快猫短视频

IN FEBRUARY 2001, an international consortium of scientists announced the complete, or nearly complete, sequence of the human genome. There it was, arrayed before us, the instruction manual for making a human. Anyone may read this manual 鈥� it is freely available on the Web. But it is hardly worth the bother. The average English speaker may as well attempt the Analects of Confucius in the original for all the wisdom that the human genome imparts.

Even geneticists find most of its contents baffling. Here and there they pick out words whose meanings are clear. Others can be guessed at, perhaps because they are cognates of more familiar ones. Some of the grammar, the rules by which genes combine to give their utterances meaning, can be understood. But the grammar is vastly more complex than that of any human language. Its literature is not exactly a closed book, but it is one we have scarcely begun to read.

That is not to say that we don鈥檛 know how to interpret the genome. It is a matter of doing experiments: of engineering embryos in which particular genes have been added, altered or deleted altogether. By studying the results of such changes we can infer what the genes do in the first place. This is what developmental geneticists do, and in the past 30 years they have created literally thousands of mutations in an attempt to unravel, gene by gene, the programmes that make embryos.

But these embryos have, of course, all belonged to animals: fruit flies, worms, mice, and so on. They tell us a lot about humans since the genetic grammars of all creatures are quite similar. But just as, over time, the vocabulary and grammatical rules of spoken languages diverge from one another, so too do the languages of genes. We need, ultimately, some direct way into the human genome and into the human body. And since it is unethical to create mutants, we have to find them.

Fortunately, human mutants are not hard to spot. Genetic changes that cause some of us to look, feel, or behave differently from almost everyone else have been found in about 1500 genes. Their effects can be extraordinarily far-flung. There is a mutation that gives you red hair and also makes you fat. Another causes partial albinism, deafness, and fatal constipation. Yet another gives you short fingers and toes, and malformed genitals.

快猫短视频s have long understood the value of human mutations; the great teratology collections such as the Gordon Museum at Guy鈥檚, King鈥檚 and St Thomas鈥� Hospital in London, the Vrolik Museum at the University of Amsterdam and the M眉tter Museum in Philadelphia bear witness to that. These rows of deformed babies in bottles might look like a Victorian freak show, but such specimens have been, and remain, the source of much of our knowledge about how humans develop.

What do these specimens tell us? To answer that, let us look at one of the most terrible congenital abnormalities 鈥� a condition called cyclopia, which gives infants a single monstrous eye in the middle of the forehead, located beneath what is left of the nasal cavity.

Cyclopia is, in all its manifestations, one of the most common of all brain deformities, afflicting 1 in 16,000 live-born infants and 1 in 200 miscarried fetuses; it is always fatal. Cyclopia can be caused by toxins, including alcohol, but most cases are caused by mutations in a gene called sonic hedgehog.

This gene codes for a signalling protein of a class known as morphogens, which tell other cells where they are and so what they should become and where they should go. The embryo is awash with morphogens that criss-cross it in concentration gradients and collectively form, at scales large and small, a cartesian grid by which cells can navigate their fates. Collectively, they give the body its geometry.

The single eye of a cyclopic child is only the external sign of a disorder that reaches deep within its skull. All normal vertebrates have split brains. Humans, most obviously, have left and right cerebral hemispheres, which we invoke when speaking of our left or right 鈥渂rains鈥�. Cyclopic infants do not. Instead of two distinct hemispheres, their forebrains are fused into an apparently indivisible whole.

The fact that infants with defects in sonic hedgehog have a single cerebral hemisphere tells us something important. When the forebrain first forms in the normal embryo it is a unitary object, a simple bulge at the end of the neural tube. Only later does it split into a left and right brain, and this split is induced by sonic hedgehog. During the formation of the neural tube, the protein appears in a small piece of embryonic tissue directly beneath the developing forebrain. It then filters upwards and cleaves the brain in two.

This process is especially important in the making of eyes. Long before the embryo has eyes, a region of the forebrain is dedicated to their neural wiring. This region 鈥� the optic field 鈥� first appears as a single band crossing the embryo鈥檚 forebrain. Sonic hedgehog moulds the optic field鈥檚 topography, reducing it to two smaller fields on either side of the head. Mutations that inhibit the sonic hedgehog protein prevent this happening 鈥� thus the single, staring eye of the cyclopic infant.

But sonic hedgehog does more than give us distinct cerebral hemispheres. Mice in which the gene has been completely disabled have malformed hearts, lungs, kidneys and guts. They are always stillborn and have no paws. Their faces are reduced to a strange kind of trunk: they have no eyes, ears or mouths. These malformations suggest that sonic is used throughout the developing mouse embryo. So, too, in humans. In particular it seems to be used repeatedly in the making of our heads and faces.

Making faces

A human embryo鈥檚 face is formed from five lumpy prominences that start out distinct but later fuse. Two become the upper jaw, two the lower jaw, while one makes the nose and forehead. These five prominences all secrete sonic hedgehog, which controls their growth and so the geometry of the face.

More exactly, it regulates facial width, setting the spaces between ears, eyes and nostrils. We know this because chicken embryos whose faces are dosed with extra sonic hedgehog develop unusually wide faces. Increase the dose still further and their faces become so wide that they start duplicating structures and end up with two beaks side by side.

