Mutants (4 page)

Changing the meaning of a single gene can have extraordinarily far-flung effects on the genetic grammar of the body. 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. In altering the meanings of genes, mutations give us a hint of what those genes meant to the body in the first place. They are collectively a Rosetta Stone that enables us to translate the hidden meanings of genes; they are virtual scalpels that slice through the genetic grammar and lay its logic bare.

Interpreting the meaning of mutations requires the adoption of a reverse logic that is, at first, counter-intuitive. If a mutation causes a child to be born with no arms, then, although it is tempting to speak of a gene for ‘armlessness’, such a mutation is really evidence for a gene that helps ensure that most of us do have arms. This is because most mutations destroy meaning. In the idiolect of genetics, they are ‘loss-of-function’ mutations. A minority of mutations add meaning and are called ‘gain-of-function’. When interpreting the meaning of a mutation it is important to know which of these you are dealing with. One way to tell is by seeing how they are inherited. Loss-of-function mutations tend to be recessive: they will only affect a child’s body when it inherits defective copies of the gene from both its
parents. Gain-of-function mutations tend to be dominant: a child need have only one copy of the gene in order to see its effects. This is not an invariable distinction (some dominantly inherited mutations are loss-of-function) but it is a good initial guide. Gain or loss, both kinds of mutations reveal something about the function of the genes that they affect, and in doing so, reveal a small part of the genetic grammar. Mutations reverse-engineer the body.

Who, then, are the mutants? To say that the sequence of a particular gene shows a ‘mutation’, or to call the person who bears such a gene a ‘mutant’, 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 genome of genomes, 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, is not a standard; it is merely 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 promoted and executed this great enterprise ever claim as much for it). This arbitrariness does not diminish in the slightest degree the value of this genomic sequence; after all, the genomes of any two people are 99.9 per cent identical, so anyone’s sequence reveals almost everything about everyone’s. On the other hand, a genome nearly three thousand million base-pairs
long implies a few million base-pairs that differ between any two people; and it is in those differences that the interest lies.

If there is no such thing as a perfect or normal genome, can we find these qualities in a given gene? Perhaps. All of our thirty thousand genes show at least some variety. In the most recent generation of the world’s inhabitants, each base-pair in the human genome mutated, on average, 240 times. Not all of these mutations change the meanings of genes or even strike genes at all. Some alter one of the vast tracts of the human genome that seem to be devoid of sense. Containing no genes that contribute to the grammar of the body, these regions are struck by mutation again and again; the scalpel slices but with no consequences to body or mind. 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 alter the meaning of genes, a small minority will be beneficial and will become, with time, more common. So common, in fact, that it is hardly fair to refer to them as ‘mutations’, and instead we call them ‘variants’ or, more technically, ‘polymorphisms’. In Africa, the Δ32 polymorphism of the CCR5 gene is currently increasing in frequency because it confers resistance to human immunodeficiency virus and so to AIDS. This is something new, but many polymorphisms are ancient. They 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, intelligence, addictive habits. They may cause disease, but mostly the diseases of old age such as senile dementia and heart attacks.

How common does a mutation have to be before it becomes a polymorphism? The answer is a bit arbitrary, but if a variant sequence has a global frequency of 1 per cent or more it is assumed that it cannot have caused much harm in its history, and may even have conferred some benefit to its carriers. By this criterion, at least one polymorphism has been detected in about 65 per cent of the human genes in which they have been sought, but some genes have dozens. This variety should not overwhelm us. Most human genes have one variant that is far more common than all others, and it is quite sensible to speak of that variant as being normal, albeit only in the statistical sense.

Perfection is far more problematic. The only reason to say that one genetic variant is ‘better’ than another is if it confers greater reproductive success on those who bear it; that is, if it has a higher Darwinian fitness than other variants. It is likely that the most common variant is the best under most circumstances, but this cannot be proved, for the frequencies of gene variants are shaped by history, and what was best then need not be best either now or in the future. To prefer one polymorphism over another – or rather to prefer the way it surfaces in our looks – is merely to express a taste. By this I mean the sort of claim made by the great French naturalist George Leclerc Buffon when he asserted that, for their fair skin and black eyes, the women of the Caucasus Mountains were lovelier than all others. Or when Karen Blixen eulogised the beauty of the Masai
morani
. Recognition of, even a delight in, human genetic diversity does not, however, commit us to a thorough-going genetic relativism. Many of the mutations that batter our genomes do us harm by any criterion.

