by Steve Jones
After many miles of dull and repetitive DNA terrain, we begin to see places where some product is made. These are the functional genes. They, too, have some surprises in their structure. Each can be recognised by the order of the letters in the DNA alphabet, which start to read in words of three letters written in the genetic code, as a hint that it could produce a protein. In most cases there are few clues about what its product does, although its structure can be deduced (and its shape inferred) from the order of its DNA letters.
Most genes are arranged in groups that make related products, with about a thousand of these 'gene families' altogether. One is involved in the manufacture of the red pigment of the blood. Most of the DNA in the bone-marrow cells which produce the red cells of the blood is switched off. One small group of genes is hard at work. As a result they are better known than any other. Much of human molecular biology grew from research on thisparticular genetic industrial centre, the giobin genes.
They have two factories. One is halfway along the genetic road to John o'Groat's — in Leeds. It makes one part of the protein involved in carrying oxygen. The beta-globin industrial estate contains about half a dozen sections of DNA that code for related things. That responsible for part of adult haemoglobin (and involved, when it goes wrong, in sickle-cell disease) is quite small: about three feet long on this map's scale. A few feet away is another one which makes a giobin found in the embryo. Close to that is the decayed hulk ot some equipment which stopped working years ago. The beta-globin factory covers about a hundred feet altogether, most of which seems to he unused space between functional genes. It co-operates with a sister estate, the alpha-globin unit, a long way away, (near London, on this mythical map) which produces a related protein. When joined together, the two products make the red blood pigment itself. Most genes are arranged in families, either close together or scattered all over the genome.
The map of ourselves shows that genes are of very different size, from about five hundred letters long to more than two million. One makes the largest known protein, titin, a molecular shock-absorber; a long, pleated structure found in muscles, in blood cells and in chromosomes. Whatever the size of its product, titin is by no means the largest gene. Most human genes have their functional segments interrupted by lengths of non-coding DNA — in Huntington's disease, for example, by nearly seventy In many genes (such as the one which goes wrong in muscular dystrophy) the great majority of the DNA codes for nothing. The non-coding material, whose importance varies greatly from gene to gene, participates in the first part of the production process, but this segment of the genetic alphabet is snipped out of the message before the protein is assembled. This seems an odd way to go about things, but it is the one which evolution has come up with.
The general picture began to emerge as soon as the mappers began work. In the year 2000 — almost exactly a century after the rediscovery of Mendel's rules — their labours were, in effect, complete and the whole human gene sequence was laid our in all its tedium before a less than startled world. Three thousand million letters (or, as now it appears, slightly more) is a lot. For accuracy, each section had to be sequenced ten times or more and even at a thousand DNA bases a second (which is what the machinery pumps out) that was not easy. Sixteen centres, in France, Japan, Germany, China, Britain and the United States combined to do the job. Most were funded by governments or charities, with the notorious exception of the Celera Genomics company (their motto: 'Discovery Can't Wait!1), whose head defected from a government programme. Advances in technology reduced the original estimate of three billion dollars by ten times which, for a project — described by President Clinton as the most wondrous map ever produced — with far more scientific weight than the Moon landings, was a remarkable bargain. For much of the time, the private and public sectors were at daggers drawn (vividly illustrated by Celera's description of the director of one public laboratory behaving as if he had been bitten by a rabid dog).
Because (as so often in science) much of the effort lies not in obtaining information, but in making sense of it, a shotgun marriage between the rivals was, at the last moment, arranged. To 'annotate' the genome — to work out just what the newly-sequenced genes do — was a task so formidable that it demanded the use of one of the world's most powerful supercomputers.
From the mass of data, the small segments that code for proteins and the even smaller sections that act as the on-off switches for the working genes, are picked out (which is where the computing power comes in). Fortunately, many human genes look rather like those in fruit flies, yeast and nematode worms (all of which have been sequenced) and a massive comparison of each length of human DNA with those in other creatures points at common segments that must, presumably, represent working genes. However, some useless sections disguise themselves as valuable by chance and some pieces have been defined as working genes — again, perhaps wrongly — only by a slight shift in the ratio of particular pairs of bases. As a result, and even with the complete DNA sequence, the precise number of genes needed to make;i human being remains, and will remain, uncertain (although most of the researchers guess at a figure of fifty thousand or so).
