Читать книгу The Language of the Genes - Steve Jones, Steve Jones - Страница 8

It is always painful to watch an unfamiliar game and to try to work out what is going on. Although I lived in the United States for several years, and although the sport is now shown on British television, I have almost no idea how American football works. There is a clear general desire to score, but how play stops and starts and why the spectators cheer at odd moments remains a closed book. A deep lack of interest in ball games helps in my case, but cricket is equally dull to sporting enthusiasts from other countries. They just do not understand the rules.

The rules of the game known as sexual reproduction are not obvious from its results. As a consequence, how inheritance works was a closed book until quite recently. Part of the problem is that the way sex works is so different from how it seems that it ought to. It seems obvious that a character acquired by a parent must be passed on to the next generation. After all, blacksmiths’ children tend to be muscular and those of criminals less than honest. In the Bible, Jacob, when allowed to choose striped kids from Laban’s herd of goats, put striped sticks near the parents as they mated in the hope of increasing the number available. Later, pregnant women looked on pictures of saints and avoided people with deformities. It took a series of painful trials in which generations of mice were deprived of their tails to show that acquired characters were not in fact inherited. Of course, Jews had been doing the same experiment for thousands of years.

Another potent myth about inheritance is that the characters of a mother and a father pass to their blood, which is mixed in their offspring. Children are, as a result, a blend of the attributes of their parents. This idea – a sort of genetics of the average – copes quite well with traits such as height or weight but fails to explain why a child may look like a distant relative rather than its father or mother. The idea lasted until just a few years ago. The stud book is the record kept by racehorse breeders. A mare who had borne a foal by mating with a non-stud stallion was struck off as her blood was deemed to be polluted. Indeed, a survey of elderly women in Bristol showed that half believed in the chance of a woman having a black baby if she had sex with a black man many years before. The crones of the west country, like the breeders of horses, had never managed to work out the instructions for the reproductive game.

The only section of The Origin of Species which does not make good reading today is Chapter Five, ‘Laws of Variation’. Darwin got it wrong and, after much agonising, suggested that the organs of parents passed material to the blood and then to sperm and egg. Children were, he thought, intermediate between those who produced them. Such a mode of inheritance would be fatal to the idea of evolution. The problem was pointed out by Fleeming Jenkin, the first Professor of Engineering at the University of Edinburgh. Writing in 1867 – and with a sturdy disregard of today’s proprieties – Jenkin imagined ‘a white man wrecked on an island inhabited by negroes. Suppose him to possess the physical strength, energy and ability of a dominant white race. There does not follow the conclusion that after a … number of generations the inhabitants of the island will be white. Our shipwrecked hero would probably become king; … he would have a great many wives, and children … much superior in average intelligence to the negroes, but can anyone believe that the whole island will gradually acquire a white or even a yellow population? A highly favoured white cannot blanch a nation of negroes.’

Jenkin saw that the attributes of a distant ancestor, valuable as they might be, are of little help to later generations if bloods mix. Characters would then blend over the years until their effects disappear. However useful an ink drop in a gallon of water might be at some time in the future it is impossible to get it back from a single mixed drop. Genetics by blending means that any advantageous character would be diluted out in the next generation. Fortunately, the blood myth is wrong.

It was shot down by Galton himself. He transfused blood from a black rabbit to a white to see if the latter had black offspring. It did not. Inheritance by dilution had been disproved, but Galton had nothing to put in its place.

Unknown to either Darwin or to his cousin the rules of genetics had already been worked out by another biological genius. Gregor Mendel lived in Bohemia and published in a rather obscure scientific journal, the Transactions of the Brunn Natural History Society. His breakthrough was overlooked for thirty-five years after it was published in 1866. Mendel, an Augustinian monk, attempted a science degree but failed to complete it. Like Darwin and Galton he suffered from bouts of depression which prevented him from working for months at a time. Nevertheless, he persisted with his experiments. He found that the inherited message is transmitted according to a simple set of regulations – the grammar of the genes. Later in his career (and setting a precedent for the present age) he was unable to continue with research because of the pressures of administration. The study of inheritance came to a halt for almost half a century.

Grammar is always more tedious than vocabulary, but cannot be avoided. The rest of this chapter explores the basic rules of genetics. Those who teach the subject still have an obsession with Mendel and his peas and I make no excuse for having them as a first course.

Mendel made a conceptual breakthrough. Instead of (like his predecessors) working on traits such as height or weight (which could only be measured) Mendel was more or less the first biologist to count anything. This put him on the road to his great discovery.

