The Language of the Genes

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.

Because genes copy themselves, there is no need to go back to the source to find an ancestor; but, sometimes, the source has been preserved. The Egyptian pharaoh Tutankhamun was buried at about the same time as another mummy, Smenkhare. Their blood groups can still be identified and show them to have been brothers. The first piece of human fossil DNA was found in the dried corpse of an Egyptian child, buried in the sands. It had survived for two and a half thousand years. Since then, many pieces of ancient DNA have turned up (although their analysis is confused by a tendency for contamination with modern material).

It has, nevertheless, become possible to read ancestral genes directly. Some ancient DNA, like that of the Easter Islanders, whose civilization was destroyed by constant warfare and ecological vandalism, has no equivalent in the modern world and remains, like their enigmatic statues, as the sole evidence of a people who left no posterity. Sometimes, it adds to the clues of the present. Agriculture began in Japan with the Jomon people, about ten thousand years ago, but they also spent much of their time as hunters. Farming did not take off as a way of life, with rice as a staple diet, until the Yayoi tribes who followed them, thousands of years later. Rice was brought by the Chinese, and the Japanese argue about how many of their genes entered the country with the crop. Many believe that the immigrants drove out most of the natives; that people moved, rather than ideas. However, DNA extracted from a two-thousand-year-old Chinese burial site links its inhabitants with modern Chinese, but not with the fossil DNA of the extinct Japanese. It proves that few mainlanders made the journey. Instead, the locals of two millennia ago, much like their modern descendants, picked up and used a new technology invented in a foreign land. Modern Japan, on the other hand, does have biological links with the Chinese, so that a movement from the mainland had an impact much later.

Some ancestral voices are particularly fluent in telling the story of the past. Mitochondria are small energy-producing structures in the cell. Each has its own piece of DNA, a closed circle of about sixteen thousand DNA bases, quite distinct from that in the cell nucleus. Eggs are full of mitochondria but those in sperm are killed off as they enter the egg. As a result, such genes are inherited almost exclusively through females. Like Jewishness, they pass from mothers to daughters and sons, but daughters alone pass them on to the next generation.

Every family, every nation and every continent can trace descent from its mitochondrial Eve, a woman (needless to say, one of many alive at the same time) upon whom all their female lineages converge. Sometimes she lived not long ago: in New Zealand, for instance, nearly all Maoris share the same mitochondrial identity, hinting that just a few women founded their nation a thousand years ago. A world family tree based on mitochondria finds its roots in Africa, with more diversity in that continent than anywhere else. To track more recent paths of migration shows that mitochondria are an accurate record of history: thus, in the New World, native mitochondria have a tie with those of Siberia, confirming an ancient pattern of migration.

Shared genes link New Zealand, Siberia and the rest of the world to an African ancestor. The first modern human appeared in Africa over a hundred thousand years ago, in the continent that gave rise to most of our pre-human kin and of the apes to whom we claim affinity. A few of these African relatives from a deeper branch of the tree are alive today. One, the chimpanzee, has always seemed a near neighbour; and Koko (an inhabitant of the Gombe Stream Reserve) was the first animal to have an obituary in The Times.

As any literate teenager knows, Tarzan of the Apes was proved to be the son of Lord Greystoke by virtue of the inky fingermarks in a childhood notebook. Galton had shown that chimpanzees have fingerprints that look much like those of a human being. Chimps and men, they prove, share genes. A joint heritage goes beyond the fingertips. A distinguished geneticist of the 1940s once tested whether chimps share our variation in the ability to taste the bitter chemical PROP by feeding it to three of the inhabitants of London Zoo. Two swallowed the drink with every sign of delight, but the third spat the liquid all over the famous professor as further evidence of common ancestry.

The biological affinity goes much further. Apes have blood groups like our own, their chromosomes are almost identical, and a test of the overall similarity of DNA shows that humans share ninety-eight per cent of their genetic material with chimpanzees. We trace relatedness to the rest of the animal kingdom as well, with about a quarter of our genes similar to others in remote places among the insects or the jellyfish. Mice and men have much more in common, including dozens of inherited diseases. We share even more genes with rabbits and plenty with remote branches of existence, from bacteria to yeasts to bananas. All living creatures seem to need a set of ‘housekeeping genes’ that do the basic work of the cell, and many of the seven hundred such structures are shared. Most have changed little since they began. An unkind experiment in which more and more of the five hundred genes in a simple bacterium were destroyed showed that it needs, at an absolute minimum, three hundred or so; nearly all of which have parallels in our own DNA. This common core shows that the most unlikely beings speak the same genetic language.

