Steve Jones - The Language of the Genes

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.

Once, the only way to measure the rate of new mutations to haemophilia (or any other inherited illness) was to count the sufferers, estimate the damage done to their chances of passing on the error and work out from this how often it must happen. Technology has changed everything. Now it is possible to compare the genes of haemophiliac boys with those of parents and grandparents to see when the mutation took place.

If the mother of such a boy already has the haemophilia mutation on one of her two X chromosomes, then she must herself have inherited it and the damage must have occurred at some time in the past. If she has not, then her son's new genetic accident happened when the egg from which he developed was formed within her own body. In a survey of a British families with sons with haemophilia B (whose gene, that for Factor IX, is 33,000 bases long) many different mutations were found, most unique to one family. Eighty per cent of the mothers of affected boys had themselves inherited a mutation. However, in most cases the damaged gene was not present in their own father (the grandfather of the patient). In other words, the error in the DNA must have taken place when his grandparental sperm was being formed.

A quick calculation of the number of new mutations against the size of the British population gives a rare for the haemophilia B gene of about eight in a million. The difference in the incidence of changes between grandfathers and their daughters suggest that the rate is nine rimes higher in males than in females. The sex difference is easy to explain. There are many more chances for things to go wrong in men (who — unlike women — produce their sex cells throughout life, rather than making a store of them early on, and hence have many more DNA replications in the germ line than do females). For some genes the rate of mutation among males is fifty times higher than in the opposite sex. Men, it seems, are the source of most of evolution's raw material.

Most people with severe forms of haemophilia have each suffered a different genetic error. Such mistakes happen in a parent's sex cells and disappear at once because the child dies young. Those with milder disease often share the same change in their DNA; an error that took place long ago and has spread to many people. The shared mutation is a clue that these individuals descend from a common ancestor. The non-functional DNA in and around the haemophilia gene is full of changes which appear to have no effect at all and have passed down through hundreds of generations. Near the gene itself is a region with many repeats of the same message. The number of copies often goes up and down, but its high error rate seems to do no damage.