The Language of the Genes

by Steve Jones

l tin- cell. Identical twins have only a one in three chance of both being affected, so that something other than DNA (perhaps ilu- poor nutrition of their pregnant mother) is also involved. Insulin production varies in a gradual way from person to person with a threshold at which the illness sets in. The level at which this is set is under genetic control and may be modified by some unknown environmental cause.

  Because the genetic component of this form of diabetes is, in some patients, simple and quite strong, a DNA test can be used to identify a proportion of the children at risk and to begin treatment before any damage is done. Even so, most patients — those with genes of minor effect, or those exposed to the unknown environmental stress — will not be revealed by a genetic test.

  The people of the Pacific island of Nauru have had riches thrust upon them by phosphate mining. Instead offish and vegetables they eat fat and sugar. Eight out of ten adult Nauruans have non-insulin dependent diabetes and the island has one of the shortest life spans in the world. Perhaps the local genes for susceptibility to sugar were at an advantage in times when starvation was followed by glut. Not until glut was the norm did they become dangerous.

  The biological heritage of Nauru is shared by the natives of the New World. Many Mexican-Americans suffer from 'New World Syndrome, they are fat and have difficulty in controlling levels of blood sugar. The risk goes up with the number of Amerindian ancestors, which at first sight makes a good case that genes are paramount. But the disease is almost unknown among American Indians living in their home communities. It affects them only if they change their diet by moving north. Differences among Americans in the incidence of New World Syndrome arise I it Mil boih nature and nurture.

  This second type of diabetes is even more complicated and more recalcitrant to screening than is the childhood form. Genes do play a part, but they separate populations rather than individuals. Among those with Pacific or Native American ancestry, diabetes runs in families, but no single gene accounts for more than a tenth of any individual's susceptibility. Many variants are involved, scattered through the genome, with little clue as to what they do. Some have at best an ambiguous role: a search in America for eleven genes supposed to be involved in the Itrirish population turned up only two.

  The most notable aspect of non-insulin dependent diabetes is the power of the environment. A change in diet is to blame. Native Americans' or Pacific Islanders' genes are less able to cope with large amounts of fat and starch than are those of Europeans, and the illness follows. DNA is a less effective predictor than is diet. A change in habits would benefit the whole population, whether or not they are at specific risk of the illness.

  For diabetes, what seemed to be a single disease is in fact two, or several, or many, each of which might demand different treatments. Some therapies are successful, some less so; and some involve not drugs but a change in habits. Certain patients may be detected before symptoms appear by virtue of the genes they carry, but others will be missed by any screening programme. A few people will develop diabetes whatever their diet, while others may, in spite of an inherited susceptibility, avoid it because of how they live. The genetics of the illness — like that of many others — involves a minority of individuals with a single gene that predisposes to disease, and a larger number who have drawn an unlucky hand of several low-value genetic cards, which can come in many ways. Together they increase the danger but any one is of little use in prediction. For the adult-onset form, to identify those at high risk may concentrate their minds but in the end the genes have little relevance: to ban cheeseburgers would do more ih;m anything medicine can do.

  Many (and perhaps most) diseases are rather like this. Susceptibility will be difficult to test for. Variation in otic gene that makes a protein important in controlling Kit levels in the blood influences the chances of heart disease (although, of course, diet is also important). It also has a great effect on the chances of pre-senile dementia, Alzheimer's disease. For those with two copies of one form of the gene, the disease usually begins before the age of seventy, fifteen years earlier than those inheriting two copies of a more favourable allele. Most patients have no overt predisposition at all; many of those at high risk die for other reasons before the symptoms appear, and footballers, whatever their genes, are in danger of a similar illness because they head the ball. Heart disease is just as complicated. Some families inherit a tendency towards high levels of blood cholesterol, bur almost two hundred different combinations of genes can generate the effect. Risk of the disease is affected by how fat a person is (which may itself have a genetic element), blood pressure and insulin levels as well as the genes more directly implicated. As a result, such families are easier to identify with a simple blood-cholesterol test than with the most complicated DNA technology.

  All this means that the study of the inheritance of common illnesses is plagued with results that cannot be replicated. Many claims that particular genes are associated with mental diseases such as schizophrenia or depression have not been sustained on further study. In spite of plans for huge (and expensive) sweeps through the genetic undergrowth, with thousands of sick people scanned to sec if their DNA is special, the chances of success in the search for the genes involved are small. As a result genetics will have less of a role in the diagnosis and treatment of common disease than is often claimed. What it may do first is to show that what once appeared to be single illnesses — from schizophrenia to obesity — are in fact many, each of which might need a separate treatment. As a result, the prospect of screening whole populations for those at risk is far away.

