MBE Advance Access published March 8, 2012

The Functional A Allele Was Resurrected via Recombinationin the Human ABO Blood Group Gene
Takashi Kitano,*,1 Antoine Blancher,2 and Naruya Saitou3
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Department of Biomolecular Functional Engineering, College of Engineering, Ibaraki University, Hitachi, Japan
Laboratoire d’Immunogénétique Moléculaire (LIMT, EA3034), Faculté de Médecine Purpan, Université Paul Sabatier, Toulouse III,
France3
Division of Population Genetics, National Institute of Genetics, Mishima, Japan*Corresponding author: E-mail: tkitano@mx.ibaraki.ac.jp.
Associate editor: Naoko Takezaki
2

Abstract

Key words: ABO blood group, phylogenetic network, recombination.

Introduction
The human ABO blood group system consists of three allele
groups: A, B, and O. The A and B alleles, differing at two
critical sites, code for glycosyltransferases, which transfer
N-acetylgalactosamine and galactose, respectively, to a common precursor called H (Yamamoto et al. 1990; Yamamotoand Hakomori 1990) (for an updated review of the ABO, seealso Yamamoto et al. 2012). The most frequent null O alleles
have a point deletion (D261) in exon 6 (Yamamoto 2000),
which induces a frameshift, resulting in a truncated protein
deprived of any glycosyltransferase activity (Yamamoto et al.
1990). The main conclusions of the previous studies about
the evolution of the ABO gene in the human lineage (e.g.,
Saitou and Yamamoto 1997; Seltsam et al. 2003; Roubinet
et al. 2004; Calafell et al. 2008) can be summarized as follows.
Major alleles A101, B101, O01, and O02 are observed in mosthuman populations. The ancestral allele was A, and B diverged from A with substitutions on the two critical sites
in exon 7, and O diverged from A with one-base deletionin exon 6, followed by the divergence of O01 and O02. Thesemajor alleles are maintained by some kind of positive selection. Although this study agrees with this rough outline,
there is a further finding: the current A type, that is
A101, had been formed by recombination between B101
and O01. We reveal this by conducting a phylogenetic network analysis, which is a powerful tool to find recombination
events.

Materials and Methods
We used the ABO data produced by the Seattle SNPs project (Akey et al. 2004), which is a set of 90 23-kb sequencesin European American and African American. These data
are the same as those used by Calafell et al. (2008), exceptthat sequences of O47, a minor haplotype, were excluded.
A distance-based phylogenetic network (supplementary
fig. S1, Supplementary Material online) of 58 haplotypes(from 90 sequences) of the human ABO blood group genes(supplementary table S1, Supplementary Material online)
was constructed by using the Neighbor-Net method(Bryant and Moulton 2004) implemented in the SplitsTree4
program (Huson and Bryant 2006). When a gorilla sequence(Kitano T, Kim CG, Kohara Y, Saitou N, unpublished data)
was included in the phylogenetic network (supplementary
fig. S1, Supplementary Material online), it clustered withthe chimpanzee sequence in an outgroup to all the humansequences. Thus, we decided to use only the chimpanzee
sequence (supplementary table S1, Supplementary Material
online) as the outgroup in further analyses. The six representative human haplotypes (O02_H29, O01_H49, O09_H07,
A201_H41, A101_H11, and B101_H19), which represent
the most frequent alleles of each haplogroup (Calafell
et al. 2008), were used for further analyses (fig. 1). Basedon the phylogenetic network of 58 haplotype sequencesof the human ABO blood group genes (supplementary
fig. S1, Supplementary Material online), it is clearly shownthat these six representative haplotypes are not outliers
but are representative of each haplogroup.
Phylogenetic networks were also constructed manuallyfollowing the procedure of Bandelt (1994) and Saitou andYamamoto (1997). Phylogenetic trees were constructed byusing the neighbor joining method (Saitou and Nei 1987)
with p distance. MEGA version 4 (Tamura et al. 2007) wasused to edit variable positions, which were used in the construction. Gene conversion among three haplotypes(O02_H29, O01_H49, and B101_H19) was detected bymeans of GENECONV (Sawyer 1989). Because it is clear© The Author 2012. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, pleasee-mail: journals.permissions@oup.com

Mol. Biol. Evol. doi:10.1093/molbev/mss021

Advance Access publication January 27, 2012

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Research
articleFunctional A and B alleles are distinguished at two critical sites in exon 7 of the human ABO blood group gene. The mostfrequent nonfunctional O alleles have one-base deletion in exon 6 producing a frameshift, and it has the A type signaturein two critical sites in exon 7. Previous studies indicated that B and O alleles were derived from A allele in human lineage.
In this study, we conducted a phylogenetic network analysis using six representative haplotypes: A101, A201, B101, O01,
O02, and O09. The result indicated that the A allele, possibly once extinct in the human lineage a long time ago, wasresurrected by a recombination between B and O alleles less than 300,000 years ago.