Peas, like many garden plants, exist in true-breeding lines within which all individuals look the same. Different lines are distinct in characters such as seed shape (which can be round or wrinkled) and seed colour, which may be yellow or green. Peas also have the advantage that each plant carries both male and female organs. Using a small brush it is possible to fertilise any female flower with pollen from any male. Even a male flower from the same plant can be used. The process, a kind of botanical incest, is called self-fertilisation.

Mendel added pollen (male germ cells) from a line with yellow peas to the female part of a flower from a green pea line. In the next generation he got an unexpected result. Instead of all the offspring being intermediate, all the plants in the new generation looked like one of the parents and not the other. They all had yellow peas. This is not at all what would be expected if the ‘blood’ of the two lines was blended into a yellowish-green mixture.

The next step was to self-fertilise these first-generation yellow plants; in other words to expose their eggs to pollen from the same individual. That gave another unforeseen outcome. Both the original colours, yellow and green, reappeared in the next generation. Whatever it was that produced green could still do so, even though it had spent time within a plant with yellow peas. This did not fit at all with the idea that the different properties of each parent were blended together. Inheritance was, his experiment showed, based on particles rather than fluids.

Mendel did more. He added up the numbers of yellow and green peas in each generation. In the first generation (the offspring of the crossed pure lines) all the plants had yellow peas. In the second, obtained by self-fertilising the yellow plants from the first generation, there were always, on the average, three yellows to one green. From this simple result, Mendel deduced the fundamental rule of genetics.

Pea colour was, he thought, controlled by pairs of factors (or genes, as they became known). Each adult plant had two factors for pea colour, but pollen or egg received only one. On fertilisation – when pollen met egg – a new plant with two factors (or genes) was reborn. The colour of the peas was determined by what the plant inherited. In the original pure lines all individuals carried either two ‘yellow’ or two ‘green’ versions of the seed colour gene. As a result, crosses within a pure line gave a new family of plants identical to their parents.

When pollen from one pure line fertilised eggs from a different line new plants were produced with two different factors, one from each parent. In Mendel’s experiment these plants looked yellow although each carried a hidden set of instructions for making green peas. In other words, the effects of the yellow version were concealing those of the green. The factor for yellow is, we say, dominant to that for green, which is recessive.

Plants with both variants make two kinds of pollen or egg. Half carry the instructions for making green peas and half for yellow. There are hence four ways in which pollen and egg can be brought together when two plants of this kind are mated, or a single one self-fertilised. One quarter of fertilisations involve yellow with yellow, one quarter green with green; and two quarters – one half – yellow with green.

Mendel had already shown that yellow with green produces an individual with yellow peas. Yellow with yellow, needless to say, produces plants with yellow peas, and in a plant with two green factors the pea is green. The ratio of colours in this second generation is therefore three yellow to one green. Mendel worked backwards from this ratio to define his basic rule of inheritance.

Mendel made crosses using many different characters – flower colour, plant height and pea shape – and found that the same ratios applied to each. He also tested the inheritance of pairs of characters considered together. For example, plants with yellow and smooth peas were crossed with others with green and wrinkled peas. His law applied again. Patterns of inheritance of colour were not influenced by those for shape. From this he deduced that separate genes (rather than alternative forms of the same one) must be involved for each attribute. Both for distinct forms of the same trait (yellow or green colour, for example) and for quite different ones (such as colour and shape) inheritance was based on the segregation of physical units. Mendel was the first to prove that offspring are not the average of their parents and that genetics is based on differences rather than similarities.

Biologists since his day have delighted in picking over his results (and accusing him of fraud because they may fit his theories too well). They argue about what he thought his factors were, and speculate about why his work was ignored. Whatever lies behind its long obscurity, Mendel’s result was rediscovered by plant breeders in the first year of the twentieth century and was soon found to apply to hundreds of characters in both animals and plants. Mendel had the good luck, or the genius, needed to be right where all his predecessors had been wrong. No science traces its origin to a single individual more directly than does genetics, and Mendel’s work is still the foundation of the whole enormous subject which it has become.

Mendel rescued Darwin from his dilemma. A gene for green pea colour or for white skin, rare though it may be, is not diluted by the presence of many copies of genes for other colours. Instead, it can persist unchanged over the generations and will become more common should it gain an advantage.