  Even so, the science can bring unwelcome news to some. Many inherited diseases cannot be treated even if they are diagnosed, which at once raises the question as to who would want a test. Half of those who have a parent with Huntington's disease may contract it. Because of the delay in symptoms appearing, those at risk were once left in uncertainty about their fate. The first signs often appear in a patient's thirties or forties as a general restlessness and depression, followed by involuntary movements and ending in paralysis and death, usually within twenty years of diagnosis. As symptoms may not appear until middle age, those in danger are left in an ambiguous position. In Britain a mere one in ten choose to be tested. For them, doubt is preferable to certainty (even if, among those who do test positive, the fear that many would commit suicide has not been realised). In contrast, half those at risk of inherited breast cancer (where drugs may help although their efficacy has not been proved) take up the offer, and eight-tenths accept a test for familial colon cancer, which can in effect be cured by surgery. For those at risk of a genetic illness whether a condition is treatable is central. For a disease about which nothing can be done, most people see little point in a test.

  All this is a tribute to common sense. Some decisions are less rational. One in ten of those offered the chance of testing to see if they carry a single copy of a cystic fibrosis gene by post agrees and one in four when an appointment is made; but almost everyone given the chance of an immediate check accepts. All the great killers in the developed world are influenced by genes; and, in principle at least, genetics might be able to tell many people the probable date of their death long before it happens. Why, one might ask, would anyone want to know?

  As the blind seer Tiresias put it in Oedipus Rex, ll low terrible it is to have wisdom when it does not benefit those who have it!'. Genetics — science in general — produces knowledge; wisdom, how that knowledge is to be used, demands much more and may come only after long and painful experience. Tiresias himself was struck blind for revealing the secrets of the gods. Those of the genes are still in part concealed: and the two of every three people that they will kill can, for the time being, be grateful for that.

  Chapter Seven THE BATTLE OE THE SEXES

  Biologists have an adolescent fascination with sex. Like teenagers, they are embarrassed by the subject because of their ignorance. What sex is, why it evolved and how it works were once the biggest unsolved problems
in biology. The pastime must be important as it is so expensive. If some creatures can manage with just females, so that every individual produces copies of herself, why do so many bother with males? A female who gave them up might be able to produce twice as many daughters as before and they would carry every one of her genes. Instead, a sexual female wastes time, first in the search for a mate and then in the birth of sons who carry but half of her inheritance. It is still not certain why males exist; and why, if they are unavoidable, nature needs so many. Surely, one or two would be enough to impregnate all the females but, with few exceptions, the ratio of one to the other remains stub bornly equal throughout the living world.

  An obsession with sex goes back a long way. The Venus of Galgenberg, an elegant serpentine statuette without the exaggerated breasts and buttocks of later variations on the theme, is thirty thousand years old. Aesthetic interest in the female form goes back even further. A small pebble from an excavation in Israel has been grooved to resemble a woman's body. At eight hundred thousand years old, it is the oldest known work of art.

  Curiosity about the meaning of sex is not new. Plato, in the Symposium, suggested that there were once three sexes; males, females and androgynes or hermaphrodites. The third sex was split apart by an angry Zeus and doomed to spend eternity forever seeking its partner: 'Zeus moved their privates to the front and made them propagate upon themselves. If, in all these claspings, a man should chance upon a woman, conception would take place and the race would be continued; whereas if man should conjugate with man, he might at least obtain such satisfaction as would allow him to turn his energies to the everyday affairs of life'. This provided Plato with an explanation tor the origin of sex and the sex ratio and a neat explanation of the variety of sexual attractions common from ancient Greece to the present day. Two thousand years later the English wit Sydney Smith had the same idea, although his three sexes were men, women and clergymen.

  To define sex is easy enough. It makes individuals who contain genes from more than one line of descent, so that inherited information from different ancestors is brought together. In an asexual lineage everyone has one mother, one grandmother, one great-grandmother and so on in an unbroken chain of direct descent from the ur-mother who began the lineage. Sexual organisms are different, because the number of ancestors doubles each generation. Everyone has two parents, four grandparents and so on. Each sperm or egg has half the number of genes present in body cells and in each the genes are scrambled into new arrangements by recombination. When they meet, the novel arrays come together to produce a new and unique individual. Reshuffling the genetic message is at the heart of sexual reproduction.

  The nature of sex is illustrated by two eponymous heroes of British history, King Edward VII (who flourished in the years before the First World War) and the King Edward variety of potato (which has fed the British working class for almost as long). The potato, unlike the royals, reproduces asexually. Every King Edward potato is identical to every other and each has the same set of genes as the hoary ancestor of all potatoes that bear that name. This is convenient for the farmer and the grocer, which is why sex is not encouraged among potatoes. King Edward himself was a different kettle of fish. Malt his genes came from his mother, Queen Victoria, and half from his father, Prince Albert. He himself was a new and unique genetic mixture who combined some of the qualities of the two and of an ever-widening pool of more distant ancestors.

  It is easier to define sex than to understand it. Men have made many attempts to justify their existence. Mutation may help to explain why life is not entirely female. A harmful change to the DNA in a sexless being will be carried by all her descendants. None can ever get rid of it, destructive though it might be, unless it is reversed by another change in the same gene (which is unlikely). In time, a second error will occur in another gene in the family line. A decay of the genetic message sets in as one generation succeeds another, just like the decay that takes place within an ageing body as its cells divide without benefit of sex.

