Steve Jones - The Language of the Genes

All this means that to establish whether someone is a carrier of a simple error, without prior knowledge of the mutation involved, may not be easy. Ironically enough, in alkaptonuria — the first inborn error to be discovered, with its simple pattern of inheritance — almost everyone who bears this rare condition has the same unique mutation. For the more frequent illness cystic fibrosis, however, well over a thousand different mutations are known. Some are quite common. One among them is responsible for seventy per cent of cases in Western Europe. Two thousand miles to the East, that change is found in just a small proportion of patients. Even in Jewish populations in the United States it is involved in only a third oi the damage and in some populations (such of those of North Africa) quite a different mistake causes the majority of harm. One illness, an alteration in a single gene, has, it transpires, a multiplicity of causes.

Life is even harder for the many conditions that do not follow Mendelian rules. A few are affected by genes of moderate effect. One form of heart disease is much influenced by variation in a gene involved in the transmission of messages from nerves to muscles, although several other segments of DNA with a weak effect are also involved. Thousands of women die of breast cancer, and for a few, one of two genes known to predispose to the disease are responsible. These are carried by one in eight hundred or so women and represent hundreds of different DNA changes. Removal of the breasts is of some help to those who carry the gene, but this is a drastic move that is not acceptable to many (although small doses of anti-cancer drugs may also help). All this, combined with the rarity of the gene, the fact that nineteen out of every twenty breast-cancer patients do not carry a mutated version but develop the disease for unknown reasons, and the lack of any general test, means that a population screen would not be worthwhile.

In Ashkenaze Jews some damaged versions of this gene are more common because, by chance, most ot tin* population descend from a rather small group of founders. One in fifty or so Ashkenazim carry one of three Jisiinct mutations that predispose to breast cancer. A screen ot the whole population might, it seems, pay off, but even here reality is complicated. Because many women with the disease get it for reasons unconnected with these two genes, and because the disease often does not show itself until middle age, the extra burden of risk faced by bearers of the gene is only about one in twenty. All this means that many geneticists feel that screening for an inherited predisposition to breast cancer is nor useful even here.

To make life even more difficult for the hapless screener, what seems to be the same disease may arise from errors in quite different genes and, quite often, a condition that has a simple genetic cause in some patients may have almost no inherited component in others. Many illnesses that once appeared to be one have been subdivided. 'Fever' was seen as a unitary disorder with a single treatment and 'cancer' was much the same. That simplistic view changed long before genetics; but genes have speeded up the process.

In spite of the complexity of mutation, nobody doubts that — say — cystic fibrosis is one disease. However, most inherited diseases are not due to simple errors in one or even a few genes: instead, they are (like fever itself) symptoms of a great constellation of failures in the body's machinery. A single gene may be involved in certain cases but not others, or genes of small effect may band together in unpredictable ways. The DNA at fault may differ from population to population, or from family to family; and an inborn problem may not show itself until it is exposed to a particular challenge. As a result, some conditions appear to have an environmental cause in some patients, and a genetic one in others. Such complexity means that to unravel the big killers like heart disease or obesity will not be easy. Even when the job is done, it is not clear how the information will be of much help in screening.

Take, for example, diabetes. Diabetes mellitus affects one in ten people. The cause, a loss of control of blood sugar, seems simple. The illness causes kidney damage, blindness, heart disease, nerve destruction and death and, in the USA, costs $100 billion a year to treat.

It comes in two flavours. One results from a failure of the pancreas, the gland that makes insulin. That problem is quite rare (affecting about one child in a thousand), starts young and can be treated with the missing hormone. The other, non-insulin-dependent diabetes mellitus, is commoner, appears later, and is resistant to insulin treatment. Six million Americans have this illness without knowing it and it is becoming more common. The two forms, similar as they seem, involve separate sets of genes and present medicine with quite different problems. What is more, each condition itself conceals several ailments, some influenced by inheritance, some not.

The insulin-dependent form was once thought to be caused by viruses, by diet, or even by urban living. None of the ideas was sustained. In fact, genes are involved, with the risk to brothers or sisters of patients twenty times higher than that to the general population. Early-onset diabetes is associated with the systems of recognition on the surface of cells. Those with certain combinations of cell-surface cues face a tenfold increase in risk. The illness, it seems, results from an attack by the immune system on its own body.

A single gene explains a third of the variation in the chance of getting the disease. At least twenty others may predispose to it, some involved in the insulin machinery and others at work in unrelated pans <>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.