The Language of the Genes

Chapter One A MESSAGE FROM OUR ANCESTORS

The rich were the first geneticists. For them, vague statements of inherited importance were not enough. They needed – and awarded themselves – concrete symbols of wealth and consequence that could persist when those who invented them were long dead. The Lion of the Hebrew Tribe of Judah was, until a few years ago, the symbol of the Emperor of Ethiopia, while those of England descend from the lions awarded to Geoffroy Plantagenet in 1177. The fetish for ancestry means that royal families are important in genetics (Prince Charles, for example, has 262,142 ancestors recorded on his pedigree). The obsession persists against all attempts to deny it. Heraldry was cut off by the American Revolution, but George Washington himself attempted to make a connection with the Washingtons of Northamptonshire and used, illegally, their five-pointed stars as a book plate.

Heraldic symbols were invented because only when the past is preserved does it make sense. For much of history wealth was dissipated on funerary ornaments to remind the unborn from whence they sprang. University College London contains an eccentric object; the stuffed body of the philosopher Jeremy Bentham (who was associated with the College at its foundation). Bentham hoped to start a fashion for such ‘auto-icons’ in the hope of reducing the cost of monuments to the deceased. It did not catch on, although the popularity of his corpse with visitors suggests that it ought to have done.

Such pride in family would now be greeted, mainly, with derision. Harold Wilson, the British Prime Minister of the 1960s, did as much when he mocked his predecessor, Lord Home, for being the Seventeenth Earl of that name. Lord Home deflected the jest when he pointed out that his critic must be the seventeenth Mr Wilson. He made a valid claim: that while only a few preserve their heritage in an ostentatious way, every family, aristocratic or not, retains the record of their ancestors. Everyone, however deficient in history, can decipher their past in the narrative of the DNA.

Some can use inherited abnormalities. A form of juvenile blindness called hereditary glaucoma is found in France. Parish records show that most cases descend from a couple who lived in the village of Wierr-Effroy near Calais in the fifteenth century. Even today pilgrims pray in the village church of Sainte Godeleine, which contains a cistern whose waters are believed to cure blindness. Thirty thousand descendants have been traced and for many the diagnosis of the disease was their first clue about where their ancestors came from and who their relatives might be. The gene went with French emigrants to the New World.

Human genetics was, until recently, restricted to studying pedigrees that stood out because they contained an inborn disease. Its ability to trace descent was limited to those few kindreds who appear to deviate from some perfect form. Biology has now shown that perfection is a mirage and that, instead, variation rules. Thousands of characters – normal diversity, not diseases – distinguish each nation, each family and each person. Everyone alive today is different from everyone who ever has lived or ever will live. Such variation can be used to look at shared ancestry in any lineage, healthy or ill, aristocratic or plebeian. Every modern gene brings clues from parents and grandparents, from the earliest humans a hundred thousand years and more ago and from the origin of life four thousand million years before that.

Most of genetics is no more than a search for diversity. Some differences can be seen with the naked eye. Others need the most sophisticated methods of molecular biology. As a sample of how different each individual is we can glance beneath the way we look to ask about variation in how we sense the world and how the world perceives us.

Obviously, people do not much resemble each other. The inheritance of appearance is not simple. Eye colour depends first on whether any pigment is present. If none is made the eye is pale blue. Other tints vary in the amounts of the pigment made by several distinct genes, so that colour is not a dependable way of working out who fathered a particular child. The inheritance of hair type is also rather complex. Apart from very blonde or very red hair, the genetics of the rest of the range is confused and is further complicated by the effects of age and exposure to the sun.

Even a trivial test shows that individuals differ in other ways. Stick your tongue out. Can you roll it into a tube? About half those of European descent can and half cannot. Clasp your hands together. Which thumb is on top? Again, about half the population folds the left thumb above the right and about half do it the other way. These attributes run in families but their inheritance, like that of physical appearance, is uncertain.

People vary not just in the way the world sees them, but how they see it. A few are colour-blind. They lack a receptor for red, green or blue light. All three are needed to perceive the full range of colour. The absence of (or damage to) one (usually that for green, less often for red, almost never for blue) gives rise to a mild disability that may have made a difference when gathering food in ancient times. The three genes involved have now been tracked down. Those for red and green are similar and diverged not long ago, while the blue receptor has an identity of its own. John Dalton, best known for his atomic theory, was himself so colour-blind as to match red sealing-wax with a leaf (which must have made things difficult for a chemist). He believed that his own eyes were tinted with a blue filter and asked that they be examined after his death. They were, and no filter was found, but, a century and a half later, a check of the DNA in his pickled eyeballs showed him to have lacked the green-sensitive pigment.

