Sequence variation at the human ABO locus

Abstract

The ABO blood group is the most important blood group system in transfusion medicine. Since the ABO gene was cloned and the molecular basis of the three major alleles delineated about 10 years ago, the gene has increasingly been examined by a variety of DNA-based genotyping methods and analysed in detail by DNA sequencing. A few coherent observations emerge from these studies. First, there is extensive sequence heterogeneity underlying the major ABO alleles that produce normal blood groups A, B, AB and O when in correct combination with other alleles. Second, there is also extensive heterogeneity underlying the molecular basis of various alleles producing ABO subgroups such as A # , A x and B $ . There are over 70 ABO alleles reported to date and these alleles highlight the extensive sequence variation in the coding region of the gene. A unifying system of nomenclature is proposed to name these alleles. Third, extensive sequence variation is also found in the non-coding region of the gene, including variation in minisatellite repeats in the 5h untranslated region (UTR), 21 single nucleotide polymorphisms (SNPs) in intron 6 and one SNP in the 3h UTR. The haplotypes of these variations reveal a specific relationship with the major ABO alleles. Fourth, excluding the common alleles, about half of the remaining alleles are due to new mutations and the other half can better be explained by intragenic recombination (both crossover and gene conversion) between common alleles. In particular, the recombination sites in hybrid alleles can be quite precisely defined through haplotype analysis of the SNPs in intron 6. This indicates that recombination is equally as important as point mutations in generating the genetic diversity of the ABO locus. Finally, a large number of ABO genotyping methods are available and are based on restriction analysis, allele specific amplification, mutation screening techniques or their combinations. The ABO blood group system (MIM number : 110300) was discovered by K Landsteiner a century ago. It is the most important blood group system in transfusion medicine. The serological and genetic characteristics of the system and the biosynthesis of its antigens have been well established (Daniels, 1995 ;Watkins, 1980 The antigenic determinants of the system are oligosaccharides found on glycoproteins and glycolipids. As such they are not direct gene products of the ABO gene. Instead, the ABO gene encodes enzymes known as glycosyltransferases which transfer specific sugar residues to a precursor substance (the H antigen) to produce the A and B antigens. There are three major alleles at the ABO locus : alleles A, B and O. The A allele encodes α1 4 3 N-acetylgalactosaminyltransferase (A transferase ; EC 2n4.1n40) which adds N-acetylgalactosamine (GalNAc) to the H antigen to form the A antigen. The B allele encodes α1 4 3 galactosyltransferase (B transferase ; EC 2n4.1n37) which transfers galactose

Identification of Mislabeled Samples and Sample Mix-ups in Genotype Data Using Barcode Genotypes

“…Future versions of Wunderbar may try to incorporate and take advantage of such information. In particular knowledge of sex, and easily obtained phenotypes like eye and hair color [8] as well as blood type [9] and similar phenotypic information that have direct parallels on the genotypic level would be useful to incorporate in the model.…”

Patterns of human genetic variation inferred from comparative analysis of allelic mutations in blood group antigen genes

“…The observed patterns of recurrent mutations across the gene had led many, including the laboratories of Calafell, Olsson, Roubinet, Ogasawara, Seltsam, Yamamoto, Yip, and others to propose that recurrent mutation patches were the result of interchromosomal recombinations, including both crossovers and gene conversions [Calafell et al, 2008;Hosseini-Maaf et al, 2003, 2005Ogasawara et al, 2001;Olsson and Chester, 1998;Roubinet et al, 2004;Seltsam et al, 2003;Yamamoto, 2000;Yip, 2002]. On the basis of sequence homologies of parent alleles, hybrid alleles were identified and breakpoint regions of recombinations proposed.…”

“…Routine screening for a match between donors and recipients in the course of blood transfusion increases the chance of identifying variant phenotypes of donors bearing variant alleles within any one blood group system. Accordingly, a relatively large number of alleles can be documented for each blood group system to enable an unequivocal correlation between the phenotypes and genotypes [Blumenfeld and Huang, 1995;Calafell et al, 2008;Chester and Olsson, 2001;Ferrer-Admetlla et al, 2009;Huang, 2009;Huang et al, 2000b;Olsson and Chester, 2001;Oriol et al, 2000;Seltsam et al, 2003;Yip, 2002]. It should be noted that this way of selection of alleles results in sampling based predominantly on antigen epitopic alterations.…”

Polymorphisms and allele frequencies of the ABO blood group gene among the Jomon, Epi-Jomon and Okhotsk people in Hokkaido, northern Japan, revealed by ancient DNA analysis

“…Recent studies have revealed that the ABO blood group gene possesses a high degree of polymorphisms at the molecular level 19 and that allele frequencies of the ABO gene are different among various populations. [20][21][22][23][24][25][26] Therefore, allele frequencies and distributions of the ABO gene can be appropriate indices for investigating the genetic relationships between populations.…”