Soon after the crucial rules were rediscovered they were used to interpret patterns of human inheritance. It is not possible to carry out breeding experiments on our fellow citizens. They would take too long, for one thing. Instead, biologists must rely on the experiments which are done as humans go about their sexual business. They use family trees or pedigrees – from the French pied de grue, crane’s foot, after a supposed resemblance of the earliest aristocratic pedigrees (which were arranged in concentric circles) to a bird’s toes. Some are fanciful, going back to Adam himself, but geneticists usually have fewer generations to play with, although one or two pedigrees do trace back for hundreds of years.

The first was published in 1903. It showed the inheritance of shortened hands and fingers in a Norwegian village. Such fingers ran in families and showed a clear pattern. The trait never skipped a generation. Anyone with short fingers had a parent, a grandparent and so on with the same thing. If an affected person married someone without the abnormality (as most did), about half their children were affected. If any of their normal children married another person with normal hands the character disappeared from that branch of the family.

The pattern is just what we expect for a dominant character. Only one copy of the damaged DNA (as in the case of yellow pea colour) is needed to show its effects. Most sufferers, coming as they do from a marriage between a normal and an affected parent, have a single copy of the normal and a single copy of the abnormal form, one from either parent. As a result, their own sperm – or eggs – are of two types, half carrying the normal and half the abnormal variant. When they marry, half their children carry a copy of the damaged gene. The chance of any child of a normal and an affected person having short fingers is hence one in two. An unaffected couple never has a child showing the abnormality as neither of them possesses the flawed instruction that makes it.

Other inherited traits do not behave in this simple way. They are recessives. To show the effect, two copies of the inherited factor, one from each parent, are needed. The parents themselves usually each have a single copy and appear quite normal. Most do not know that they are at risk of having an affected child. Sometimes, though, their offspring looks more like a distant relative or an ancestor than it does either parent. Before Mendel, that pattern was inexplicable. Such children were sometimes called ‘throwbacks’. Now we know that they are obeying Mendel’s laws. They have, by chance, inherited two copies of a recessive abnormality while their mother and father each have just one.

In Britain, one child in several thousand is an albino, lacking any pigment in eyes, hair or skin. Elsewhere, the anomaly is more common. In some North American Indians, about one person in a hundred and fifty is an albino. According to the Book of Enoch (one of the apocryphal books of the Bible), Noah himself suffered from the condition. If he did, there is not much sign of the gene in his descendants.

The great majority of albino children are born to parents of normal skin colour. They must each have a single copy of the albino factor matched with another copy of that for full pigmentation. Half the father’s sperm carry the altered gene. Should one of these fertilise one of that half of his partner’s eggs which carry the same thing, then the child will have two copies of the recessive form and will lack pigment. In a marriage such as this, the chance of any child being an albino is a half times a half. This one in four probability is the same for all the children. It is not the case, as some parents think, that having had one albino child means that the next three are bound to be normal.

Patterns of inheritance in humans can, then, follow the same rules as those found in peas. However, biology is rarely pure and never simple. Much of the history of human genetics has been a tale of exceptions to Mendel’s laws.

For example, variants do not have to be dominant or recessive. In some blood groups, both show their effects. Someone with a factor for group A and group B has AB blood, which shares the properties of both. At the DNA level, the whole concept of dominance or recessivity goes away. A change in the order of bases can be identified with no difficulty, whether one or two copies are present. Molecular biology makes it possible to see genes directly, rather than having to infer what is going on, as Mendel did, from looking at what they make.

Another result which would have surprised Mendel is that one gene may control many characters. Thus, sickle-cell haemoglobin has all kinds of side-effects. People with two copies may suffer from brain damage, heart failure and skeletal abnormalities (all of which arise from anaemia and from the blockage of blood vessels). In contrast, some characters (such as height or weight) are controlled by many genes. What is more, Mendelian ratios sometimes change because one or other type is lethal, or bears some advantage.

All this (and much more) means that the study of inheritance has become more complicated in the past century and a half. Nevertheless, Mendel’s laws apply to humans as much as to any other creature.

They are beguilingly simple and have been invoked to explain all conceivable – and some inconceivable – patterns of resemblance. In the early days, long pedigrees claimed to show that outbursts of bad temper were due to a dominant gene and that there were genes for going to sea or for ‘drapetomania’ – pathological running away among slaves. This urge for simple explanations persists today, but mainly among non-scientists. Geneticists have had their fingers burned by simplicity too often to believe that Mendelism explains everything.

Mendel had no interest in what his inherited particles were made of or where they might be found. Others began to wonder what they were. In 1909 the American geneticist Thomas Hunt Morgan, looking for a candidate for breeding experiments hit upon the fruit fly. It was an inspired choice and his work, with Drosophila melanogaster (the black-bellied dew lover, to translate its name) was the first step towards making the human gene map.

