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dadamowiki A wikipedia of Dr. D'Adamo's research |
ABO and Secretor Blood group Genetics
See Also- Allele
- Autosomal dominant
- Genetic drift
- Genetic linkage
- Locus
- Neutral theory of molecular evolution
- 9q34
- 19q13.3
Description
Glycosphingolipids carrying A or B oligosaccharides are integral parts of the membranes of RBCs, epithelial and endothelial cells; they are also present in soluble form in plasma. Glycoproteins that carry identical oligosaccharides are responsible for the A and B activity of secreted body fluids such as saliva. A and B oligosaccharides that lack carrier protein or lipid molecules are found in milk and urine.
Genes at three separate loci (ABO, Hh, and Sese) control the occurrence and the location of the A and B antigens . Three common alleles -A, B and O- are located at the ABO locus on chromosome 9q34 . The A and B genes encode Glycosyltransferases that produce the A and B antigens, respectively. The O gene is considered to be amorphic since no detectable blood group antigen results from its action. The RBCs of group O persons lack A and B, but carry an abundant amount of H antigen because this antigen is the precursor material on which A and B antigens are built.
Family studies have shown that the genes at the remaining two loci , Hh and Sese ( secretor ), are closely linked. The chromosome on which they are located has not yet been identified. It is suggested that one of these loci may have arisen through gene duplication of the other. Two recognized alleles reside at each locus. Of the two alleles at the H locus, one of these, H, produces an enzyme that acts at the cellular level to construct the antigen on which A or B are built. The other allele at this locus, h, is very rare. No antigenic product has been linked to h, so this gene is also considered an amorph . The possibility exists that other alleles occur at the Hh locus that differ from H in that they cause the production of only very small amounts of H antigen.
Secretor Genetics
The Sese gene is directly responsible for the expression of H (and indirectly responsible for the expression of A and B) on the glycoproteins in epithelial secretions such as saliva. Eighty percent of the population are secretors because they have inherited the Se gene and produce H in their secretions that can be converted to A and/or B (depending on the genetic background of the secretor ). The se gene, having no demonstrable product, is an Amorph .
Oligosaccharide chains on which the A and B antigens are built can exist as simple structures of a few sugar molecules linked together in linear fashion. They can also exist as more complex structures that are composed of many sugar residues connected together in branching chains. It has been proposed that the differences in cellular A, B and H activity seen between specimens from infants and adults may be related to the number of branched structures carried on the cellular membranes of each group.(6) The RBCs of infants are thought to carry A, B and H antigens built predominantly on linear oligosaccharides. Linear oligosaccharides have only one terminus to which the H, then A and B, sugars can be added. In contrast, the RBCs of adults appear to carry a high proportion of branched oligosaccharides. Branching creates additional portions on the oligosaccharide that can be converted to H and then to A and B antigens .
A and B genes do not produce antigens directly but instead produce enzymes called glycosyltransferases that add specific sugars to oligosaccharide chains that have been converted to H by the action of the H gene. H antigens are constructed on precursor oligosaccharide chain endings called Type 1 and Type 2. ( {{Watkins WM. The glycosyltransferase products of the A, B, H and Le genes and their relationship to the structure of the blood group antigens. In: Mohn JF, Plunkett RW, Cunningham RK, Lambert RM, eds. Human blood groups. Basel: S Karger, 1977:134-42.}} ) The number 1 carbon of the terminal 6-carbon sugar b-D-galactose ( Gal ) is linked to the number 3 carbon of subterminal N-acetyl-glucosamine (GlcNAc) in Type 1 chains and to the number 4 carbon of GlcNAc in Type 2 chains. Blood group-active glycoproteins present on cell surfaces or in body fluids carry either Type 1 or Type 2 chains. Glycosphingolipids present in the plasma and those on the membranes of most glandular and parenchymal cells also have either Type 1 or Type 2 chain endings. In contrast, the glycolipid antigens produced by the RBCs; appear to be formed exclusively of Type 2 chains. These chains are carried on a class of glycosphingolipids called paraglobosides.
At the cellular level, the H gene transferase produces a Fucosyltransferase that adds fucose (Fuc) in alpha (1-2) linkage to the terminal Gal of Type 2 chains. The A and B gene transferases can only attach their immunodominant sugars when the Type 2 (or Type 1) chains have been substituted with Fuc (ie, changed to H) thus, the A and B antigens are constructed at the expense of H. The A gene-specified N-acetyl-galactosaminyl-transferase and the B gene-specified galactosaminyl-transferase add GalNAc and Gal respectively in alpha (1-3) linkages to the same Gal acted on by the H gene transferase.
The alleles at the ABO locus that result in subgroups ( phenotypes of A and B that differ from each other with respect to the amount of A or B carried on the RBCs) produce transferases that differ from one another in their ability to convert H antigen . ( {{Hakomori SI. Blood group ABH and Ii antigens of human erythrocytes: chemistry, polymorphism and their developmental change. Sernin Hematol 1981;18:39-47.}} , {{Beattie KM. Discrepancies in ABO grouping. In: A seminar on problems encountered in pretranfusion tests. Washington DC: American Association of Blood Banks, 1972;12965.}} ) The O gene is thought to produce a protein that can be detected immunologically but has no detectable transferase activity. As a consequence, the RBCs of group O persons carry readily detectable, unconverted H antigen. The secretion of Sese persons contain Type I and Type 2 chains with no H, A or B activity. It has been suggested that the H and Se genes each encode a different Fucosyltransferase . ( {{Oriol R, Danilovs J, Hawkins BR. A new genetic model proposing that the Se gene is a structural gene closely linked to the H gene.
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