THROWING SWITCHES

      I cannot resist a literary analogy. The opening sentence of Charles Dickens’s novel David Copperfield reads: ‘Whether I shall turn out to be the hero of my own life, or whether that station will be held by anybody else, these pages must show.’ The opening sentence of J.D. Salinger’s novel The Catcher in the Rye reads: ‘If you really want to hear about it, the first thing you’ll probably want to know is where I was born, and what my lousy childhood was like, and how my parents were occupied and all before they had me, and all that David Copperfield kind of crap, but I don’t feel like going into it.’ In the pages that follow, to a close approximation, Dickens and Salinger use the same few thousand words. There are words that Salinger uses but not Dickens, like elevator or crap. There are words that Dickens uses but not Salinger, like caul and pettish. But they will be few compared with the words they share. Probably there is at least 90 per cent lexical concordance between the two books. Yet they are very different books. The difference lies not in the use of a different set of words, but in the same set of words used in a different pattern and order. Likewise, the source of the difference between a chimpanzee and a human being lies not in the different genes, but in the same set of 30,000 genes used in a different order and pattern.

      I say this with confidence for one main reason. The most stunning surprise to greet scientists when they first lifted the lid on animal genomes was the discovery of the same sets of genes in wildly different animals. In the early 1980s, fly geneticists were thrilled to discover a small group of genes they called the hox genes that seemed to set out the body plan of the fly during its early development – roughly telling it where to put the head, the legs, the wings and so on. But they were completely unprepared for what came next. Their mouse-studying colleagues found recognisably the same hox genes, in the same order, doing the same job. The same gene tells a mouse embryo where (but not how) to grow ribs as tells a fly embryo where to grow wings: you can even swap them between species. Nothing had prepared biologists for this shock. It meant, in effect, that the basic body plan of all animals had been worked out in the genome of a long-extinct ancestor that lived more than 600 million years before and preserved ever since in its descendants (and that includes you).

      Hox genes are the recipes for proteins called ‘transcription factors’, which means that their job is to ‘switch on’ other genes. A transcription factor works by attaching itself to a region of DNA called a promoter.³⁴ In creatures such as flies and people (as opposed to bacteria, say), promoters consist of about five separate stretches of DNA code, usually upstream of the gene itself, sometimes downstream. Each of those sequences attracts a different transcription factor, which in turn initiates (or blocks) the transcription of the gene. Most genes will not be activated until several of their promoters have caught transcription factors. Each transcription factor is itself a product of another gene somewhere else in the genome. The function of many genes is therefore to help switch other genes on or off. And the susceptibility of a gene to being switched on or off depends on the sensitivity of its promoters. If its promoters have shifted, or changed sequence so that the transcription factors find them more easily, the gene may be more active. Or if the change has made the promoters attract blocking transcription factors rather than enhancing ones, the gene may be less active.

      Small changes in the promoter can therefore have subtle effects on the expression of the gene. Perhaps promoters are more like thermostats than switches. It is here in the promoters that scientists expect to find most evolutionary change in animals and plants – in sharp contrast to bacteria. For example, mice have short necks and long bodies; chickens have long necks and short bodies. If you count the vertebrae in the neck and thorax of a chicken and a mouse, you will find that the mouse has 7 neck and 13 thoracic vertebrae; the chicken has 14 and 7 respectively. The source of this difference lies in one of the promoters attached to one of the hox genes, Hoxc8, a gene found in both mice and chickens whose job is to switch on other genes that lay down details of development. The promoter is a 200-letter paragraph of DNA and it has just a handful of letters different in the two species. Indeed, changes in as few as two of these letters may be enough to make all the difference. The effect is to alter the expression of the Hoxc8 gene slightly in the development of the chicken embryo. In the chicken embryo the gene is expressed in a more limited part of the spine, giving the animal a shorter thorax compared with a mouse.³⁵ In the python, Hoxc8 is expressed right from the head and goes on being expressed for most of the body. So pythons consist of one long thorax – they have ribs all down the body.³⁶

      The beauty of the system is that the same gene can be reused in different places and at different times simply by putting a set of different promoters beside it. The ‘eve’ gene in fruit flies, for example, whose job is to switch on other genes during development, is switched on at least ten separate times during the fly’s life, and it has eight separate promoters attached to it, three upstream of the gene and five downstream. Each of these promoters requires 10–15 proteins to attach to it to switch on expression of the eve gene. The promoters cover thousands of letters of DNA text. In different tissues, different promoters are used to switch on the gene. This, incidentally, seems to be one reason for the humiliating fact that plants usually have more genes than animals. Instead of reusing the same gene by adding a new promoter to it, a plant reuses a gene by duplicating the whole gene and changing the promoter in the duplicated version. The 30,000 human genes are probably used in at least twice as many contexts during development thanks to batteries of promoters.³⁷

      To make grand changes in the body plan of animals, there is no need to invent new genes, just as there is no need to invent new words to write an original novel (unless your name is Joyce). All you need to do is switch the same ones on and off in different patterns. Suddenly, here is a mechanism for creating large and small evolutionary changes from small genetic differences. Merely by adjusting the sequence of a promoter, or adding a new one, you could alter the expression of a gene. And if that gene is itself the code for a transcription factor, then its expression will alter the expression of other genes. Just a tiny change in one promoter will produce a cascade of differences for the organism. These changes might be sufficient to create a wholly new species without changing the genes themselves at all.³⁸

      In one sense, this is a bit depressing. It means that until scientists know how to find gene promoters in the vast text of the genome, they will not learn how the recipe of a chimpanzee differs from that of a person. The genes themselves will tell them little, and the source of human uniqueness will remain as mysterious as ever. But in another sense it is also uplifting, reminding us, more forcefully than ever, of a simple truth that is all too often forgotten, that bodies are not made, they grow. The genome is not a blueprint for constructing a body; it is a recipe for baking a body. The chicken embryo is marinaded for a shorter time in the Hoxc8 sauce than the mouse embryo. This is a metaphor I shall return to frequently in the book, for it is one of the best ways of explaining why nature and nurture are not opposed to each other, but work together.

      As the hox story illustrates, DNA promoters express themselves in the fourth dimension: their timing is all. A chimp has a different head from a human being not because it has a different blueprint for the head, but because it grows the jaws for longer and the cranium for less long than does the human being. The difference is all timing.

      The process of domestication, by which the wolf was turned into the dog, illustrates the role of promoters. In the 1960s, a geneticist named Dmitri Belyaev was running a huge fur farm near Novosibirsk in Siberia. He decided to try to breed tamer foxes, because however well they had been handled and however many generations they had been kept in captivity, foxes were nervous and shy creatures in the fur farm (with good reason, presumably). So Belyaev started by selecting as breeding stock the animals that allowed him closest before fleeing. After 25 generations he did indeed have much tamer foxes, which, far from fleeing, would approach him spontaneously. The new breed of foxes not only behaved like dogs, they looked like dogs: their coats were piebald, like collies, their tails turned up at the end, the females came on heat twice