Many fruit fly traits were inherited in a simple Mendelian way, but some showed odd patterns of inheritance. When peas were crossed it made no difference which parent carried green or yellow seeds. The results were the same whether the male was green and the female yellow, or vice versa. Some traits in flies gave a different result. For certain genes – such as that controlling the colour of the eye, which may be red or white – it mattered whether the mother or the father had white eyes. When white-eyed fathers were crossed with red-eyed mothers all the offspring had red eyes but when the cross was the other way round (with white-eyed mothers and red-eyed fathers) the result was different. All the sons had white eyes and the daughters red. To Morgan’s surprise, the sex of the parent that bore a certain variant had an effect on the appearance of the offspring.

Morgan knew that male and female fruit flies differ in another way. Chromosomes are paired bodies in the cell which appear as dark strands. Most of the chromosomes of the two sexes look similar but one pair – the sex chromosomes – are different. Females have two large X chromosomes; males a single X and a much smaller Y.

Morgan noticed that the pattern of inheritance of eye colour followed that of the X chromosome. Males, with just a single copy of the X (which comes from their mother, the father providing the Y) always looked like their mother. In females, the copy of the X chromosome from the mother was accompanied by a matching X from the father. In a cross between white-eyed mothers and red-eyed fathers, the female offspring have one X chromosome bearing ‘white’ and another bearing ‘red’. Just as Mendel would have expected, they have eyes like only one of the parents, in this case the one with red eyes.

The eye colour gene and the X chromosome hence show the same pattern of inheritance. Morgan suggested that this meant that the gene for eye colour was actually on the X chromosome. He called this pattern ‘sex-linkage’. Chromosomes were already candidates as the bearers of genes as, like Mendel’s hypothetical particles, their number is halved in sperm and egg compared to body cells.

Everyone has forty-six chromosomes in each body cell. Twenty-two of these are paired, but the sex chromosomes, X and Y, are distinct. Because the Y carries few genes, in males the ordinary rules of Mendelian dominance and recessivity do not apply. Any gene on the single X will show its effects in a male, whether or not it is recessive in females.

The inheritance of human colour blindness is just like that of Drosophila eye colour. When a colour-blind man marries a normal woman none of his children is affected, but a colour-blind woman whose husband has normal vision passes on the condition to all her sons but none of her daughters. Because all males with the abnormal X show its effects (while in most females the gene is hidden by one for normal vision) the trait is commoner in boys than in girls. Many other abnormalities show the same pattern.

Sex-linkage leads to interesting differences between the sexes. For the X chromosome, females carry two copies of each gene, but males only one. As a result, women contain more genetic information than do men. Because of the two different sensors for the perception of red controlled by a gene on the X chromosome, many women must carry both red receptors, each sensitive to a slightly different point in the spectrum. Males are limited to just one. As a result, some women have a wider range of sensual experience for colour at least – than is available to any man.

Whatever the merits of seeing the world in a different way, women have a potential problem with sex-linkage. Any excess of a chromosome as large as the X is normally fatal. How do females cope with two, when just one contains all the information needed to make a normal human being (or a male)? The answer is unexpected. In almost every cell in a woman’s body one or other of her two X chromosomes is switched off.

Tortoiseshell cats have a mottled appearance, which comes from small groups of yellow and black hairs mixed together. All tortoiseshells are females and are the offspring of a cross in which one parent passes on a gene for black and the other transmits one for yellow hair. Because the coat-colour gene is sex-linked about half the skin cells of the kitten switch off the X carrying the black variant and the remainder that for yellow. The coat is a mix of the two types of hair, the size of the patches varying from cat to cat.

The same happens in humans. If a woman has a colour-blind son, she must herself have one normal and one abnormal colour receptor. When a tiny beam of red or green light is scanned across her retina her ability to tell the colour of the light changes as it passes from one group of cells to the next. About half the time, she makes a perfect match but for the rest she is no better at telling red and green apart than is her colour-blind son. Different X chromosomes have been switched off in each colour-sensitive cell, either the normal one or that bearing the instruction for colour blindness.