Something like this also occurs naturally in humans. Several genetic disorders are marked by extremely wide-set eyes, a trait known as hypertelorism. One of these disorders is caused by mutations in a gene that normally limits sonic hedgehog鈥檚 activity. Patients with another hypertelorism syndrome resemble the sonic-dosed chickens in having very broad noses, noses with two tips, or even two noses.

Disorders of this sort prompt the question of just how wide a face can be. If, as a face becomes wider and wider, parts start duplicating, might a completely duplicated face ensue 鈥� or even two individuals? It is not merely an academic question. A famous pig born in Iowa arrived in the world with two snouts, two tongues, two oesophagi and three eyes. It may have started out as two twin embryos that conjoined in extraordinary intimacy. But given that the duplication was confined to the face and forebrain it is more likely that it grew from a single embryo with a very wide head. The pig, dubbed 鈥淒itto鈥�, died in 1998, and its head is preserved in a jar at the University of California, San Francisco.

Just as cyclopic infants and two-faced pigs reveal the devices that give us split brains and determine the width of our faces, practically any part of the body can be analysed in the same way. Mutations that cause dwarfism reveal the controls of growth; hermaphrodites speak of the molecular devices that give us two sexes; people born without hands and feet tell us what it takes to make a limb.

But it is not just obvious physical abnormalities that are useful to geneticists. When you start looking for them, mutants are everywhere. It is just a case of knowing what to look for.

What does it take to be a mutant? To say that the sequence of a particular gene shows a 鈥渕utation鈥�, or to call the person who carries it a 鈥渕utant鈥�, is to make an invidious distinction. It is to imply, at the least, deviation from some ideal of perfection. Yet humans differ from each other in very many ways, and those differences are, at least in part, inherited. Who among us has the ideal, non-mutant genome, the one by which all other genomes will be judged?

The short answer is that no one does. Certainly the human genome, the one whose sequence was published in Nature on 15 February 2001 (vol 409, p 860), is not a standard; it is a composite of the genomes of an unknown number of unknown people. As such, it has no special claim to normality or perfection (nor did the scientists who executed the enterprise ever claim that it did).

This arbitrariness does not diminish the value of the sequence; the genomes of any two people are 99.9 per cent identical, so anyone鈥檚 sequence reveals almost everything about everyone else鈥檚. On the other hand, there is a great deal of difference between individuals. In a genome nearly 3000 million base pairs long, a difference of even 0.01 per cent adds up to a few million base pairs.

All of our 30,000 genes show at least some variety. Not all of these mutations change the meanings of genes or even occur within genes at all. Some alter one of the vast tracts of the human genome that seem to be devoid of meaning. Other mutations strike the coding regions of genes but do not materially alter the sequences of the proteins that they encode; these, too, are silent.

Of the mutations that do alter the meaning of genes, a small minority will be helpful and will become more common with time. So common, in fact, that it is hardly fair to refer to them as mutations at all, and instead we call them 鈥渧ariants鈥� or 鈥減olymorphisms鈥�. In Africa, for example, a mutation in the CCR5 gene, which encodes a protein found on immune cells, is growing more common because it confers resistance to HIV.

Mutational storm

Polymorphisms are the stuff from which human diversity is made. They give us variety in skin colour, height, weight and facial features, and they surely also give us at least some of our variety in temperament and intelligence.

How common does a mutation have to be to qualify as a polymorphism? The answer is a bit arbitrary, but if a sequence has a global frequency of 1 percent or more it is assumed to be beneficial, or at least not harmful, and classed as a polymorphism. By this criterion, about 65 per cent of the human genes that have been examined contain at least one polymorphism; some have dozens.

Not all mutations are so benign. Many of the alterations that batter our genomes do us harm by any criterion. Each new embryo has on average about a hundred mutations that its parents did not have. These new mutations are unique to a particular sperm or ovum, and were acquired while these cells were in the parental gonads. Of these hundred mutations, about four change the amino acid sequences of proteins, about three in a harmful way. To be more precise, they affect the ultimate reproductive success of the embryo, at least enough to ensure that, with time, natural selection will drive the mutations to extinction.

These are uncertain numbers: the fraction of harmful mutations can only be estimated by indirect methods. But if they are at all correct, their implications are terrifying. They tell us that our health and happiness are being continually eroded by an unceasing supply of genetic errors. But matters are worse than that. Not only are we each burdened with our own unique suite of harmful mutations, we also have to cope with those we inherited from our parents, and they from theirs, and so on.

What, then, is the total mutational burden on the average human being? The length of time that a given mutation will be passed down from one generation to the next depends on the severity of its effects. If we suppose that an average mutation has only a mildly negative effect upon reproductive success and so persists for a hundred generations, an estimate of three new mutations per generation leads to the depressing conclusion that the average newly conceived human bears 300 mutations that impair its health in some fashion. No one escapes this mutational storm. But we are not all equally subject to its force. Some of us, by chance, are born with an unusually large number of mild mutations, while others are born with rather few.

Who, then, are the mutants? There can be only one answer, and it is one that is consistent with our everyday experience of the normal and the pathological. We are all mutants. But some of us are more mutant than others.