Wednesday, February 21, 2007

ABO Blood Types

 
I described glycoproteins in a previous posting (Glycoproteins). Recall that these are proteins with long oligosaccharide chains attached to them. The oligosaccharides are normally put on as the proteins are being processed for export to the exterior of the cell. The process involves attaching a “core” oligosaccharide then modifying it once it is bound to the glycoprotein. The modifications include removing some sugar residues and adding others.

The cell surface of blood cells is covered with glycoproteins and the carbohydrate chains project out into the blood stream where they can easily be recognized by antibodies. We make antibodies to all sorts of things but the ones that attack our own cells are removed before they can do any harm. This anti-self screening of antibodies is one of the things that goes wrong in auto-immune diseases.

The proteins on the erythrocyte cell surface contain a wide variety of different oligosaccharides that are attached in various ways to the protein. However, it spite of this variation, there are a few structures that are very common. One of the most common “core” structures is something called H-antigen. It is composed of many different sugars but the outside end of the H-antigen structure always consists of a fucose (Fuc) residue, a galactose residue (Gal), and an N-acetylglucosamine (GlcNAc) residue.

In most primates, including humans, this core oligosaccharide is subsequently modified by adding an N-acetylgalactosamine (Monday’s Molecule #14) residue to form a branched structure at the end of the oligosaccharide (see diagram below). The enzyme that catalyzes this reaction is called N-acetylaminogalactosyltransferase or A enzyme. The gene for this enzyme is located on chromosome 9. The OMIN (Online Mendelian Inheritance in Man) entry for the ABO blood group is 110300. It contains a wealth of information on the topic.

If your red blood cells have oligosaccharides with a terminal GalNAc then you have blood type A. If you have a completely defective gene for A enzyme then your cells will have the unmodified H antigen structure and your blood type will be O. People with blood type A will not have antibodies to H antigen since this is the normal precursor to A antigen and there will always be some on the cell surface. In other words, the H antigen will be recognized as self.

Normal red blood cells are recognized as “self” so we don’t have antibodies against our own cells. However, we will have antibodies against the red blood cells of other people’s blood if their cell surface carbohydrates are different from ours. This is the basis of ABO blood group and it’s why we have to match blood types in a blood transfusion.

The ABO blood group was discovered over one hundred years ago by Karl Landsteiner (Nobel Laureate: Karl Landsteiner). The biochemical basis was only elucidated in the 1970’s when the technology for examining the carbohydrate structure of glycoproteins was worked out.

There’s an allele of the A enzyme gene that involves only a very small number of mutations but the result is to switch the enzyme from one that transfers GalNAc to one that transfers galactose (Gal). The variant enzyme is called B enzyme (galactosyltransferase) and the B antigen structure has a terminal galactose (Gal) instead of a terminal GalNAc.

If you are homozygous for the B allele on chromosome 9 then all of your red blood cells will have the B antigen oligosaccharide on their surface. You will not make antibodies against this structure because it’s “self.” You also won’t have antibodies against H-antigen for the reasons explained earlier. But you won’t recognize A antigen as self so your antibodies will attack any foreign cells that come from people with the normal wild-type allele (A).

People with blood type A will have antibodies against B antigen. They can receive blood from people with O blood type but they will reject blood from people with B blood type. You now have all the information you need to figure out who can give and receive blood from every possible combination of alleles: AA, AO, AB, BO, and OO.

There are no known natural effects of these differing blood types. People with A, B, AB and O phenotypes do not differ in fitness in any major way that we have been able to detect. This suggests that the complete absence of the enzyme (null mutation) is neutral in the current human population and so is the switch from one form of the enzyme to another. (Suggestions that blood type determines susceptibility to some infections are common in the scientific literature. Most of them have not held up. The best correlation is a possible association between blood type O and susceptibility to cholera. This looks pretty good but the cause-and-effect relationship is still up in the air.)

The ABO alleles seem to be segregating in the human population by random genetic drift. The O allele (non-functional enzyme) is the most common allele. The B allele is the least common—probably because it arose more recently. Some Native American populations are homogeneous for the O allele; in those populations everyone has blood type O. (For maps of the frequencies A and B alleles see Distribution of Blood Types.)


