native American population was almost exclusively type O, save for some Canadian tribes, who were very often type A, and Eskimos, who were sometimes type AB or B.
It was not until the 1920s that the genetics of the A B O blood groups fell into place, and not until 1990 that the gene involved came to light. A and B are 'co-dominant' versions of the same gene, O being the 'recessive' form of it. The gene lies on chromosome I 3 8 G E N O M E
9, near the end of the long arm. Its text is 1,062 'letters' long, divided into six short and one long exons ('paragraphs') scattered over several 'pages' - 18,000 letters in all — of the chromosome. It is a medium-sized gene, then, interrupted by five longish introns. The gene is the recipe for galactosyl transferase,1 an enzyme, i.e. a protein with the ability to catalyse a chemical reaction.
The difference between the A gene and the B gene is seven letters out of 1,062, of which three are synonymous or silent: that is, they make no difference to the amino acid chosen in the protein chain.
The four that matter are letters 523, 700, 793 and 800. In people with type A blood these letters read C, G, C, G. In people with type B blood they read G, A, A, C. There are other, rare differences.
A few people have some of the A letters and some of the B letters, and a rare version of the A type exists in which a letter is missing near the end. But these four little differences are sufficient to make the protein sufficiently different to cause an immune reaction to the wrong blood.2
The O group has just a single spelling change compared with A, but instead of a substitution of one letter for another, it is a deletion.
In people with type O blood, the 258th letter, which should read
'G', is missing altogether. The effect of this is far-reaching, because it causes what is known as a reading-shift or frame-shift mutation, which is far more consequential. (Recall that if Francis Crick's ingenious comma-free code of 1957 had been correct, reading-shift mutations would not have existed.) The genetic code is read in three-letter words and has no punctuation. An English sentence written in three-letter words might read something like: the fat cat sat top mat and big dog ran bit cat. Not exactly poetry, I admit, but it will do. Change one letter and it still makes fairly good sense: the fat xat sat top mat and big dog ran bit cat. But delete the same letter instead, and read the remaining letters in groups of three, and you render the whole sentence meaningless: the fat ats att opm ata ndb igd ogr anb itc at. This is what has happened to the A B O
gene in people with the O blood group. Because they lack just one letter fairly early in the message, the whole subsequent message says D I S E A S E 139
something completely different. A different protein is made with different properties. The chemical reaction is not catalysed.
This sounds drastic, but it appears to make no difference at all.
People with type O blood are not noticeably disadvantaged in any walk of life. They are not more likely to get cancer, be bad at sports, have little musical ability or something. In the heyday of eugenics, no politician called for the sterilisation of people with the O blood group. Indeed, the remarkable thing about blood groups, the thing that has made them so useful and so politically neutral, is that they seem to be completely invisible; they correlate with nothing.
But this is where things get interesting. If blood groups are invisible and neutral, then how did they evolve to the present state? Was it pure chance that landed the inhabitants of the Americas with type O blood? At first glance the blood groups seem to be an example of the neutral theory of evolution, promulgated by Motoo Kimura in 1968: the notion that most genetic diversity is there because it makes no difference, not because it has been picked by natural selection for a purpose. Kimura's theory was that mutation pumps a continual stream of mutations that do not affect anything into the gene pool, and that they are gradually purged again by genetic drift
- random change. So there is constant turnover without adaptive significance. Return to earth in a million years and large chunks of the human genome would read differently for entirely neutral reasons.
'Neutralists' and 'selectionists' for a while grew quite exercised about their respective beliefs, and when the dust settled Kimura was left with a respectable following. Much variation does indeed seem to be neutral in its effects. In particular, the closer scientists look at how proteins change, the more they conclude that most changes do not affect the 'active site' where the protein does its chemical tricks. In one protein, there have been 250 genetic changes since the Cambrian age between one group of creatures and another, yet only six of them matter at all.3
But we now know the blood groups are not as neutral as they seem. There is indeed a reason behind them. From the early 1960s, 1 4 0 G E N O M E
it gradually became apparent that there was a connection between blood groups and diarrhoea. Children with type A blood fell victim to certain strains of infant diarrhoea but not to others; children with type B blood fell victim to other strains; and so on. In the late 1980s, people with the O group were discovered to be much more susceptible to infection with cholera. Dozens of studies later, the details grow more distinct. Not only are those people with type O
blood susceptible, but those with A, B and AB differ in their susceptibility. The most resistant people are those with the AB
genotype, followed by A, followed by B. All of these are much more resistant than those with O. So powerful is this resistance in AB
people that they are virtually immune to cholera. It would be irresponsible to say that people with type AB blood can safely drink from a Calcutta sewer — they might get another disease - but it is true that even if these people did pick up the
Nobody yet knows how the AB genotype offers protection against this most virulent and lethal of human diseases, but it presents natural selection with an immediate and fascinating problem.
Remember that we each have two copies of each chromosome, so A people are actually AAs, that is they have an A gene on each of their ninth chromosomes, and B people are actually BBs. Now imagine a population with just these three kinds of blood groups: A A , BB and A B . The A gene is better for cholera resistance than the B gene. AA people are therefore likely to have more surviving children than BB people. Therefore the B gene is likely to die out
- that's natural selection. But it doesn't happen like that, because AB people survive best of all. So the healthiest children will be the offspring of A A s and BBs. All their children will be A B , the most cholera-resistant type. But even if an AB mates with another A B , only half their children will be A B ; the rest will be AA and B B ,