Even when the functional segments are found, the task of understanding what they do has only just begun. The complete sequence, hailed by Presidents (and Prime Ministers) though it might be, is little more than an arbitrary step on the road to understanding.
Even so, the genome has revealed if not its secrets, at least its structure; and that is remarkable enough. Take, as an instance, chromosome 22; as the smallest of the twenty-three pairs, the Rutland of the genome, and, in the last weeks of the twentieth century, the first to have its entire sequence established. It was mapped with an error rate of fewer than one in fifty thousand bases and just a few short gaps. Apart from its small size {at thirty-three and a half million bases it represents a hundredth of the whole sequence) it is an unremarkable chromosome, quite representative of its larger cousins (the biggest of which, chromosome i, is eight times longer).
Before the global map, a few scattered genes had been Tracked to chromosome 2.2.. They included genes for, among others, a rare disease that causes heart problems and facial distortion, a birth defect called 'cat's eye syndrome' and genes involved in a severe disease of nerve degeneration.
The clone by clone approach — tearing out pages of the map, sequencing each one and ordering them by looking at the overlaps — revealed about a thousand segments of DNA that looked us if they might code tor a protein. Seven hundred or so are identical to genes already found within ourselves or elsewhere and m;iy represent iiselul bits of DNA. Many, no doubt, cause diseases when (hey go wrong. Some may be impostors; segments that make nothing but have, by chance, an identity that resembles that of a productive section of the genome. Even this, the smallest chromosome, has no shortage of genes. The smallest is a mere thousand bases long, its largest more than five hundred times bigger. Some are uninterrupted, but most are fractured by many inserted sequences of non-coding DNA. To make matters even more complicated, two genes appear within the structure of others. They are genes within genes; read (like a Hebrew sentence in an English book) not from left to right but from right to left.
Most of the remainder of the chromosome is a story of waste and decay. It hides within itself eight or so lengthy duplications, in which whole segments of the instructions are, for some reason, doubled up. The wrecks of genes are everywhere, and about a fifth of the sequences that might once have made something are present only as pseudogenes. Most of the actual workers are — just like the producers of the red blood pigment — members of gene families; and most of those families are filled with genetic black sheep, pseudogenes, who rest on their laurels while their kin go about their business. Some of its genes are responsible for proteins associated with the immune system. They work together as a family of dozens of productive members, but are accompanied by twice as many decayed relatives with a home nearby.
Thirty or so disorders — from cance
rs to errors in foetal development to a tendency towards schizophrenia — have now been uncovered on this short chromosome: a small part of the thousands that inflict the human race, but a hint of the huge numbers of ways that DN A can go wrong. Most of the proteins mapped to chromosome 22 have no known function. What some do can be guessed at by comparing them with others from elsewhere in the human genome, or from the rest ol life, but the majority are anonymous factories, hard at work but with, as yet, no hint about what they made.
Other chromosomes have the same general nature as does the smallest, although each has its quirks. The next in line, chromosome 21, has a personality of its own. Already famous as the sources of the commonest human inborn abnormality, Down's syndrome (present in about one in seven hundred live births) and as the site of one of the genes predisposing to Alzheimer's disease, this structure has some thirty-three million base pairs — about one per cent of the total. One end is stuffed with copies of the same sequence, multiplied again and again; but the other has the machinery. Not, however, very much; for chromosome 21, although about the same size as number 2.2, has only half its number of genes.
Its two hundred and twenty-five working segments (nine-tenths of which were new to science) seem a modest endowment. Perhaps its depauperised state explains why chromosome 21 is the only chromosome (apart from the sex chromosomes) which the body can tolerate in extra copy. Children with Down's syndrome suffer from fifty or more distinct problems, ranging from heart disease and a tendency to leukemia to difficulties in breathing. One severe problem is their premature ageing and memory loss. That symptom resembles those of Alzheimer's disease — and one of the genes responsible for the early-onset form of that illness is found in chromosome 2.1. Perhaps some of the chromosome's other genes will turn out to be associated with other ailments common to Down's children.
Its other genes include those reponsible for two forms of inborn deafness and for amyotrophic lateral sclerosis: a condition known in the United States as Lou Gehrig's Disease after the New York Yankee shiver who died of the illness, but in Britain indissoluhly linked 10 ilu- ^reat physicist Stephen Hawking. Those with the condition suffer from a loss of nerve cells in the brain *** spinal cord and, as a result, slowly lose all power of movement. The problem lies with an enzyme whose job is to clean up wastes inside the cell: when it fails, the nerves are slowly poisoned.
