By the time you have finished this chapter you will be a different person. I do not mean by this thai your views about existence — or even about genes — will alter, ilili* >tit',h perhaps they may. What I have in mind is simpler. In ihe next half hour or so your genes, and your life, will he altered by mutation; by errors in your own genetic message. Mutation — change — happens all the time, within ourselves and over the generations. We are constantly corrupted by it; but biology provides an escape from the inevitability of genetic decline.

Evolution is no more than the perpetuation of error. It means that progress can emerge from decay. Mutation is at the heart of human experience, of old age and death but also of sex and of rebirth. All religions share the idea that humanity is a decayed remnant of what was once perfect and that it must be returned to a higher plane by salvation, by starting again from scratch. Mutation embodies what faith demands: each man's decline but mankind's redemption.

The first genes appeared some four thousand million years ago as short strings of molecules which could make rough copies of themselves. At a reckless guess, the original molecule in life's first course, the primeval soup, has passed through four thousand million ancestors before ending up in you or me (or in a chimp or a bacterium). Every one of the untold billions of genes that has existed since then emerged through the process of mutation. A short message has grown to an instruction manual of three thousand million letters. Everyone has a unique edition of the instruction book that differs in millions of ways from that of their fellows. All this comes from the accumulation of errors in an inherited message.

Like random changes to a watch some of these accidents are harmful. But most have no effect and a few may even be useful. Every inherited disease is due to mutation. Now that medicine has, in the western world at least, almost conquered infection, mutation has become more important. About one child in forty horn in Britain has an inborn error of some kind and about a third of all hospital admissions of young children involve a genetic disease. Some damage descends from changes which happened long ago while others are mistakes in the sperm or egg of the parents themselves. Everyone carries single copies of damaged genes which, if two copies were present, would kill. As a result, everyone has at least one mutated skeleton in their genetical cupboard.

Because there are so many different genes the chance of seeing a new genetic accident in one of them ts small. Even so, in a few cases, novel errors can be spotted.

Before Queen Victoria, the genetic disease haemophilia (a failure of the blood to clot) had never been seen in the British royal family. Several of her descendants have suffered from it. The biochemical mistake probably took place in the august testicles of her father, Edward, Duke of Kent. The haemophilia gene is on the X chromosome, so that to be a haemophiliac a male needs to inherit just one copy of the gene while a female needs two. The disease is hence much more common among boys. This was known to the Jews three thousand years ago. A mother was allowed not to circumcise her son if his older brother had bled badly at the operation and, more remarkably, if her sister's sons had the same problem.

As well as its obvious effects after a cut, haemophilia does more subtle damage. Affected children often have many bruises and may suffer from internal bleeding which can damage joints and may be fatal. Once, more than half the affected boys died before the age of five. Injection of the clotting factor restores a more or less normal life.

Several of Victoria's grandsons were haemophiliacs, as was one of her sons, Leopold. Two of her daughters — Beatrice and Alice — must have been carriers. The Queen herself said that 'our poor family seems persecuted by this disease, the worst I know'. The most famous suflerer was Alexis, the son of Tsar Nicholas of Russia and Queen Alexandra, Victoria's granddaughter. One reason for Rasputin's malign influence on the Russian court was his ability to calm the unfortunate Alexis. The gene has disappeared from the British royal line, and no haemophiliacs are known among the three hundred descendants of Queen Victoria aiive today. In Britain, about one male in five thousand is affected.

Somewhat incidentally, another monarch, George III, may have carried a different mutation. The gene responsible for porphyria can lead to mental illness and might have been responsible for his well-known madness. The retrospective diagnosis was made from the notes of the King's physician, who noticed that the royal urine had the purple ^lport-wine' colour characteristic of the disease. A distant descendant also showed signs of the illness. One of the King's less successful appointments was that of his Prime Minister, Lord North, who was largely responsible for the loss of the American Colonies. It is odd to reflect that both the Russian and the American Revolutions may in part have resulted from accidents to royal DNA.

Research on human mutation once involved frustration ameliorated by anecdotes like these. It has been turned on its head by the advance of molecular biology. In the old days, the 1980s, the only way to study it was to find a

patient with an inherited disease and to try to work out what had gone wrong in the protein. The change in the DNA was quite unknown. This was as true for haemophilia as for any other gene. In fact, haemophilia seemed a rather simple error. Different patients showed rather different symptoms, but the mode of inheritance was simple and all seemed to share the same disease.

Now whole sections of DNA from normal and haemophiliac families can be compared to show what has happened and, like the genetic map itself, things have got more complicated. Molecular biology has made geneticists' lives much less straightforward. First, uncontrollable bleeding is not one disease, but several. To make a clot is a complicated business that involves several steps. Proteins are arranged in a cascade which responds to the damage, produces and then mobilises the material needed and assembles it into a barrier. A dozen or more different genes scattered all over the DNA take part in the production line.

Two are particularly likely to go wrong. One makes factor VIII in the clotting cascade. Errors in that gene lead to haemophilia A, which accounts for nine tenths of all cases of the disease. The other common type — haemophilia B — involves factor IX. In a rare form of the illness factor VII is at fault.

Factor VIII is a protein of two thousand two hundred and thirty-two amino acids, with a gene larger than most — about 186,000 DNA bases long, which, on the scale from Land's End to John o'Groat's, makes it about a hundred yards long. Just a twentieth of its DNA codes for protein. The gene is divided into dozens of different functional sections separated by segments of uninformative sequence. Much of this extraneous material consists of multiple copies of the same two-letter message, a 'CA repeat'. There is even a ^lgene-within-a-gene' (which produces something quite different) in the factor VIII machinery.

The haemophilia A mutation, which once appeared to be a simple change, is in fact complicated. All kinds of mistakes can happen. Nearly a thousand different errors have been found. Their virulence depends on what has gone wrong. Sometimes, just one important letter in the functional part of the structure has changed; usually a different letter in different haemophiliacs. The hits of the machinery which join the working pieces ot the product together are very susceptible to accidents of this kind. In more than a third of all patients part, or even the whole, of the factor VIII region has disappeared. A few haemophiliacs have suffered from the insertion of an extra length of DNA into the machinery which has hopped in from elsewhere.