Pharaoh Psamtik the First, who flourished in the seventh century before Christ, searched for the first word of all. He put a baby in the care of a dumb nurse and noted the sounds it made. One word was (or seemed to be) ‘becos’, the Phrygian for bread, suggesting to Psamtik that the Phrygians (who lived in what is modern Turkey) were the first people of all. A computer search through the millions of DNA letters now sequenced from dozens of organisms also hints at a shared structure from bacteria to humans; the father (or mother) of all genes, that might have persisted since life began. The scientist who published the ur-sequence has turned the information to a useful end. Assigning musical notes to each DNA letter he used them as a theme for a ‘symphony of life’.

Gene sharing, from bacteria to humans, proves the unity of existence. It also defines the limits of what biology can say. A chimp may share ninety-eight per cent of its DNA with ourselves but it is not ninety-eight per cent human: it is not human at all – it is a chimp. And does the fact that we have genes in common with a mouse, or a banana, say anything about human nature? Some claim that genes will tell us what we really are. The idea is absurd.

One gene is found in a certain form in men, but a different one in all other apes. It codes for a molecule on the cell surface much involved in communication between cells, brain cells more than most. Perhaps this is the gene – or one of the genes – that makes us human. Its message spelt out in the four DNA letters, A, G, C and T starts like this: AACCGGCAGACAT … Altogether, it has three thousand letters. Together they contain an important part of the tedious biological story of being a man or woman rather than a chimpanzee or gorilla. Needless to say, that ancestral bulletin does nothing to tell us – or apes – what it means to be part of humankind. That calls for a lot more than a sequence of DNA bases and lies outside the realm of science altogether.

St Bede – whose writings are the best source of information about England before the eighth century – had a powerful metaphor for existence. To him human existence was ‘As if when on a winter’s night you sit feasting with your ealdormen and thegns, a single sparrow should fly swiftly into the hall, and coming in at one door instantly fly out through another. In that time in which it is indoors it is indeed not touched by the fury of the winter, but yet, this smallest space of calmness being passed almost in a flash, from winter going into winter again, it is lost to your eyes. Somewhat like this appears the life of man; but of what follows or what went before, we are utterly ignorant.’

His allegory was a religious one but has a biological parallel. Genes have a memory of their own. To read it gives new hope of looking beyond the hall into which our own brief existence is confined. It allows us to learn what went before in the life of our own species; to guess at what happened much earlier, and even to speculate about what fate may hold for generations yet to come.

Chapter Two THE RULES OF THE GAME (#ulink_559629fe-b0bd-5b16-8ab4-ef521f9f6c32)

It is always painful to watch an unfamiliar game and to try to work out what is going on. Although I lived in the United States for several years, and although the sport is now shown on British television, I have almost no idea how American football works. There is a clear general desire to score, but how play stops and starts and why the spectators cheer at odd moments remains a closed book. A deep lack of interest in ball games helps in my case, but cricket is equally dull to sporting enthusiasts from other countries. They just do not understand the rules.

The rules of the game known as sexual reproduction are not obvious from its results. As a consequence, how inheritance works was a closed book until quite recently. Part of the problem is that the way sex works is so different from how it seems that it ought to. It seems obvious that a character acquired by a parent must be passed on to the next generation. After all, blacksmiths’ children tend to be muscular and those of criminals less than honest. In the Bible, Jacob, when allowed to choose striped kids from Laban’s herd of goats, put striped sticks near the parents as they mated in the hope of increasing the number available. Later, pregnant women looked on pictures of saints and avoided people with deformities. It took a series of painful trials in which generations of mice were deprived of their tails to show that acquired characters were not in fact inherited. Of course, Jews had been doing the same experiment for thousands of years.

Another potent myth about inheritance is that the characters of a mother and a father pass to their blood, which is mixed in their offspring. Children are, as a result, a blend of the attributes of their parents. This idea – a sort of genetics of the average – copes quite well with traits such as height or weight but fails to explain why a child may look like a distant relative rather than its father or mother. The idea lasted until just a few years ago. The stud book is the record kept by racehorse breeders. A mare who had borne a foal by mating with a non-stud stallion was struck off as her blood was deemed to be polluted. Indeed, a survey of elderly women in Bristol showed that half believed in the chance of a woman having a black baby if she had sex with a black man many years before. The crones of the west country, like the breeders of horses, had never managed to work out the instructions for the reproductive game.