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that A101 as well as with A201 and O09 evolved from a recombinant allele, three haplotypes were excluded from thesearch of gene conversion analysis.

Results and Discussion
Six representative human ABO haplotype sequences wereselected (see Materials and Methods; fig. 1) for the phylogenetic network analysis. As shown in figure 1, 11 sites areshared by only O01 and O02 (yellow partitions). Although
O09 shares D261 with O01 and O02 alleles, its sequence is,by and large, quite similar to A101. Thus, the O09 allele
most probably evolved from an A101-like common ancestral allele by a gene conversion on exon 6, introducing D261
from some other O allele. The enzyme encoded by the allele
A201 is a weaker NAcGal-transferase than the enzyme encoded by the A101 allele and has 21 supplementary aminoacids of the C-terminal compared with the A101 protein
because of a frameshift caused by a point deletion in
the antepenultimate codon resulting (Yamamoto et al.
1992).
Large reticulations are observed in this phylogenetic network of the six haplotypes (fig. 2). Kitano et al. (2009)
showed the relationship among recombinant and parental
alleles in a phylogenetic network. To explain how to infera recombination event from a phylogenetic network, we
use model data (fig. 3). First, an ancestral sequence(anc) produces two sequences (p1 and p2) by accumulating five (indicated by blue letters in fig. 3A and blue lines in
fig. 3B) and four substitutions (indicated by red letters in
fig. 3A and red lines in fig. 3B), respectively. Then, a recombination between sites 6 and 7 produces two recombinants, r1 and r2 (fig. 3A). Assuming that r1 and r2 were
produced by a single recombination event, transmissionof both recombinant alleles to the next generation is highly
improbable. We assumed that r2 had disappeared. Afterthe recombination, three nucleotide substitutions (sites
7, 12, and 13 indicated by green letters in fig. 3A and green
lines in fig. 3B) accumulate to p1, p2, and r1, respectively,
and also three nucleotide substitutions (sites 3, 10, and 14
indicated by orange letters in fig. 3A and orange lines in
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fig. 3B) accumulate to produce an outgroup (out). The phylogenetic network (fig. 3B) represents the relationship of
the three present-day alleles (p1, p2, and r1) and an outgroup allele (out). Two parental alleles (p1 and p2) are located on opposing vertices of the rectangle with longexternal branches, whereas a recombinant allele (r1) has
a short external branch and is located on the vertex opposing to the outgroup allele (out). A nucleotide substitution(site 7) on the short external branch of a recombinant allele(r1) is regarded as a nucleotide substitution, which occurs
after the recombination event. In contrast, long externalbranches of two parental alleles (p1 and p2) contain nucleotide substitutions both before (9 and 15 for p1, and
1 and 6 for p2) and after (13 for p1 and 12 for p2) therecombination event.
Following this model, we can infer that A101 is a recombinant lineage, whereas B101 and O01 are parental allele lineages because O01 and B101 are located on opposing
vertices of the rectangle with long external branches,
whereas A101 has a short external branch and is locatedon the vertex opposing to the outgroup (fig. 2). In fact,

FIG. 2. The phylogenetic network for six major haplotypes (O02,
O01, O09, A101, A201, and B101) of the human ABO genes withchimpanzee A. The color of each branch indicates each partition infigure 1. Numbers on each branch denote numbers of substitutions.
Five parallel substitutions are also shown (site 96: P1, site 107: P2,
site 129: P3, site 156: P4, site 202: P5, in which P1, P3, and P5 wereparallel with chimpanzee A).

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FIG. 1. Parsimony informative sites for six major haplotypes (O02, O01, O09, A201, A101, and B101). Corresponding chimpanzee A sites are also
shown. Site numbers followed figure 2 of Calafell et al. (2008). Two sites (197 and 198) enclosed by a red square are two critical sites (codons
266 and 268), which determine A/B activity in exon 7. The site 160 enclosed by a black square is D261 in exon 6. Some exons are shown byboxes below. Untranslated regions (UTRs), some exons (E), and introns (I) are indicated. Partitions indicate dividing patterns: dark blue ([A101,
A201, O09, B101], [ChimpA, O02, O01]), yellow ([O02, O01], [ChimpA, A101, A201, O09, B101]), purple ([Chimp, O02, O01, A101], [O09, A201,
B101]), light blue ([O01, A101, A201, O09, B101], [ChimpA, O02]), green ([O01, A101, A201, O09], [ChimpA, O02, B101]), brown ([Chimp,O01], [O02, O09, A201, A101, B101]), orange ([Chimp, O02, O01, A101, B101], [O09, A201]).

