Molecular genetics to genomics – historical overview of the ABO research

Abstract

Next‐generation sequencing (NGS) enables the sequencing of thousands of genes, the exomes and even entire genomes in single experiments for $2000 or less. Genome sequencing reveals not only the exome but also the regulatory elements of transcription/translation. RNA sequencing determines which genes and spliced transcripts are expressed. We have been studying the blood group ABO genes, A and B glycosyltransferases (AT/BT), and A/B oligosaccharide antigens since we cloned human AT cDNAs in 1990. We have applied diverse scientific disciplines including genetics, biochemistry, enzymology and glycobiology to those studies and demonstrated the central dogma of ABO: A/B alleles at the ABO genetic locus encode AT/BT, which synthesize A/B antigens, respectively. We identified 4 amino acid substitutions between AT and BT and inactivating mutations in O alleles, elucidating the allelic basis of ABO. We became the first who succeeded in genotyping the ABO locus, discriminating AA/AO genotypes, as well as BB/BO, which was impossible by the immunological approach. We have also demonstrated mutations in several subgroup alleles and cis‐AB and B(A) alleles. Taking advantage of big data recently generated on genome sequences and associated information deposited in public databases, we expanded our research from humans to other organisms, as well as from ATs/BTs and ABO genes to evolutionarily related α1,3‐Gal(NAc) transferases and their genes. Combining phylogenetic analyses with functional assays we developed, we have successfully scaled up our research to the genomic level, deciphering the molecular mechanisms responsible for important biological phenomena associated with ABO.