Colour-blindness marks the extreme of a system of normal variation in perception. When asked to mix red and green light until they match a standard orange colour, people divide into two groups that differ in the hue of the red light chosen. There are two distinct receptors for red, differing in a single change in the DNA. About sixty per cent of Europeans have one form, forty per cent the other. Both groups are normal (in the sense that they are aware of no handicap) but one sees the world through rather more rose-tinted spectacles than the other. The contrast is small but noticeable. If two men with different red receptors were to choose jacket and trousers for Father Christmas there would be a perceptible clash between upper and lower halves.

In the 1930s, a manufacturer of ice trays was surprised to receive complaints that his trays made ice taste bitter. This baffled the entrepreneur as the ice tasted just like ice to him, but was a hint of inherited differences in the ability to taste. To some, a trace of a substance used in the manufacturing process is intolerable, while to others a concentration a thousand times greater has no taste at all. Much of the difference depends on just one gene which exists in two forms. That observation, the ability or otherwise to perceive a substance, now called PROP, was the key to a new universe of taste. Genetic ‘supertasters’ are very sensitive to the hops in beer, to pungent vegetables like broccoli, to sugar and to spices, while non-tasters scarcely notice them. Half the population of India cannot taste the chemical at all, but just one African in thirty is unable to perceive it. Students of my day thought it witty to make tea containing PROP to see the bafflement of those who could drink it and those who could not. Today’s undergraduates have more sense.

As truffle-hunters know, scent and taste are related. There is genetic variation in the ability to smell, among other things, sweat, musk, hydrogen cyanide and the odour of freesias. Many animals communicate with each other through the nose. Female mice can smell not only who a male is, but how close a relative he might be. Humans also have an odorous identity, as police dogs find it more difficult to separate the trails of identical twins (who have all their genes in common) than those of unrelated people. Man has more scent glands than does any other primate, perhaps as a remnant of some uniqueness in smell which has lost its importance in a world full of sight. The tie between sex and scent in ourselves is made by a rare inborn disease that both prevents the growth of the sex organs and abolishes the sense of smell, suggesting that the two systems share a common pathway of development in the early embryo.

Variation in the way we look, see, smell and taste is but a tiny part of the universe of difference. The genes that enable mice to recognise each other by scent are part of a larger system of identifying outsiders. The threat of infection means that every creature is always in conflict with the external world. The immune system determines what should be kept out. It differentiates ‘self’ from ‘not-self’ and makes protective antibodies that interact with antigens (chemical clues on a native or foreign molecule) to define whether any substance is acceptable. The millions of antibodies each recognises a single antigen. Cells bear antigens of their own that, with great precision, separate each individual from his fellows. Antigens are a hint of the mass of uniqueness beneath the bland surface of the human race.

When blood from two people is mixed, it may turn into a sticky mess. The process is controlled by a system of antigens called the blood groups. Only certain combinations can mix successfully. Some groups, ABO and Rhesus for example, are familiar, while others, such as Duffy and Kell, are less so. Because of their importance in transfusion, millions of people have been tested. A dozen systems are screened on a routine basis and each comes in a number of forms. This small sample of genes generates plenty of diversity. The chances of two Englishmen having the same combination of all twelve blood groups is only about one in three thousand. Of an Englishman and a Welshman it is even less and of an English person and an African less again.

Since the discovery of the blood groups and other cues on the surfaces of cells, there has been a technical revolution. Like the stone age revolution a thousand centuries ago, it depends on simple tools that can be used in many ways. The DNA of different people can now be compared letter by letter, to test how unique we are. The Human Genome Diversity Project is a spin-off from the main mapping effort which has tested thousands of people. On the average, and depending on what piece of the DNA is tested, two people differ in about one or two DNA letters per thousand; that is, in about three to six million places in the whole inherited message. Some of the differences involve changes in single bases (single nucleotide polymorphisms, or ‘snips’ as they are called), some in the number of short repeats of particular sequences (‘microsatellites’ and ‘minisatellites’) and some turn on the presence or absence of bits of mobile DNA that leapt into a particular place in the genome long ago. Blood groups show how improbable it is that two will be the same when a mere twelve variable systems are used. The chance that they both have the same sequence of letters in the whole genetic alphabet is one in hundreds of billions. Genetics has made individuals of us all. It disproves Plato’s myth of the absolute, that there exists one ideal form of human being, with rare flaws that lead to inborn disease.

Variation helps us to understand where we fit in our own family tree, in the pedigree of humankind, and in the world of life. Relatives are more likely to share genes because they have an ancestor in common. As all genes descend from a carrier long dead they can be used to test kinship, however distant that might be. The more variants two people share the more they are related. This logic can be used to sort out any pattern of affinity.