  In a sexual creature, by contrast, the new mutation can be purged as it passes to some descendants but not others. Quite often, one unfortunate will, by chance, inherit several damaged genes, and all are lost at the cost of a single death. Sex also has a more positive effect: as the environment changes some new combinations of genes may be better able to cope with the novel challenge. New mixtures of genes produce successful individuals who have been dealt a favourable hand and others who inherit a less advantageous set. George Bernard Shaw illustrated this in a hackneyed but accurate phrase. When an actress asked if she could bear his child, who might have her body and his brains, Shaw pointed out the risk of having an infant with her brains and his body. Sex reshuffles life's cards: it makes beautiful geniuses who survive and ugly fools who do not. It is a convenient way to bring together the best and purge the worst and to separate the fate of genes from that of those who carry them.

  Recombination is a redemption, which, each generation, reverses biological decay. In some ways, it is the key to immortality; a fountain of eternal youth — not for those who indulge in it, but for the genes they carry. Sex speeds up evolution because each generation consists of now combinations of genes, rather than thousands of copies of the same one. Instead of always drawing the same hand in nature's card game (which might be successful in one encounter but will not be so in all), every fertilised egg has a new deal and a new chance to win. The chance may be a small one, but as so many hands are dealt sex becomes a worthwhile, albeit expensive, gamble against a hostile world.

  To abandon males can cause problems. The majority of all-female plants can be used for only a few years. They become so loaded with genetic damage that they no longer thrive, or cannot keep up in the evolutionary race with their parasites who in time prevail. Their lineage has become old and tired. Potatoes show the risks of celibacy. The Irish famine happened because the plants used belonged to an old and sexless variety. In the mid-nineteenth century every tuber in European was descended from one or two introductions from the New World made three hundred years earlier. The new crop soon spread throughout Europe. Louis XVI of France, in an astute exploitation of the rustic mind, put guards on the first fields during the day but removed them at night. The peasants, impressed by the apparent value of the crop, were quick to steal examples and to grow them on their own land. In Ireland in 1840 every adult ate several pounds of potatoes a day (in part because their grain was exported to England to pay rent).

  Famine struck with great speed and ruinous effect. In i 845, the Irish Freeman's journal wrote 'We regret to have to state that we have had communications from more than one correspondent announcing the fact of what is called 'cholera' in potatoes in Ireland, especially in the North. In one instance the party had been digging potatoes — the finest he had ever seen from a particular field, and a particular ridge in that field until Monday last; and digging in the same ridge on Tuesday he found the tubers all blasted and unfit for the use of man or beast.' In the next five years, a million and a half people starved. Their crop had been attacked by a fungus, the potato blight, which is sexual and has many generations to each one among its hosts. The parasites evolved at a greater rate than could the potato. Nowadays, plants with new sets of genes are tried every few years to counter this. Other asexual crops, such as bananas, have as yet escaped the fate of the Irish potato (although it cannot be indefinitely delayed). The potatoes were forced into an evolutionary dead end from which the sole escape is sex.

  Because of the dangers, rather few animals have abandoned that pastime. They include the odd lizard or fish, but none of our close relatives. Even greenflies, which manage without it for most of the time, require a bout once a year or so. With occasional exceptions such as rotifers (tiny denizens of fresh water, among whom no male has ever been found), all-female lineages derive from recent ancestors with a normal sex life, as a hint that chastity is an evolutionary dead end. Just why abstinence is undesirable is still not certain. In spite of th
e attractions of the mutation theory the frank answer is that, although the reason for the existence of women is obvious enough, there is still plenty of room for argument about the point of being a man.

  The perils of abstinence can be seen in men themselves, as they possess the Y, the only chromosome that has abandoned the hobby. When germ cells are formed, all the other chromosomes line up next to each other — chromosome 2 with chromosome 2 or X with X, for example — and indulge in recombination, the sexual orgy of genetic exchange. In a male, the Y does line up with the X, but its embrace of its fellow is less than enthusiastic. Only the tip of the Y exchanges material with its opposite. The rest of the chromosome is held in a kind of biological purdah, safe from the advances of other genes.

  Chastity has had terrible effects on the Y. It has long sequences of meaningless DNA letters, many repeated thousands of times. Perhaps this is a hint of what might happen to asexual lineages if abstinence goes on for long enough. Mutations accumulate and cannot be shed and junk DNA may creep in and prove impossible to dislodge. Apart from its narrow role in ensuring the persistence of men, the Y chromosome is a warning of the dangers of continence.

  Other parts of the genome have also moved in the same direction. Comparison of the physical map of the genes with the linkage map (based, as it is, on recombination) shows that some parts of our DNA are sexier than others, at least in the sense that more recombination takes place at these well named 'hot-spots'. What is more, females are on this criterion sexier than males, as women show more recombination than do their partners.