Chromosome 2.1 may look like a run-down industrial estate with few of its windows lit up; but at the other extreme of economic activity, chromosome 6 is full of active genes. It is in the forefront of the body's genetic defences. One section has long been known to be responsible for much of the body's immune defences. The crucial segment is only about a tenth the size of chromosome 2.1, but contains well over a hundred genes (as well as a respectable number of relics that have given up the functional ghost). Many share a certain identity and have arisen by duplication from ancient ancestral genes. Much of their job involves binding to the proteins of an invader and passing on information as to its identity to the white blood cells that then swing into attack. Others code for statements of individual entity on the cell surface.
Because so many genes are involved, there is plenty of opportunity for reshuffling. Combined with a high rate of mutation at many of the individual sequences, this generates a mass of diversity from person to person and from place to place, as a reminder that to sequence a human genome is only a step in the much larger task of looking for differences among individuals. As some of the genes on chromosome six come in as many as two hundred forms the task will be a lengthy one; but it will be worthwhile because, for reasons unknown, some members of the defence force have the habit of turning on the body itself to give a range of auto-immune diseases such as rheumatoid arthritis, the skin disease psoriasis, and some forms of diabetes.
Whatever the details of its individual chromosomes, the picture to emerge from the completed human genome project is one of size, and ol complexity. Like the New World that stretched be!ore the first explorers, the genome is, above all, big; and like all large objects has a gravitational attraction for metaphors. Printed out, the information gathered by the Human Genome Project will fill two hundred telephone books or, in a single line, stretch the length of the Mississippi; a secretary would take twenty years to type (and a cantor fifty to sing) the whole thing, and so, symbolically, on.
Through all the symbolism and hyperbole is emerging an uneasy feeling that all this has been a race only to the starting line of understanding our genes and not to the winning post. The journal Nature reported the analysis of one of the very simplest viral genomes in the 1970s under the headline 'Sequencing is Not Enough'. That message emerges with renewed strength from the human genome project.
Even so, its completion is a milestone in the history of genetics. To look at an ancient chart — even one as faulty as that of Herodotus — is to realise that maps contain within themselves a great deal about the lives of those who drew them. They show the size and position of cities, the paths of migration, and the record of peoples long gone. The chart of the genes is made; and now the real journey can begin.
Chapter Four. CHANGE OR DECAY
By the time you have finished this chapter you will be a different person. I do not mean by this thai your views about existence — or even about genes — will alter, ilili* >tit',h perhaps they may. What I have in mind is simpler. In ihe next half hour or so your genes, and your life, will he altered by mutation; by errors in your own genetic message. Mutation — change — happens all the time, within ourselves and over the generations. We are constantly corrupted by it; but biology provides an escape from the inevitability of genetic decline.
Evolution is no more than the perpetuation of error. It means that progress can emerge from decay. Mutation is at the heart of human experience, of old age and death but also of sex and of rebirth. All religions share the idea that humanity is a decayed remnant of what was once perfect and that it must be returned to a higher plane by salvation, by starting again from scratch. Mutation embodies what faith demands: each man's decline but mankind's redemption.
The first genes appeared some four thousand million years ago as short strings of molecules which could make rough copies of themselves. At a reckless guess, the original molecule in life's first course, the primeval soup, has passed through four thousand million ancestors before ending up in you or me (or in a chimp or a bacterium). Every one of the untold billions of genes that has existed since then emerged through the process of mutation. A short message has grown to an instruction manual of three thousand million letters. Everyone has a unique edition of the instruction book that differs in millions of ways from that of their fellows. All this comes from the accumulation of errors in an inherited message.
Like random changes to a watch some of these accidents are harmful. But most have no effect and a few may even be useful. Every inherited disease is due to mutation. Now that medicine has, in the western world at least, almost conquered infection, mutation has become more important. About one child in forty horn in Britain has an inborn error of some kind and about a third of all hospital admissions of young children involve a genetic disease. Some damage descends from changes which happened long ago while others are mistakes in the sperm or egg of the parents themselves. Everyone carries single copies of damaged genes which, if two copies were present, would kill. As a result, everyone has at least one mutated skeleton in their genetical cupboard.
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 fem
ale 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.