Genome: The Autobiography of a Species in 23 Chapters. Matt Ridley

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       CHROMOSOME 4 Fate

      Sir, what ye’re telling us is nothing but scientific Calvinism.

       Anonymous Scottish soldier to William Bateson after a popular lecture ¹

      Open any catalogue of the human genome and you will be confronted not with a list of human potentialities, but a list of diseases, mostly ones named after pairs of obscure central-European doctors. This gene causes Niemann–Pick disease; that one causes Wolf–Hirschhorn syndrome. The impression given is that genes are there to cause diseases. ‘New gene for mental illness’, announces a website on genes that reports the latest news from the front, ‘The gene for early-onset dystonia. Gene for kidney cancer isolated. Autism linked to serotonin transporter gene. A new Alzheimer’s gene. The genetics of obsessive behaviour.’

      Yet to define genes by the diseases they cause is about as absurd as defining organs of the body by the diseases they get: livers are there to cause cirrhosis, hearts to cause heart attacks and brains to cause strokes. It is a measure, not of our knowledge but of our ignorance that this is the way the genome catalogues read. It is literally true that the only thing we know about some genes is that their malfunction causes a particular disease. This is a pitifully small thing to know about a gene, and a terribly misleading one. It leads to the dangerous shorthand that runs as follows: ‘X has got the Wolf–Hirschhorn gene.’ Wrong. We all have the Wolf–Hirschhorn gene, except, ironically, people who have Wolf–Hirschhorn syndrome. Their sickness is caused by the fact that the gene is missing altogether. In the rest of us, the gene is a positive, not a negative force. The sufferers have the mutation, not the gene.

      Wolf–Hirschhorn syndrome is so rare and so serious – its gene is so vital – that its victims die young. Yet the gene, which lies on chromosome 4, is actually the most famous of all the ‘disease’ genes because of a very different disease associated with it: Huntington’s chorea. A mutated version of the gene causes Huntington’s chorea; a complete lack of the gene causes Wolf–Hirschhorn syndrome. We know very little about what the gene is there to do in everyday life, but we now know in excruciating detail how and why and where it can go wrong and what the consequence for the body is. The gene contains a single ‘word’, repeated over and over again: CAG, CAG, CAG, CAG…The repetition continues sometimes just six times, sometimes thirty, sometimes more than a hundred times. Your destiny, your sanity and your life hang by the thread of this repetition. If the ‘word’ is repeated thirty-five times or fewer, you will be fine. Most of us have about ten to fifteen repeats. If the ‘word’ is repeated thirty-nine times or more, you will in mid-life slowly start to lose your balance, grow steadily more incapable of looking after yourself and die prematurely. The decline begins with a slight deterioration of the intellectual faculties, is followed by jerking limbs and descends into deep depression, occasional hallucination and delusions. There is no appeal: the disease is incurable. But it takes between fifteen and twenty-five horrifying years to run its course. There are few worse fates. Indeed, many of the early psychological symptoms of the disease are just as bad in those who live in an affected family but do not get the disease: the strain and stress of waiting for it to strike are devastating.

      The cause is in the genes and nowhere else. Either you have the Huntington’s mutation and will get the disease or not. This is determinism, predestination and fate on a scale of which Calvin never dreamed. It seems at first sight to be the ultimate proof that the genes are in charge and that there is nothing we can do about it. It does not matter if you smoke, or take vitamin pills, if you work out or become a couch potato. The age at which the madness will appear depends strictly and implacably on the number of repetitions of the ‘word’ CAG in one place in one gene. If you have thirty-nine, you have a ninety per cent probability of dementia by the age of seventy-five and will on average get the first symptoms at sixty-six; if forty, on average you will succumb at fifty-nine; if forty-one, at fifty-four; if forty-two, at thirty-seven; and so on until those who have fifty repetitions of the ‘word’ will lose their minds at roughly twenty-seven years of age. The scale is this: if your chromosomes were long enough to stretch around the equator, the difference between health and insanity would be less than one extra inch.²

      No horoscope matches this accuracy. No theory of human causality, Freudian, Marxist, Christian or animist, has ever been so precise. No prophet in the Old Testament, no entrail-gazing oracle in ancient Greece, no crystal-ball gipsy clairvoyant on the pier at Bognor Regis ever pretended to tell people exactly when their lives would fall apart, let alone got it right. We are dealing here with a prophecy of terrifying, cruel and inflexible truth. There are a billion three-letter ‘words’ in your genome. Yet the length of just this one little motif is all that stands between each of us and mental illness.

      Huntington’s disease, which became notorious when it killed the folk singer Woody Guthrie in 1967, was first diagnosed by a doctor, George Huntington, in 1872 on the eastern tip of Long Island. He noticed that it seemed to run in families. Later work revealed that the Long Island cases were part of a much larger family tree originating in New England. In twelve generations of this pedigree more than a thousand cases of the disease could be found. All were descended from two brothers who emigrated from Suffolk in 1630. Several of their descendants were burnt as witches in Salem in 1693, possibly because of the alarming nature of the disease. But because the mutation only makes itself manifest in middle age, when people have already had children, there is little selective pressure on it to die out naturally. Indeed, in several studies, those with the mutations appear to breed more prolifically than their unaffected siblings.³

      Huntington’s was the first completely dominant human genetic disease to come to light. That means it is not like alkaptonuria in which you must have two copies of the mutant gene, one from each parent, to suffer the symptoms. Just one copy of the mutation will do. The disease seems to be worse if inherited from the father and the mutation tends to grow more severe, by the lengthening of the repeat, in the children of progressively older fathers.

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