This detective work is easiest when close – or identical – relatives are involved. The US Army tests the fit of dead bodies to their previous owners by storing DNA samples from soldiers in the hope of identifying their corpses after death. DNA can also say a lot about the immediate family. Once, immigration officers faced with applicants for entry often refused to believe that a child was the offspring of the woman who claimed it. Comparison of the genes of mother and child almost always showed that the mother was telling the truth. Our society being what it is, the tests are now less used than they were. However, not all families are what they seem. Attempts to match the genes of parents and offspring in Britain or the United States reveal quite a high incidence of false paternity. Many children have a combination of genes which cannot be generated from those of their supposed parents. Often, they show that the biological father is not the male who is married to the biological mother. In middle class society about one birth in twenty is of this kind.

Such detective work can skip generations. During the Argentinian military dictatorship of the 1970s and 1980s thousands of people disappeared. Most were murdered. Some of the victims were pregnant women who were killed after they had given birth. Their children were stolen by military families. When civilian rule was restored, a group of mothers of the murdered women began to search for their grandchildren, whose DNA was compared with those who claimed to be their parents. The message passed in the genes enabled more than fifty children to be restored to their biological families, two generations on.

Other families have no hope of restoration. Bones dug up in a cellar in Ekaterinburg in 1991 were suspected to be those of the last Tsar and his family, shot in 1918. Checks of their DNA against modern relatives proves that the skeletons are, indeed, the remains of the Romanovs. Intriguingly enough, the skeleton of one young girl imprisoned with the group was missing. A woman known as Anna Anderson (who died in Virginia in 1984) claimed for many years to be the absent child, Anastasia, the daughter of the Tsar. Her assertion was rejected by a German court, but was accepted by thousands of émigré Russians. A check of the genes contained in a sample of her tissue found after her death showed her not to be related to the Romanovs, but instead to be (as many had suspected) a Pole, Franziska Schanzkowska, who had been rescued from a suicide attempt in a Berlin canal and ever after believed herself to be of noble blood.

Anna Anderson’s claim to the Russian Eagle was false; but everyone has been granted a genetic coat of arms to democratize the search for descent. Like that of the Romanovs, it records who the forebears were and from whence they came. When people move they take more than their escutcheons. The DNA goes too, so that maps of genes do more than just record ancestry. They recreate history.

History itself may suggest where to start. Alex Haley, in his book Roots, used documents on the slave trade to try to find his African ancestors. He found just one, Kunta Kinte, who had been taken as a slave from the Gambia in 1767; and later became suspicious of the tales told to him by a native story-teller upon which Roots was in part based. The genes of today’s Black Americans might have solved his problem.

The African slave trade began in the days of the Roman Empire. By AD 800 Arab traders had extended it to Europe, the Middle East and China. In the fifteenth century the Spanish and Portuguese started what became a mass migration, at first from the Guinea Coast, modern Mauritania. Mediaeval Venice had black gondoliers and by the sixteenth century one person in ten in Lisbon was of African origin. Soon, a bull of Pope Nicholas V instructed his followers to ‘attack, subject, and reduce to perpetual slavery the Saracens, Pagans and other enemies of Christ, southward from Cape Bojador and including all the coast of Guinea’.

The main trade was to the New World. About fifteen million Africans were shipped across the Atlantic. They came from all over West Africa and were dispersed over much of North and South America. The United States imported less than a twentieth of the total, but by the 1950s the USA had a third of all New World people of African descent, suggesting that slaves were treated less brutally there than in the Caribbean or Brazil. Slave-owners had their own preferences. In South Carolina slaves from the Gambia were favoured over those from Biafra as the latter were thought to be hard to control. In Virginia the preference was in the opposite direction.

Many Africans have an abnormal form of the red pigment of the blood, haemoglobin. One of the amino acids has suffered a genetic accident, a mutation. This ‘sickle-cell’ form protects against malaria. Its protective role has disappeared with the control of the disease in the United States, but many thousands of Black Americans still carry the gene as an unwelcome record of their past. Anyone, however light their skin, who has the sickle-cell variant must have had at least one African ancestor. The disease was first recognised in 1910, and was at once used as a statement of racial identity: anyone with the illness (whatever their colour) must, by definition, be a Negro. Indeed, its very presence was seen as proof of the degenerate nature of American Blacks. The related disorders in southern Europe also showed, in the words of one racial theorist, that such people were ‘not white clear through’ and that their immigration to the USA would ‘produce a hybrid race of people as worthless and futile as the good-for-nothing mongrels of Central America.’

The fact that many Black Americans have a copy of the gene for sickle-cell haemoglobin says little more than that they originated in West Africa, which we knew already. Molecular technology tells a tale of just who the ‘mongrels’ are. It uncovers a mass of variation around the haemoglobin genes and gives an insight into the ancestry of many Americans, black or not; including the great majority who do not carry a copy of sickle-cell at all.

