Steve Jones - The Language of the Genes

All this hints that mutation is an active process, with plenty of churning round within the DNA. This new fluidity once alarmed geneticists as it violates the idea of gene as particle (admittedly a particle which sometimes makes mistakes) which used to be central to their lives. So powerful is the legacy of Mendel that his followers have sometimes been reluctant to accept results which do not fit. This is very true of some of the new and bizarre aspects of mutation.

Scientists, in general, despise doctors, loi in.my years, physicians reported a strange genetical effect called 'anticipation*. The malign effects of some inherited disi-.isi's seemed to show themselves at a younger age with mcli generation that passed. The effect was named eighty years ago by an enthusiastic eugenical doctor called Mott. He thought that it presaged the inevitable degeneration of society: 'The law of anticipation of the insane represents… rotten twigs continually dropping off the tree of life.' Later geneticists were resistant to the idea and it disappeared from view. In fact it represents a new kind of mutation, an inherited error which gets worse as the generations succeed and which is now known to be common.

The process is seen in a disease called the fragile X syndrome, the most important single cause of inborn mental impairment, with symptoms that range from mild to crippling. Many children diagnosed as autistic have in fact a minor form of this illness. At first sight its inheritance is odd, as in some families it is found in just one person, whereas others have dozens of affected members. Boys tend to suffer more damage than do girls, with mental retardation and, sometimes, a characteristic face with large ears, and heart problems.

Although both males and females are affected, the gene is sex-linked. Males never pass it on to their sons, but girls whose mothers have it are carriers, and some may be affected. Fragile-X is one of the few genetic diseases in which the damage can be seen down the microscope, for near the end of every affected X chromosome is a small constriction which looks as if it might be about to break. About one woman in two hundred and fifty has one or other X chromosome damaged in this way. Many show no symptoms at all and neither do their children. Others have signs of the disease, as do their offspring, while a fraction albeit themselves normal may have children with the illness.

The mutation is a multiplication of a three-letter DNA repeat — C, G and G — within a gene. Its protein helps form the connections made as the young brain begins to respond to experiences from the outside world. The damage is not in the coding section of the gene, but in its on-off switch. The mutation is flexible. Most people have thirty or fewer repeats, and some have as few as half a dozen. When the number creeps above fifty or so, children are in danger and may find it hard to speak or to read and as it rises over two hundred (and severely affected individuals have more than a thousand repeats) the full symptoms set in.

The strangest aspect of fragile X — and, we now know, of many other mutations — is that the number of repeats (and the amount of damage) changes from generation to generation. The daughter of a mother who has fragile X is more likely to have an affected child than was her own parent although (or so it seems) she has passed on exactly the same gene. Each generation, the number of copies changes, going up when it is transmitted through a female, but staying the same or decreasing when a man passes on the damaged chromosome.

One form of muscular dystrophy also shows more virulent effects as the generations succeed. Again, a repeated sequence is involved. The pedigrees of one group of the children with the disease shows that all shared an ancestor who b'ved in the seventeenth century. He was healthy; as were, for two hundred years, his descendants; but suddenly some, distant relatives though they now are, began to suffer from dystrophy. More copies of a DNA repeat within the crucial gene had been made each generation. Once a critical number was reached the symptoms appear. Each generation, more and more appear, and the effects of the damaged gene become more severe as it passes down the lineage. Huntington's Disease, too, is duo to a repeal of the three DNA letters CACi. Each triplet codes Inr.1 single amino acid, which shoulders itself into tin* inuklle ul tin 1hunt-ingtin molecule. Some people liavi- li-wcr than uti copies, some more than a hundred. Once more tluui.ihoui thirty-five copies are made, the symptoms of the disease emerge, and the more repeats, the earlier they do so. Those with fifty are in danger of illness while still in their twenties. Half a dozen other diseases of the nervous and muscular system are due to such three-letter intruders. Why nerves should be so prone to them is not certain, although the tendency of such augmented proteins to form great clumps in the cell may have something to do with it.

If the rate of mutation to haemophilia is taken as the norm, there must be about one new DNA change in a functional gene per five generations. This means ten million changes in functional genes per generation in Britain. The actual incidence may be even higher. Hormonal changes in women who are attempting to become pregnant show that eight out of ten fertilised eggs are lost. Many may carry new lethal mutations. Often, they involve the loss of all or part of a chromosome, and the incidence of such errors in still-born children is ten times that among those born alive.

Each gene has its own mutation rate. The frequency varies more than a thousand times from gene to gene. Larger genes with more interspersed pieces of DNA go wrong more often than smaller ones, and certain combinations of bases change more readily than others. The short segments of repeated DNA outside the functional genes (such as those involved in the 'genetic fingerprint') have a high rate of error. As many as one person in ten may pass on a change. The rate of mutation itself has evolved, too, and is controlled by enzymes which can repair injured DNA. When these are themselves damaged it shoots up.

Many things increase the mutation rate. Radiation, for example, can have a powerful effect. Plenty of mutations do not arise from the natural instability of the genes, but from damage inflicted from outside (as many of the early workers on radium, many of whom died of cancer, soon found out). Up to two thirds of the sperm cells of cancer patients who have been given large X-ray doses carry chromosomal changes. Evidence from other animals makes lower doses of radiation a real cause for concern, given the link between agents that cause mutations in sperm and egg and those that cause cancer. The acceptable dose for humans is set in part by research on mice (which seem to be more susceptible than we ourselves are) and there have been calls to have the limits increased; but nobody denies that radiation damages our genes. Sunlight, too, is harmful to cells and even an increase in temperature can increase the rate of error.

The biggest avoidable source of radiation in Britain is radon gas, which leaks from granite. People who live in granite houses in Cornwall may be exposed to more excess radiation than are those who work in nuclear power stations (although their equivalents in the granite city of Aberdeen may in part reverse the effect as they wear the kilt, with its cooling influence). In the United States, houses built with radioactive sands in their foundations have been demolished as their occupants faced twenty times the average dose. In the UK, those at risk are advised to install fans to stop the build-up of gas. Other sources of radiation include the cosmic rays experienced during air travel and medical X-rays, but for most people these involve very small doses.

Chemicals are much more important agents of genetic damage. The number of chromosome errors in nuclear power-station workers is ************ that of the general public, but the number in those employed in coal-fired stations is even higher because ****** noxious byproducts of burning coal. Bacteria are used to test a huge number of likely, and some unlikely, substances. Some, such as those once used in hair dyes, had a powerful effect and have been banned. Others, those in black pepper, in Earl Grey tea and in some pesticides, also cause mutations. Some of the most potent are quite natural. Plants produce many toxic chemicals for defence against insects and even lettuce, the epitome of a healthy diet, contains substances that cause mutations in mice. Almost half of all cancers may be influenced by the food we eat; and the vast majority of the pesticides — perhaps more than 99.9 % — in the Western diet are perfectly natural. Cynics argue that organic foods are more dangerous than food which has been sprayed because of the noxious chemicals found in the moulds which grow on them. Fresh fruits and vegetables reduce the rate, and some plants, such as broccoli and tomatoes, are filled with anti-mutagens that may help protect those who eat them.