A Allele Was Resurrected via Recombination · doi:10.1093/molbev/mss021

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FIG. 3. Explanation of a recombination in a phylogenetic network byusing model data. A nucleotide sequence data (A) and a corresponding phylogenetic network (B) are shown. See text for thedetails.

the upstream region of A101 is similar to B101, whereas its
downstream region is similar to O01 (fig. 4A). The recombination occurred immediately after D261 or site 160 infigure 4A. The phylogenetic trees of the upstream andthe downstream regions (fig. 5) clearly show different

branching patterns, confirming that allele A was derived
from a recombination event between B101 and O01 lineages. As for allele O01, it looks like a mosaic of B101 andO02 (fig. 4B). In addition, we detected three gene conversions among O02, O01, and B101 (supplementary fig. S2,
Supplementary Material online) using GENECONV (Sawyer
1989).
The figure 6 describes an evolutionary scheme of the six
major alleles of the human ABO gene. We assume A as

FIG. 4. Parsimony informative sites among some representative haplotypes. (A) Parsimony informative sites among O01, A101, and B101,
extracted from figure 1. Site numbers followed figure 2 of Calafell et al. (2008). Untranslated regions (UTRs), some exons (E), and introns (I) areindicated. O01 (green background) and B101 (blue background) are putative parental alleles for the recombinant allele A101. Two sites
enclosed by a red square are two critical sites (codons 266 and 268), which determine A/B activity. The site enclosed by a black square is D261.
(B) Parsimony informative sites among O02, O01, and B101, extracted from figure 1. O02 and B101 are shown by purple and blue backgrounds,
respectively.

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FIG. 5. Phylogenetic trees of the upstream region (A) and thedownstream region (B) of the data by using the neighbor joining
method. These two regions are divided by the midpoint betweensites 160 and 161. Compared sites are 19,068 bp and 2,086 bp foreach tree construction. A101, A201, and O09 are enclosed by a blacksquare. The chimpanzee A allele is used as an outgroup, andmidpoint rooting was used. Percent of bootstrap values are shownon each branch.

Kitano et al. · doi:10.1093/molbev/mss021

ancestral type in humans because chimpanzees mainly
have A alleles (Blancher and Socha 1997; Kermarrec
et al. 1999; Sumiyama et al. 2000). Under the assumptionof the evolutionary rate (k 5 d/2T) of 1.1 ! 10"9 (with ‘‘d’’
the genome-wide distance value between humans andchimpanzees being 0.0127, The Chimpanzee Sequencing
and Analysis Consortium (2005), and ‘‘T’’ the human/chimpanzee divergence time being 6 Ma), the divergence time of
the lineage leading to B was estimated to be approximately
2.08 Ma from ‘‘m’’ the mean pairwise distance between
B101_H19 and O02_H29/O01_H49 (m 5 0.0044). The divergence time between O01 and O02 lineages was approximately 1.98 Ma from the mean distance between
O01_H49 and O02_H29 (m 5 0.0042). According to theestimated divergence times of haplotype lineages, the lineage leading to B first diverged more than 2 Ma, followed by
the divergence between the lineages leading to O01 andO02 alleles.
Probably the point deletion (D261) for the major O alleles appeared only once in early human evolution because
it is highly improbable that such a deletion occurred at exactly the same position more than once during this period(Roubinet et al. 2004). Roubinet et al. (2004) also mentioned that point deletions are rarely observed among
the human ABO alleles. Human O alleles appeared about
2 Ma in our estimation. Because O alleles are nonfunctional, it may be possible to accumulate additional deteriorating mutations over the 2 myr. But no stop codon orindels other than D261 observed in the O alleles. To examine how likely it is for deteriorating mutations to occur in O
alleles, we carried out the following calculations to obtaina rough estimate of numbers of mutations causing additional stop codon(s) and frameshift(s) on O alleles. The
ABO functional glycosyltransferases have 354 amino acids,
and the proportion of potential codons that can be a stopcodon by a single nucleotide substitution (such as UGU,UGC, UGG, UUA, UCA, CGA, GGA, and AGA for a stopcodon UGA) is about 0.3 [5 18/(64"3)]. Because O
4