13 comments:

  1. I wanted to make the posting scientific so I avoided any mention of religion and Intelligent Design Creationism.

    But just for the record, could some of our IDiot friends please explain these observations using their favorite paradigm?

    Why would the "designer" make a perfectly good gene like the one encoding the A enzyme and then wreck it by introducing a single base pair deletion to make the O allele?

    Would IDiots predict that chimpanzees might also have the non-functional O allele?

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  2. I recently read a book called The Making of the Fittest. In it, the author presented a number of good (at least they seemed that way to me) examples of genes which had lost their utility. These genes accumulated mutations because there was no selective pressure on them. Shouldn't we expect Type O blood to eventually become dominant if there really were no fitness associated with the various blood types?

    (Just a question...I'm a curious Biochem undergrad.)

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  3. Matt asks,

    Shouldn't we expect Type O blood to eventually become dominant if there really were no fitness associated with the various blood types?

    No. If all three alleles (A, B, O) are really neutral then we have no way of telling which one will eventually become fixed in the human population.

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  4. Hmm, I guess what I meant was that if the enzyme that results in Type O blood is really just a corrupted, non-functioning version of the A or B version of the enzyme, then wouldn't mutations in the A and B enzymes eventually trend towards being "O enzymes" (non-functional)? I don't know, I'm probably crazy.

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  5. Matt asks,

    Hmm, I guess what I meant was that if the enzyme that results in Type O blood is really just a corrupted, non-functioning version of the A or B version of the enzyme, then wouldn't mutations in the A and B enzymes eventually trend towards being "O enzymes" (non-functional)? I don't know, I'm probably crazy.

    No, you're not being crazy. I just misunderstood your question. The answer is yes, we expect that eventually one of the null alleles will take over the entire human population if the mutation really is neutral. This is because the number of mutations to non-functionality is higher than those that retain function.

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  6. I enjoyed the article very much.

    What impact the Rhesus factor have on blood types and blood donors/transfusions or is it only in the case of some pregnancies that it's a real concern?

    Also, I know this is pretty basic, but is there a generally accepted theory on why auto-immune diseases develop for specific organs/cells and not everywhere in the body?

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  7. ordinarygirl, I don't know the answer to your questions. Sorry.

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  8. One thing I've never understood is why we have antibodies to non-self A or B antigens when we've never been exposed to them. If I'm type A then I have B antibodies, even though I've never had a B-blood transfusion. Where do those antibodies come from?

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  9. Could there be such a thing as a neutral Rh factor? like neither negative or positive.

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  10. @ dlhoyt: We have anti-A and anti-B because we have been exposed to them. Yes, you have never had a blood transfusion, but micro-organisms in your gut have antigens that are similar to A and B. This causes something called cross-reactivity.

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  11. I don't understand. Why should the one allele eventually take over the population if there isn't any selective pressure?

    (I've just done the Hardy-Weinberg law and it says the frequency of alleles remains constant in the absence of selective pressure)

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  12. Anne Blythe asks,

    I've just done the Hardy-Weinberg law and it says the frequency of alleles remains constant in the absence of selective pressure.

    It's about understanding the scope of the law. Over short period, yes Hardy-Weinberg is useful and holds true. But Hardy-Weinberg works on an assumption of an ideal population, without mutation. On large time frames mutations become an important factor, and so the functional genes pick up mutations and lose functionality, in the absence of a selection pressure.

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  13. Third attempt! My line is being tapped! I am researching eugenics and believe it is actively carrying on today. Certain powers want more O blood and less B blood, though I know not why. This is consistent with attempts to wipe out the Jews in WW2. It seems from the discussions on this page that the trend towards more O blood people worldwide could be explained by interference in the natural order of things. I have discovered that Blood can mutate through diet, bone marrow transplant and blood transfusion to the donor blood, which is of course nearly always O. I also note that antibodies anti A and anti B develop in the first years of life, by sensitisation to food bacteria and viruses. I will assume that includes vaccines which contain viruses. Most of our food has additives, so it is possible that environmental factors could cause a tendency towards O blood, especially with the huge number of vaccines administered to babies.

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