Each new embryo has about a hundred mutations that its parents did not have. These new mutations are unique to a particular sperm or ovum, were acquired while these cells were in the parental gonads and were not present when the embryo’s parents were themselves embryos. Of these hundred mutations, about four will alter the meaning of genes by changing the amino acid sequences of proteins. And of these four content-altering mutations, about three will be harmful. To be more precise, they will affect the ultimate reproductive success of the embryo, at least enough to ensure that, with time, natural selection will drive them to extinction.

These are uncertain numbers: the fraction of deleterious 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 error. 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 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 deleterious effect upon reproductive success and so persists for a hundred generations, an estimate of three new mutations per generation yields the depressing conclusion that the average newly conceived human bears three hundred mutations that impair its health in some fashion. No one completely escapes this
mutational storm. But – and this is necessarily true – we are not all equally subject to its force. Some of us, by chance, are born with an unusually large number of mildly deleterious mutations, while others are born with rather few. And some of us, by chance, are born with just one mutation of devastating effect where most of us are not. 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.

[O
N THE INVISIBLE GEOMETRY OF EMBRYOS
]

I
n the volume of engraved plates that accompanies the report of their dissection, Ritta and Christina Parodi appear as a pair of small, slender, and quite beautiful infant girls. They have dark eyes, and their silky curls are brushed forward over their foreheads in the fashion of the French Empire, in a way that suggests a heroic portrait of Napoleon Bonaparte. Their brows and noses are straight, their mouths sweetly formed, and their arms reach towards each other, as if in embrace, but their expressions are conventionally grave. Distinct from the shoulders up, their torsos melt gradually into each other; below the single navel the join is so complete that they have, between them, one vulva, one rectum, one pelvis, and one pair of legs. It is a paradoxical geometry. For although the girls are, individually, so profoundly deformed, together they are symmetrical and proportionate; their construction seems less an anomaly of nature than its designed result. It may be thought that this beauty is merely a product of the engraver’s art, but a plaster-cast of their body shows the same harmony of form. If the engraver erred it was only in giving them the proportions of children older than they were; they were only eight months old when they died.

C
ONJOINED TWINS: PYGOPAGUS
. J
UDITH AND
H
éLèNE
(1701–23). F
ROM
G
EORGE
L
ECLERC
B
UFFON
1777
Histoire Naturelle GéNéRale Et ParticulièRe.

C
ONJOINED TWINS: PARAPAGUS DICEPHALUS TETRABRACHIUS
. R
ITTA AND
C
HRISTINA
P
ARODI
(1829). F
ROM
É
TIENNE
S
ERRES
1832
Recherches d’anatomie transcendante et pathologique.

THE APOTHEOSIS OF RITTA-CHRISTINA

The Parodis arrived in Paris in the autumn of 1829. Six months previously they had left Sassari, a provincial Sardinian town, in the hope of living by the exhibition of their children. Italy had been receptive; Paris was not. Local magistrates, ruling on the side of public decency, forbade the Parodis to show their children to the multitude and so deprived them of their only income. They moved to a derelict house on the outskirts of the city, where they received some payment from a procession of physicians and philosophers who came to see the children in private.

What they earned wasn’t even enough to heat the house. The
savants
, puzzling over what they found, were also continually uncovering the children. Was there one heart or two? The stethoscope gave conflicting results. They were fascinated by the differences between the children. Christina was a delight – healthy, vigorous, with a voracious appetite; Ritta, by contrast, was weak, querulous and cyanotic. When one fell asleep the other would usually do so as well, but occasionally one slept soundly while the other demanded food. Continually exposed to chills, Ritta became bronchitic. The physicians noted that sickness, too, demonstrated the dual and yet intertwined nature of the girls, for even as Ritta gasped for air, her sister lay at her side unaffected and content. But three minutes after Ritta died, Christina gave a cry and her hand, which was in her mother’s, went limp. It was 23 November 1829, and the afterlife of ‘Ritta-Christina, the two-headed girl’ had begun.

* * *

The men from the Académie Royale de Médecine were on hand within hours. They wanted a cast of the body. Deputations of anatomists followed; they wanted the body itself. How they got it is a murky affair, but within days the dissection of
l’enfant bicéphale
was announced. In the vast amphitheatre of the Muséum d’Histoire Naturelle at the Jardin des Plantes in Paris, Ritta and Christina were laid out in state on a wooden trestle table. The anatomists jostled for space around them. Baron Georges Cuvier, France’s greatest anatomist – ‘the French Aristotle’ – was there. So was Isidore Geoffroy Saint-Hilaire, connoisseur of abnormality, who in a few years would lay the foundation of teratology. And then there was Étienne Reynaud Augustin Serres, the brilliant young physician from the Hôpital de la Pitié, who would make his reputation by anatomising the girls in a three-hundred-page monograph.