alleles are nonfunctional, let us use the rate of synonymous
substitutions. Kitano et al. (2004) compared 103 proteincoding genes for hominoids. The average number ofsynonymous substitutions per synonymous site between
human and chimpanzee was 0.0157 from their data. If
we assume the average coalescence time of gene between
human and chimpanzee to be 6 Ma, the average rate ofsynonymous substitutions in the human and chimpanzee
lineage becomes 1.3 ! 10"9. If we use this estimate, theexpected number of the newly created stop codons in
the locus is estimated to be about 0.27 (5 0.3 ! 354 !
1.3 ! 10"9 ! 2 ! 106). On the other hand, the expected
number of the newly created indels (insertion and deletion)in the locus becomes about 0.42 (5 354 ! 3 ! 2.0 ! 10"10! 2 ! 106) since the indel rate for nuclear noncoding nucleotide sequences in the primate linage was estimated by
up to 2.0 ! 10"10 (Saitou and Ueda 1994). Therefore, it is
not surprising that no additional stop codon and/or frameshift appeared during the only 2 myr history of thenonfunctional O allele.
There are some distinct O lineages, such as O01, O02,
and O09, and these appearances might be independent
events by acquiring D261 by interallelic exchanges (Calafell
et al. 2008). This is exactly the case for the allele O09 because it is almost similar with A101 except for D261.
Roubinet et al. (2004) also suggested that the two major
O alleles, O01 and O02, have persisted by genetic drift
in the human population because in all human populations
studied so far, O01 and O02 are present, though in variable
proportions, and they are nonfunctional and therefore
have identical selective values.
Although modern humans have three allele types, several primates have fewer ones (Blancher and Socha 1997).
For example, chimpanzees have only A and O alleles and all
gorillas’ alleles are B. Therefore, it is possible that humanancestors only had B and O alleles during a certain period.
The A type allele was resurrected by the recombination,that is, the intact exon 6 from B101 and A type two criticalsites in exon 7 from O01 had been jointed to form the recombinant resurrected functional A allele as the A101. To
estimate the recombination time between B101 and O01
lineages, we used the mean pairwise distance in the upstream region (1–19,176) between B101_H19 and
A101_H11/A201_H41/O09_H07 (m 5 0.0005) and themean distance in the downstream region (19,177–
22,328) between O01_H49 and A101_H11/A201_H41/
O09_H07 (m 5 0.0006). These regions are same as thoseused in figure 5. The estimates of the recombination time
between B101 and O01 from the two regions were very
close (ca. 0.24 and 0.28 Ma). Thus, we conclude that the recombination time between B101 and O01, which resulted in
the resurrected A lineage, was around 260,000 years ago.
It may be speculated that Homo erectus had only B andO alleles until its later stage. O01 type alleles were found in
two Neandertal individuals (Lalueza-Fox et al. 2008). Thissuggests that the frequency of O allele was quite highamong Neandertals. The resurrection of the A allele wasbefore the emergence of anatomically modern humans,

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FIG. 6. A scheme of the evolutionary pathway of major alleles of thehuman ABO genes. A, B, and O lineages are shown by red, blue, andblack lines, respectively. Three gray horizontal lines with arrowheads
on both ends indicate gene conversions. One nucleotide deletion(D261) for O02, possible transfer of D261 for O01, and two aminoacid substitutions for B101 are shown. Because times of each geneconversion event, the D261 deletion, transfer of D261, and two
amino acid substitutions for B101 cannot be estimated, these
positions are located arbitrarily.

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A Allele Was Resurrected via Recombination · doi:10.1093/molbev/mss021

Supplementary Material
Supplementary figures S1–S2 and table S1 are available at
Molecular Biology and Evolution online (http://
www.mbe.oxfordjournals.org/).

Acknowledgments
We thank the Associate editor Naoko Takezaki and threeanonymous reviewers for their valuable comments. This
study was supported by the National Institute of Genetics
Cooperative Research Program (2009-A68, 2010-A23, and2011-A14).

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and it possibly occurred in Africa. Nowadays, the A101 is
distributed throughout the world as one of the major typesof the human ABO gene. It is reasonable to assume that the
rapid increase of A101 frequency could have been favoredby some kind of positive selection. Meanwhile, even nowadays recombinations are at work to produce some rarevariant alleles (e.g., Suzuki et al. 1997; Olsson and Chester
1998; Ogasawara et al. 2001; Yip 2002).
Various mechanisms were invoked to explain natural selection that has possibly been operating on the ABO polymorphism; 1) the ABO antigens expressed by epithelial cells
are targeted by various infectious agents, which use themto stick the cell surface, 2) in individuals of the secretor type(they express ABO antigens in secretions), mucins bear the
ABO substances and inhibit the binding of aggressive infectious agents to epithelial cells, and 3) the ABO polymorphism influences the fate of endogenous glycoproteins,
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intensely express the H antigen, the precursor of A and B
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In this context, the mechanisms that have favored themaintenance of the ABO polymorphism could have varied
a long time to face the evolution of the infectious agents,
leading to an arms race or a red queen type of evolution, ora frequency-dependent selection of alleles.

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