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

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СКАЧАТЬ death from the disease, his widow started the Committee to Combat Huntington’s Chorea; she was joined by a doctor named Milton Wexler whose wife and three brothers-in-law were suffering from the disease. Wexler’s daughter, Nancy, knew she stood a fifty per cent chance of having the mutation herself and she became obsessed with finding the gene. She was told not to bother. The gene would prove impossible to find. It would be like looking for a needle in a haystack the size of America. She should wait a few years until the techniques were better and there was a realistic chance. ‘But’, she wrote, ‘if you have Huntington’s disease, you do not have time to wait.’ Acting on the report of a Venezuelan doctor, Americo Negrette, in 1979 she flew to Venezuela to visit three rural villages called San Luis, Barranquitas and Laguneta on the shores of Lake Maracaibo. Actually a huge, almost landlocked gulf of the sea, Lake Maracaibo lies in the far west of Venezuela, beyond the Cordillera de Merida.

      The area contained a vast, extended family with a high incidence of Huntington’s disease. The story they told each other was that the affliction came from an eighteenth-century sailor, and Wexler was able to trace the family tree of the disease back to the early nineteenth century and a woman called, appropriately, Maria Concepcion. She lived in the Pueblos de Agua, villages of houses built on stilts over the water. A fecund ancestor, she had 11,000 descendants in eight generations, 9,000 of whom were still alive in 1981. No less than 371 of them had Huntington’s disease when Wexler first visited and 3,600 carried a risk of at least a quarter that they would develop the disease, because at least one grandparent had the symptoms.

      Wexler’s courage was extraordinary, given that she too might have the mutation. ‘It is crushing to look at these exuberant children’, she wrote,⁴ ‘full of hope and expectation, despite poverty, despite illiteracy, despite dangerous and exhausting work for the boys fishing in small boats in the turbulent lake, or for even the tiny girls tending house and caring for ill parents, despite a brutalising disease robbing them of parents, grandparents, aunts, uncles, and cousins – they are joyous and wild with life, until the disease attacks.’

      Wexler started searching the haystack. First she collected blood from over 500 people: ‘hot, noisy days of drawing blood’. Then she sent it to Jim Gusella’s laboratory in Boston. He began to test genetic markers in search of the gene: randomly chosen chunks of DNA, that might or might not turn out to be reliably different in the affected and unaffected people. Fortune smiled on him and by mid-1983 he had not only isolated a marker close to the gene affected, but pinned it down to the tip of the short arm of chromosome 4. He knew which three-millionth of the genome it was in. Home and dry? Not so fast. The gene lay in a region of the text one million ‘letters’ long. The haystack was smaller, but still vast. Eight years later the gene was still mysterious: ‘The task has been arduous in the extreme’, wrote Wexler,⁴ sounding like a Victorian explorer, ‘in this inhospitable terrain at the top of chromosome 4. It has been like crawling up Everest over the past eight years.’

      The persistence paid off. In 1993, the gene was found at last, its text was read and the mutation that led to the disease identified. The gene is the recipe for a protein called huntingtin: the protein was discovered after the gene – hence its name. The repetition of the ‘word’ CAG in the middle of the gene results in a long stretch of glutamines in the middle of the protein (CAG means glutamine in ‘genetish’). And, in the case of Huntington’s disease, the more glutamines there are at this point, the earlier in life the disease begins.⁵

      It seems a desperately inadequate explanation of the disease. If the huntingtin gene is damaged, then why does it work all right for the first thirty years of life? Apparently, the mutant form of huntingtin very gradually accumulates in aggregate chunks. Like Alzheimer’s disease and BSE, it is this accumulation of a sticky lump of protein within the cell that causes the death of the cell, perhaps because it induces the cell to commit suicide. In Huntington’s disease this happens mostly within the brain’s dedicated movement-control room, with the result that movement becomes progressively less easy or controlled.⁶

      The most unexpected feature of the stuttering repetition of the word CAG is that it is not confined to Huntington’s disease. There are five other neurological diseases caused by so-called ‘unstable CAG repeats’ in entirely different genes. Cerebellar ataxia is one. There is even a bizarre report that a long CAG repeat deliberately inserted into a random gene in a mouse caused a late-onset, neurological disease rather like Huntington’s disease. CAG repeats may therefore cause neurological disease whatever the gene in which they appear. Moreover, there are other diseases of nerve degeneration caused by other stuttering repeats of ‘words’ and in every case the repeated ‘word’ begins with C and ends in G. Six different CAG diseases are known. CCG or CGG repeated more than 200 times near the beginning of a gene on the X chromosome causes ‘fragile X’, a variable but unusually common form of mental retardation (fewer than sixty repeats is normal; up to a thousand is possible). CTG repeated from fifty to one thousand times in a gene on chromosome 19 causes myotonic dystrophy. More than a dozen human diseases are caused by expanded three-letter word repeats – the so-called polyglutamine diseases. In all cases the elongated protein has a tendency to accumulate in indigestible lumps that cause their cells to die. The different symptoms are caused by the fact that different genes are switched on in different parts of the body.⁷

      What is so special about the ‘word’ C*G, apart from the fact that it means glutamine? A clue comes from a phenomenon known as anticipation. It has been known for some time that those with a severe form of Huntington’s disease or fragile X are likely to have children in whom the disease is worse or begins earlier than it did in themselves. Anticipation means that the longer the repetition, the longer it is likely to grow when copied for the next generation. We know that these repeats form little loopings of DNA called hairpins. The DNA likes to stick to itself, forming a structure like a hairpin, with the Cs and Gs of the C*G ‘words’ sticking together across the pin. When the hairpins unfold, the copying mechanism can slip and more copies of the word insert themselves.⁸

      A simple analogy might be helpful. If I repeat a word six times in this sentence – cag, cag, cag, cag, cag, cag – you will count it fairly easily. But if I repeat it thirty-six times – cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag, cag – I am willing to bet you lose count. So it is with the DNA. The more repeats there are, the more likely the copying mechanism is to insert an extra one. Its finger slips and loses its place in the text. An alternative (or possibly additional) explanation is that the checking system, called mismatch repair, is good at catching small changes, but not big ones in C*G repeats.⁹

      This may explain why the disease develops late in life. Laura Mangiarini at Guy’s Hospital in London created transgenic mice, equipped with copies of part of the Huntington’s gene that contained more than one hundred repeats. As the mice grew older, so the length of the gene increased in all their tissues save one. Up to ten extra CAG ‘words’ were added to it. The one exception was the cerebellum, the hindbrain responsible for controlling movement. The cells of the cerebellum do not need to change during life once the mice have learnt to walk, so they never divide. It is when cells and genes divide that copying mistakes are made. In human beings, the number of repeats in the cerebellum falls during life, though it increases in other tissues. In the cells from which sperm are made, the CAG repeats grow, which explains why there is a relationship between the onset of Huntington’s disease and the age of the father: older fathers have sons who get the disease more severely and at a younger age. (Incidentally, it is now known that the mutation rate, throughout the genome, is about five times as high in men as it is in women, because of the repeated replication needed to supply fresh sperm cells throughout life.)СКАЧАТЬ