Molecular genetics and genomics of the ABO blood group system

The A and B oligosaccharide antigens of the ABO blood group system are produced from the common precursor, H substance, by enzymatic reactions catalyzed by A and B glycosyltransferases (AT and BT) encoded by functional A and B alleles at the ABO genetic locus, respectively. In 1990, my research team cloned human A, B, and O allelic cDNAs. We then demonstrated this central dogma of ABO and opened a new era of molecular genetics. We identified four amino acid substitutions between AT and BT and inactivating mutations in the O alleles, clarifying the allelic basis of ABO. We became the first to achieve successful ABO genotyping, discriminating between AA and AO genotypes and between BB and BO, which was impossible using immunohematological/serological methods. We also identified mutations in several subgroup alleles and also in the cis-AB and B(A) alleles that specify the expression of the A and B antigens by single alleles. Later, other scientists interested in the ABO system characterized many additional ABO alleles. However, the situation has changed drastically in the last decade, due to rapid advances in next-generation sequencing (NGS) technology, which has allowed the sequencing of several thousand genes and even the entire genome in individual experiments. Genome sequencing has revealed not only the exome but also transcription/translation regulatory elements. RNA sequencing determines which genes and spliced transcripts are expressed. Because more than 500,000 human genomes have been sequenced and deposited in sequence databases, bioinformaticians can retrieve and analyze this data without generating it. Now, in this era of genomics, we can harness the vast sequence information to unravel the molecular mechanisms responsible for important biological phenomena associated with the ABO polymorphism. Two examples are presented in this review: the delineation of the ABO gene evolution in a variety of species and the association of single nucleotide variant (SNV) sites in the ABO gene with diseases and biological parameters through genome-wide association studies (GWAS).Copyright © Annals of Blood. All rights reserved.