The human ABO blood group gene consists of three main alleles (A, B, and O) that encode a glycosyltransferase. The A and B alleles differ by two critical amino acids in exon 7, and the major O allele has a single nucleotide deletion (Δ261) in exon 6. Previous evolutionary studies have revealed that the A allele is the most ancient, B allele diverged from the A allele with two critical amino acid substitutions in exon 7, and the major O allele diverged from the A allele with Δ261 in exon 6. However, a recent phylogenetic network analysis study showed that the A allele of humans emerged through a recombination between the B and O alleles. In the previous study, a restricted dataset from only two populations was used. In this study, therefore, we used a large single nucleotide polymorphism (SNP) dataset from the HapMap Project. The results indicated that the A101-A201-O09 haplogroup was a recombinant lineage between the B and O haplotypes, containing the intact exon 6 from the B allele and the two critical A type sites in exon 7 from the major O allele. Its recombination point was assumed to be located just behind Δ261 in exon 6. 1. Introduction The human ABO blood group consists of three major types, A, B, and O . These alleles code for glycosyltransferases, with the terminal sugar chain modifications varying between types. The enzyme encoded by functional alleles of type A and B transfer a GalNac or a Gal on the precursor oligosaccharides of type H. The nucleotide sequences of the human ABO blood group genes have been previously determined and the molecular basis of these differences has been revealed [2, 3]. The alleles A and B differ in exon 7 by four nonsynonymous mutations, and two of which are critical for the sugar specificity (codons 266 and 268 encode L-G for A and M-A for B). The major O allele has a single nucleotide deletion (Δ261) in exon 6  that induces a frameshift, resulting in a truncated protein deprived of any glycosyltransferase activity. Major haplogroups (A101, A201, B101, O01, O02, and O09) exist in the human ABO blood group genes [5, 6]. A101 and B101 are the main haplogroups for the A and B alleles, respectively. The activity of A201 is reduced 20- to 50-fold compared to A101, because A201 has a point deletion at nucleotide position 1061 that results in a frameshift adding 21 additional amino acid residues to the protein . O01, O02, and O09 are the main haplogroups of the O type. A series of nucleotide differences have been observed between O01 and O02 [5, 6, 8]. Although O09 shares Δ261 with O01 and O02, its sequence is
F. Yamamoto and S. Hakomori, “Sugar-nucleotide donor specificity of histo-blood group A and B transferases is based on amino acid substitutions,” The Journal of Biological Chemistry, vol. 265, no. 31, pp. 19257–19262, 1990.
T. Kitano, A. Blancher, and N. Saitou, “The functional A allele was resurrected via recombination in the human ABO blood group gene,” Molecular Biology and Evolution, vol. 29, no. 7, pp. 1791–1796, 2012.
F. Yamamoto, P. D. McNeill, and S. Hakomori, “Human histo-blood group A2 transferase coded by A2 allele, one of the A subtypes, is characterized by a single base deletion in the coding sequence, which results in an additional domain at the carboxyl terminal,” Biochemical and Biophysical Research Communications, vol. 187, no. 1, pp. 366–374, 1992.
L. Ségurel, E. E. Thompson, T. Flutre et al., “ABO is a trans-species polymorphism in primates,” Proceeding of the National Academy of Sciences of the United States of America, vol. 109, no. 45, pp. 18493–18498, 2012.
T. Kitano, R. Noda, O. Takenaka, and N. Saitou, “Relic of ancient recombinations in gibbon ABO blood group genes deciphered through phylogenetic network analysis,” Molecular Phylogenetics and Evolution, vol. 51, no. 3, pp. 465–471, 2009.
A. Blancher and W. W. Socha, “The ABO, Hh and Lewis blood group in humans and nonhuman primates,” in Molecular Biology and Evolution of Blood Group and MHC Antigens in Primates, A. Blancher, J. Klein, and W. W. Socha, Eds., pp. 30–92, Springer, New York, NY, USA, 1997.