For the past ten years we have continuously studied the molecular genetic basis of histo-blood group ABO system, a major carbohydrate antigen system, of clinical importance in blood transfusion and transplantation medicine. We have cloned human ABO genes and elucidated the allelic basis of ABO genetic locus at the molecular level. A and B alleles have four nucleotide substitutions resulting in amino acid substitutions. These substitutions change the specificities of the glycosyltransferases coded by these two alleles. O alleles are inactive due to a single nucleotide deletion in the coding sequence which causes the frame-shift of codons or an amino acid substitution which completely abolishes the activity of the enzyme.
ABO genes are well conserved in mammals.
Comparative studies of primate ABO genes indicated some functional significance of ABO polymorphism during evolution. We have recently launched in collaboration with Dr. Perucho's laboratory, a new project to scan the human genomic DNA for methylation alterations associated with tumorigenesis. In addition to the permanent genetic alterations, other transient epigenetic alterations also play a role in cancer development. CpG island hypermethylation is one of those epigenetic changes, and has been closely correlated with the silencing of transcription of certain genes during tumorigenesis. CpG island methylation is also crucial in several physiological phenomena including the inactivation of X chromosome, cell-type dependent inactivation of certain genes, and imprinting.