The DNA in this part of the genome varies from place to place within Africa. The sickle-cell mutation itself is associated with different sets of DNA letters in Sierra Leone, Nigeria and Zaire, probably because it arose several times. The DNA around the normal version of the gene also varies and this, too, can be used to track down where in Africa the ancestors of today’s Americans came from.

That continent contains more diversity than anywhere else. Not only are its people more distinct one from the other, but different villages, tribes and nations have more individuality, because humans have been in Africa for longer than anywhere else. As a result, genes can track down the ancestry of Africans with some accuracy.

Black Americans from the north of the USA have a different set of variants from those in the south. The majority of northerners share a heritage with today’s Nigerians while their southern cousins have more affinities with peoples further west. The difference in the slave markets two hundred years ago has left evidence today. Alex Haley, by comparing his genes with those from Africa, would have learned much more about his forefathers than he could hope to uncover from the records. For any black American, a DNA test could be a first hint as to where to search for his slave ancestors – and, for a mere $250, one is now on sale (although the limited information yet available on the genes of West Africa mean that any hope of finding his native village – or even tribe – is largely vain).

Many of Alex Haley’s ancestors were probably not black at all. One particular variant in the Duffy blood group system is found only in West Africa. Europeans have a different version of this gene. Surveys of United States Blacks show that up to a quarter of their Duffy genes are of white origin, in many cases because of inter-racial matings during the days of slavery. Such liaisons were covert, but widespread. Even President Thomas Jefferson is said to have had several children by his slave mistress, Sally Hemings. The conjecture was proved by the discovery that one of her descendants carries DNA shared with that of the President’s family (a proof so firm that it has been accepted, grudgingly, by the association of Jeffersonian descendants).

A closer look at a set of DNA clues specific to Africa or to people of European origin says more about the history of slavery. In Jamaica (where whites were a small minority), just one black gene in sixteen is of European origin. In most American cities the figure is around one in six, but in New Orleans is higher, at between a fifth and a quarter. Until 1803, Louisiana was under French, rather than Anglo-Saxon, control. Gallic racial tolerance lives on in today’s genes. The differences in numbers of blacks and whites, and the small proportion of white families that have mated with blacks has transferred far fewer black genes into the American population that sees itself as white, with an overall proportion of about one gene in a hundred.

Race involves a lot more than DNA. As a result, the proportion of blacks in the United States is rising. In 1997, about thirteen per cent of Americans perceived themselves as black and, over the past two decades the country’s black population has increased at twice the rate of the white. Most of this has nothing to do with genes, but is a matter of identity. Thirty years ago anyone of mixed ancestry would do their best to classify themselves as white. Now, with the rise of black self-esteem, many find themselves more at home as blacks. As a result, any genetic measure of admixture then and now will give different results, as a reminder that race is constructed by society as much as by DNA.

Seventeenth- and eighteenth-century England, too, had a substantial black population. It disappeared; not because it died out, but because it was assimilated. Part of its heritage is, without doubt, still around in the streets of modern Britain. Dr Johnson himself had a black servant, Francis Barber, to whom he left enough money to set up in trade. Many people around Lichfield are proud to trace their descent from him, although their skins are as fair as those of their neighbours. White Britons contain other exotic genes as well. After all, the first slaves to cross the Atlantic were the Caribbean Indians sent to Spain by Columbus in 1495 and there was a sixteenth-century fashion for bringing newly discovered peoples back to Europe. The English explorer Frobisher brought back some Eskimos in 1577 and more than a thousand American Indians (including a Brazilian king) were transported to Europe. Many of the unwilling migrants died, but some brought up families. Their legacy persists, no doubt, today; but they have been absorbed so fully into the local population that only a genetic test – or provision of a dependable pedigree – can say who bears it.

Genes have taken us back for hundred of years – for fifteen generations or so where black Americans are concerned. But they bear messages from earlier in history. Sometimes, the evidence is direct, more often indirect: but in every case it links the present with the past.

For good historical reasons, a great deal is known about the genetics of Hiroshima and Nagasaki. The Americans spent many years on a survey of whether the atom bombs had increased the mutation rate. No effect was found, but a mass of information on the genes of the two cities was gathered. Each has a cluster of rare variants not present in the other. They are relics of an ancient history. Hiroshima and Nagasaki were each founded by the amalgamation of different warring clans that lived in the region eight thousand years ago. Like tribal peoples today, they had diverged in their DNAs. The slight differences between the ancient tribes persist in the modern towns. Nagasaki was one of the few ports open to the outside world during Japan’s self-imposed isolation, but has no more sign of an influx of a foreign heritage than does Hiroshima. The voices of remote ancestors echo more loudly through the two cities than do those of more recent invaders.