The only section of The Origin of Species which does not make good reading today is Chapter Five, ‘Laws of Variation’. Darwin got it wrong and, after much agonising, suggested that the organs of parents passed material to the blood and then to sperm and egg. Children were, he thought, intermediate between those who produced them. Such a mode of inheritance would be fatal to the idea of evolution. The problem was pointed out by Fleeming Jenkin, the first Professor of Engineering at the University of Edinburgh. Writing in 1867 – and with a sturdy disregard of today’s proprieties – Jenkin imagined ‘a white man wrecked on an island inhabited by negroes. Suppose him to possess the physical strength, energy and ability of a dominant white race. There does not follow the conclusion that after a … number of generations the inhabitants of the island will be white. Our shipwrecked hero would probably become king; … he would have a great many wives, and children … much superior in average intelligence to the negroes, but can anyone believe that the whole island will gradually acquire a white or even a yellow population? A highly favoured white cannot blanch a nation of negroes.’

Jenkin saw that the attributes of a distant ancestor, valuable as they might be, are of little help to later generations if bloods mix. Characters would then blend over the years until their effects disappear. However useful an ink drop in a gallon of water might be at some time in the future it is impossible to get it back from a single mixed drop. Genetics by blending means that any advantageous character would be diluted out in the next generation. Fortunately, the blood myth is wrong.

It was shot down by Galton himself. He transfused blood from a black rabbit to a white to see if the latter had black offspring. It did not. Inheritance by dilution had been disproved, but Galton had nothing to put in its place.

Unknown to either Darwin or to his cousin the rules of genetics had already been worked out by another biological genius. Gregor Mendel lived in Bohemia and published in a rather obscure scientific journal, the Transactions of the Brunn Natural History Society. His breakthrough was overlooked for thirty-five years after it was published in 1866. Mendel, an Augustinian monk, attempted a science degree but failed to complete it. Like Darwin and Galton he suffered from bouts of depression which prevented him from working for months at a time. Nevertheless, he persisted with his experiments. He found that the inherited message is transmitted according to a simple set of regulations – the grammar of the genes. Later in his career (and setting a precedent for the present age) he was unable to continue with research because of the pressures of administration. The study of inheritance came to a halt for almost half a century.

Grammar is always more tedious than vocabulary, but cannot be avoided. The rest of this chapter explores the basic rules of genetics. Those who teach the subject still have an obsession with Mendel and his peas and I make no excuse for having them as a first course.

Mendel made a conceptual breakthrough. Instead of (like his predecessors) working on traits such as height or weight (which could only be measured) Mendel was more or less the first biologist to count anything. This put him on the road to his great discovery.

Peas, like many garden plants, exist in true-breeding lines within which all individuals look the same. Different lines are distinct in characters such as seed shape (which can be round or wrinkled) and seed colour, which may be yellow or green. Peas also have the advantage that each plant carries both male and female organs. Using a small brush it is possible to fertilise any female flower with pollen from any male. Even a male flower from the same plant can be used. The process, a kind of botanical incest, is called self-fertilisation.

Mendel added pollen (male germ cells) from a line with yellow peas to the female part of a flower from a green pea line. In the next generation he got an unexpected result. Instead of all the offspring being intermediate, all the plants in the new generation looked like one of the parents and not the other. They all had yellow peas. This is not at all what would be expected if the ‘blood’ of the two lines was blended into a yellowish-green mixture.

The next step was to self-fertilise these first-generation yellow plants; in other words to expose their eggs to pollen from the same individual. That gave another unforeseen outcome. Both the original colours, yellow and green, reappeared in the next generation. Whatever it was that produced green could still do so, even though it had spent time within a plant with yellow peas. This did not fit at all with the idea that the different properties of each parent were blended together. Inheritance was, his experiment showed, based on particles rather than fluids.

Mendel did more. He added up the numbers of yellow and green peas in each generation. In the first generation (the offspring of the crossed pure lines) all the plants had yellow peas. In the second, obtained by self-fertilising the yellow plants from the first generation, there were always, on the average, three yellows to one green. From this simple result, Mendel deduced the fundamental rule of genetics.

