In 2012 one colleague welcomed him to the stage by saying that during the Kosovo war, the women on both sides persuaded their husbands to lay down arms, just so they could look at Carroll.) He got his big break after his undergraduate degree with a job in the laboratory of prominent clinician and researcher Michael Hayden in Vancouver. Hayden’s team was trying to develop a drug that could silence the huntingtin mutation. “Gene silencing in Huntington’s is really attractive,” Carroll explained, “because of the fact that it is a Mendelian disorder, so 99.9 percent of people who have Huntington’s disease have the same mutation—variable length but the same place—and vastly all of them have one good copy and one bad copy of the gene.” The drug in question would essentially be a “short piece of DNA or RNA” that shuts down the bad copy.

 • • • 

Most research on gene silencing and Huntington’s has been focused on pan-huntingtin silencing, meaning that both the mutated copy and the nonmutated copy of the gene would be shut down. It’s easier to begin with this goal, Carroll explained, but it can take researchers only so far. Mice that have both versions of the huntingtin gene silenced in utero are nonviable; mice who have the gene silenced when they are older do better. But it’s still unclear how humans would fare with such a treatment.

The best way to silence the gene would be to target only the mutated copy, which was the focus of Carroll’s work. His team found that some of the letters of DNA in noncoding regions near the mutated gene were closely correlated with the mutation. By using those letters as a kind of address for the mutation, they were able to silence the bad copy in laboratory tests. In other tests that knocked out the mutant huntingtin in mice, one unexpected consequence was a rebound effect: The mice not only stopped deteriorating but actually got better. “Scientists are calling it a ‘Huntington holiday,’” said Carroll. These drugs may not be able to stop the progression of Huntington’s forever, but they may give the brain “some space to compensate for some of the damage that it has experienced.”