by Steve Jones
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 lonj;, lor mic tiling. Instead, biologists must rely on the experiments whn.li.ire done as humans go about their sexual business. They use family trees or pedigrees — from the l-'reuch pied de grm; crane's foot, after a supposed resemblance "t 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 irs 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 fromeither 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.1 distant relative or an ancestor than it does either parent. Me fore Mendel, that pattern was inexplicable. Such children were sometimes called 'throw-backs'. 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 ics. 1 lowevcr, biology is rarely pure and never simple. Much of Mr- history of human genetics has been a tale of exceptions to Mendel's laws.
For example, variants do noi have 10 In- domin.itii or recessive. In some blood groups, both show their effects. Someone with a factor for group A and group B has Ail blood, which shares the properties of both. At the UNA 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 ringers burned by simplicity too often to believe that Mendel ism 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 Mendeiian 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 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 mitochondria! genes also shows sexual differences. When an egg is h-rlilisrii, much of its contents, including [host- crucial slim tuirs, 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 interf
erence. 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 conks I mm the role of mitochondria in burning energy and from their random shuffling as cells divide. An egg may cany both normal and abnormal mitochondria. It, in an embryo, ihosc 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 aikaptonuria — 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 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 <>l the X chromosome horn the mother was accompanied by a mulching X Irntn ihc 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, tn 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 smug 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 al! 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 colourblind son, she must herself have one normal and one abnormal colour receptor. When a tiny beam of red or green 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 canu- from the discovery it was possible to change the shape ot luck-rial colonies by inserting a 'transforming principle' extracted Irom 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, Munle! 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 clupu-r.
Chapter Three. HERODOTUS REVISED
The Greek traveller Herodotus Ml ih.u he knew the world well. He voyaged around the Mediterranean and heard much of the Phoenicians' journeys into Africa, liy pulling what he knew of the globe's landmarks together he came to the conclusion that 'Europe is as long as Africa and Asia put together, and for breadth is not, in my opinion, even to be compared with them.7 Herodotus had things in about the right places in relation to each other but the physical distances between them were hopelessly wrong.