Pea colour was, he thought, controlled by pairs of factors (or genes, as they became known). Each adult plant had two factors for pea colour, but pollen or egg received only one. On fertilisation – when pollen met egg – a new plant with two factors (or genes) was reborn. The colour of the peas was determined by what the plant inherited. In the original pure lines all individuals carried either two ‘yellow’ or two ‘green’ versions of the seed colour gene. As a result, crosses within a pure line gave a new family of plants identical to their parents.

When pollen from one pure line fertilised eggs from a different line new plants were produced with two different factors, one from each parent. In Mendel’s experiment these plants looked yellow although each carried a hidden set of instructions for making green peas. In other words, the effects of the yellow version were concealing those of the green. The factor for yellow is, we say, dominant to that for green, which is recessive.

Plants with both variants make two kinds of pollen or egg. Half carry the instructions for making green peas and half for yellow. There are hence four ways in which pollen and egg can be brought together when two plants of this kind are mated, or a single one self-fertilised. One quarter of fertilisations involve yellow with yellow, one quarter green with green; and two quarters – one half – yellow with green.

Mendel had already shown that yellow with green produces an individual with yellow peas. Yellow with yellow, needless to say, produces plants with yellow peas, and in a plant with two green factors the pea is green. The ratio of colours in this second generation is therefore three yellow to one green. Mendel worked backwards from this ratio to define his basic rule of inheritance.

Mendel made crosses using many different characters – flower colour, plant height and pea shape – and found that the same ratios applied to each. He also tested the inheritance of pairs of characters considered together. For example, plants with yellow and smooth peas were crossed with others with green and wrinkled peas. His law applied again. Patterns of inheritance of colour were not influenced by those for shape. From this he deduced that separate genes (rather than alternative forms of the same one) must be involved for each attribute. Both for distinct forms of the same trait (yellow or green colour, for example) and for quite different ones (such as colour and shape) inheritance was based on the segregation of physical units. Mendel was the first to prove that offspring are not the average of their parents and that genetics is based on differences rather than similarities.

Biologists since his day have delighted in picking over his results (and accusing him of fraud because they may fit his theories too well). They argue about what he thought his factors were, and speculate about why his work was ignored. Whatever lies behind its long obscurity, Mendel’s result was rediscovered by plant breeders in the first year of the twentieth century and was soon found to apply to hundreds of characters in both animals and plants. Mendel had the good luck, or the genius, needed to be right where all his predecessors had been wrong. No science traces its origin to a single individual more directly than does genetics, and Mendel’s work is still the foundation of the whole enormous subject which it has become.

Mendel rescued Darwin from his dilemma. A gene for green pea colour or for white skin, rare though it may be, is not diluted by the presence of many copies of genes for other colours. Instead, it can persist unchanged over the generations and will become more common should it gain an advantage.

Soon after the crucial rules were rediscovered they were used to interpret patterns of human inheritance. It is not possible to carry out breeding experiments on our fellow citizens. They would take too long, for one thing. Instead, biologists must rely on the experiments which are done as humans go about their sexual business. They use family trees or pedigrees – from the French pied de grue, crane’s foot, after a supposed resemblance of the earliest aristocratic pedigrees (which were arranged in concentric circles) to a bird’s toes. Some are fanciful, going back to Adam himself, but geneticists usually have fewer generations to play with, although one or two pedigrees do trace back for hundreds of years.

The first was published in 1903. It showed the inheritance of shortened hands and fingers in a Norwegian village. Such fingers ran in families and showed a clear pattern. The trait never skipped a generation. Anyone with short fingers had a parent, a grandparent and so on with the same thing. If an affected person married someone without the abnormality (as most did), about half their children were affected. If any of their normal children married another person with normal hands the character disappeared from that branch of the family.

The pattern is just what we expect for a dominant character. Only one copy of the damaged DNA (as in the case of yellow pea colour) is needed to show its effects. Most sufferers, coming as they do from a marriage between a normal and an affected parent, have a single copy of the normal and a single copy of the abnormal form, one from either parent. As a result, their own sperm – or eggs – are of two types, half carrying the normal and half the abnormal variant. When they marry, half their children carry a copy of the damaged gene. The chance of any child of a normal and an affected person having short fingers is hence one in two. An unaffected couple never has a child showing the abnormality as neither of them possesses the flawed instruction that makes it.