The inheritance of mitochondrial genes also shows sexual differences. When an egg is fertilised, much of its contents, including those crucial structures, is passed on to the developing embryo. Mitochondria have a pattern of inheritance quite different from those in the nucleus. They do not bother with sex, but instead are passed down the female line. Sperm are busy little things, with a long journey to make, and are powered by many mitochondria. On fertilisation these are degraded, so that only the mother’s genes are passed on. In the body, too, mitochondria are transmitted quite passively, each cell dividing its population among its descendants. Their DNA contains the history of the world’s women, with almost no male interference. Queen Elizabeth the Second’s mitochondrial DNA descends, not from Queen Victoria (her ancestor through the male line) but from Victoria’s less eminent contemporary Anne Caroline, who died in 1881.

Mitochondria, small as they are, are the site of an impressive variety of diseases. Their sixteen and a half thousand DNA bases – less than a hundredth of the whole sequence – were, a century after the death of Anne Caroline, the first to be read off. Every cell contains a thousand or so of the structures. They are the great factories of metabolism; places where food – the fuel of life – is burned. Mitochondrial genes code for just thirteen proteins, and about twice that number of the molecules that transfer information from the DNA to where proteins are made.

They are more liable to error than are others. Some of the mistakes pass between generations, while others build up in the body itself as it ages. Some of the two hundred known faults involve single changes in the DNA, others the destruction of whole lengths of genetic material. Some are frequent: thus, a certain change in one mitochondrial gene is present in about one in seven thousand births.

Mitochondrial disease involves many symptoms: deafness, blindness, or damage to muscles or the brain. Certain forms of diabetes are due to mitochondrial errors, as is an inherited muscle weakness and drooping of the eyelids. Different patients in the same family may have distinct problems; perhaps deafness in one child and brain damage in another. All this comes from the role of mitochondria in burning energy and from their random shuffling as cells divide. An egg may carry both normal and abnormal mitochondria. If, in an embryo, those with an error become by chance common in the cell lines that make brain tissue, that organ suffers; if in cells that code for insulin, then diabetes is the result. Mothers pass such genes to sons and daughters, but only daughters pass it to the next generation; a pattern quite different from sex-linked inheritance.

These, then, are the rules of the genetical game. From here on, the rest is molecular biology: mechanics rather than physics. The notion that life is chemistry came first from humans. In 1902, just two years after the rediscovery of Mendelism, the English physician Sir Archibald Garrod noticed that a disease called alkaptonuria – at the time thought to be due to an intestinal worm – was more frequent in the children of parents who shared a recent ancestor than in those of unrelated people. Its symptoms, a darkening of the urine and the earwax, together with arthritis, followed that of a recessive. The disease was, he thought, due to an inherited failure in one of the pathways of metabolism, what he called a “chemical sport’ (Darwin’s own word for a deviation from the norm). It was the first of many inborn errors of metabolism. The actual gene itself was found just four years before the century ended. The key to its discovery showed how wide the genetical net must spread. An identical was found in a fungus, and that piece of damaged DNA used to search out its human equivalent.

What genes are made of came from the discovery it was possible to change the shape of bacterial colonies by inserting a ‘transforming principle’ extracted from a relative with different shaped colonies. That substance was DNA, discovered many years before in some rather disgusting experiments using pus-soaked bandages. It was the most important molecule in biology.

The story of how the structure of DNA, the double helix, was established is too well known to need repeating. The molecule consists of two intertwined strands, each made up of a chain of chemical bases – adenine, guanine, cytosine and thymine – together with sugars and other material. The bases pair with each other, adenine with thymine and guanine with cytosine. Each strand is a complement of the other. When they separate, one acts as the template to make a matching strand. The order of the bases along the DNA contains the information needed to produce proteins. Every protein is made up of a series of different blocks, the amino acids. The instructions to make each amino acid are encoded in a three-letter sequence of the DNA alphabet.

The inherited message contained within the DNA is passed to the cytoplasm of the cell (which is where proteins are made) through an intermediary, RNA. This ribose-nucleic acid comes in several distinct forms, each involved in passing genetic information to where it is used.

The DNA molecule – the agent of continuity between generations – has become part of our cultural inheritance. The new ability to read (and to interfere with) its message has transformed our vision of our place in nature and our dominion over its inhabitants. It is, nevertheless, worth remembering that the laws of genetics were worked out with no knowledge of where or what the inherited units might be. Like Newton, Mendel had no interest in the details. He was happy with a universe of interacting and independent particles which behaved according to simple rules. These rules worked well for him, and often work just as well today.

Again like Newton, Mendel was triumphantly right, but only up to a point. Molecular biology has turned a beautiful story based on peas into a much murkier tale which looks more like pea soup. The new genetical fog is described in the next chapter.