Other inherited traits do not behave in this simple way. They are recessives. To show the effect, two copies of the inherited factor, one from each parent, are needed. The parents themselves usually each have a single copy and appear quite normal. Most do not know that they are at risk of having an affected child. Sometimes, though, their offspring looks more like a distant relative or an ancestor than it does either parent. Before Mendel, that pattern was inexplicable. Such children were sometimes called ‘throwbacks’. Now we know that they are obeying Mendel’s laws. They have, by chance, inherited two copies of a recessive abnormality while their mother and father each have just one.

In Britain, one child in several thousand is an albino, lacking any pigment in eyes, hair or skin. Elsewhere, the anomaly is more common. In some North American Indians, about one person in a hundred and fifty is an albino. According to the Book of Enoch (one of the apocryphal books of the Bible), Noah himself suffered from the condition. If he did, there is not much sign of the gene in his descendants.

The great majority of albino children are born to parents of normal skin colour. They must each have a single copy of the albino factor matched with another copy of that for full pigmentation. Half the father’s sperm carry the altered gene. Should one of these fertilise one of that half of his partner’s eggs which carry the same thing, then the child will have two copies of the recessive form and will lack pigment. In a marriage such as this, the chance of any child being an albino is a half times a half. This one in four probability is the same for all the children. It is not the case, as some parents think, that having had one albino child means that the next three are bound to be normal.

Patterns of inheritance in humans can, then, follow the same rules as those found in peas. However, biology is rarely pure and never simple. Much of the history of human genetics has been a tale of exceptions to Mendel’s laws.

For example, variants do not have to be dominant or recessive. In some blood groups, both show their effects. Someone with a factor for group A and group B has AB blood, which shares the properties of both. At the DNA level, the whole concept of dominance or recessivity goes away. A change in the order of bases can be identified with no difficulty, whether one or two copies are present. Molecular biology makes it possible to see genes directly, rather than having to infer what is going on, as Mendel did, from looking at what they make.

Another result which would have surprised Mendel is that one gene may control many characters. Thus, sickle-cell haemoglobin has all kinds of side-effects. People with two copies may suffer from brain damage, heart failure and skeletal abnormalities (all of which arise from anaemia and from the blockage of blood vessels). In contrast, some characters (such as height or weight) are controlled by many genes. What is more, Mendelian ratios sometimes change because one or other type is lethal, or bears some advantage.

All this (and much more) means that the study of inheritance has become more complicated in the past century and a half. Nevertheless, Mendel’s laws apply to humans as much as to any other creature.

They are beguilingly simple and have been invoked to explain all conceivable – and some inconceivable – patterns of resemblance. In the early days, long pedigrees claimed to show that outbursts of bad temper were due to a dominant gene and that there were genes for going to sea or for ‘drapetomania’ – pathological running away among slaves. This urge for simple explanations persists today, but mainly among non-scientists. Geneticists have had their fingers burned by simplicity too often to believe that Mendelism explains everything.

Mendel had no interest in what his inherited particles were made of or where they might be found. Others began to wonder what they were. In 1909 the American geneticist Thomas Hunt Morgan, looking for a candidate for breeding experiments hit upon the fruit fly. It was an inspired choice and his work, with Drosophila melanogaster (the black-bellied dew lover, to translate its name) was the first step towards making the human gene map.

Many fruit fly traits were inherited in a simple Mendelian way, but some showed odd patterns of inheritance. When peas were crossed it made no difference which parent carried green or yellow seeds. The results were the same whether the male was green and the female yellow, or vice versa. Some traits in flies gave a different result. For certain genes – such as that controlling the colour of the eye, which may be red or white – it mattered whether the mother or the father had white eyes. When white-eyed fathers were crossed with red-eyed mothers all the offspring had red eyes but when the cross was the other way round (with white-eyed mothers and red-eyed fathers) the result was different. All the sons had white eyes and the daughters red. To Morgan’s surprise, the sex of the parent that bore a certain variant had an effect on the appearance of the offspring.

Morgan knew that male and female fruit flies differ in another way. Chromosomes are paired bodies in the cell which appear as dark strands. Most of the chromosomes of the two sexes look similar but one pair – the sex chromosomes – are different. Females have two large X chromosomes; males a single X and a much smaller Y.