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Genetic basis of blood group diversity
Jill R. Storry and Martin L. Olsson
Blood Centre, University Hospital and Department of Transfusion Medicine, Institute of Laboratory Medicine, Lund, Sweden
Summary
In the last 18 years the genes that encode all but one of the 29
blood group systems present on red blood cells (RBCs) have
been identified. This body of knowledge has permitted the
application of molecular techniques to characterize the com-
mon blood group antigens and to elucidate the background for
some of the variant phenotypes. Just as the RBC was used as a
model for the biochemical characterization of cell membranes,
so the genes encoding blood groups provide a readily accessible
model for the study of gene expression and diversity. The
application of genotyping techniques to identify fetuses at risk
of haemolytic disease of the newborn is now the standard of
care, and the expansion of nucleic acid testing platforms to
include both disease testing and blood typing in the blood
centre is on the horizon. This review summarizes the
molecular basis of blood groups and illustrates the mechanisms
that generate diversity through specific examples.
Keywords: blood group, allele, molecular techniques, geno-
typing, genetic diversity.
For well over a century, blood group antigens have been
recognized as differences between the red blood cells (RBCs) of
one person and another. Antigens have been defined by human
antibodies, immune and naturally occurring, as well as those
deliberately stimulated in animals. Assignment of blood group
antigen status requires the novel factor to be inherited from
one generation to the next, thus demonstrating that blood
group antigens were the products of genes. Many of the
cellular components that carry blood group antigens have been
identified and characterized and indeed, the RBC has provided
a useful model for the study of cell membranes. Concurrently,
the genes encoding the blood group proteins have been
mapped to different chromosomes throughout the genome.
The development of DNA sequencing techniques, and then the
polymerase chain reaction (PCR) has paved the way for the
rapid molecular characterization of the genes encoding blood
group antigens, such that, in the last 18 years, all but one of
the 29 blood group genes have been characterized. This
knowledge, combined with continual improvements in gene
analysis are changing the way in which testing can be
performed.
Blood group antigens are part of carbohydrate or protein
structures exposed on the extracellular surface of the RBC
membrane. In blood group nomenclature, antigens encoded by
the same gene, or cluster of genes, are assigned to the same
blood group system. Each system may consist of one or more
antigens. Proteins that are glycosylated by N-linked glycans,
e.g. band 3 also carry carbohydrate antigens, like ABH and I
antigens. Currently, 29 blood group systems, which include a
total of 240 antigens, have been established by the Interna-
tional Society of Blood Transfusion (ISBT) Committee on
Terminology for Red Cell Surface Antigens. In addition, 38
antigens not yet fulfilling the requirements for classification
into a system have been gathered in collections or series of
high- and low-frequency antigens (Daniels et al, 2003). These
numbers are not static and new blood group antigens are
identified by unusual serological findings each year.
This review will discuss the genes and polymorphisms
underlying the expression of human blood group systems. A
comprehensive summary of information detailing the genesand carrier molecule(s) for each blood group system has been
collated in Table I and the single nucleotide polymorphisms
(SNPs) associated with some clinically important antigens are
shown in Table II.
References describing the cloning of the genes and the
identification of the specific polymorphisms are given in the
appropriate table. In addition, a selection of relevant references
is given throughout the text, mostly the ones that serve as
illustrative examples of different genetic principles. Additional
papers describing the elucidation of the polymorphisms
responsible for the blood group antigens within each system
can be retrieved via the GenBank accession numbers given in
Table I and at the Blood Group Antigen Database (http://
www.bioc.aecom.yu.edu/bgmut/index.htm). The interested
reader is also referred to current textbooks and reviews, a
few examples of which can be found in the reference list (Issitt
& Anstee, 1998; Reid & Yazdanbakhsh, 1998; Daniels, 2002;
Reid & Lomas-Francis, 2003).
In general, antigens belonging to blood group systems are
better characterized at the molecular level than those antigens
assigned to a collection or series. In most instances, the paucity
of genetic data regarding the latter antigens prevents assign-
Correspondence: Martin L. Olsson, Blood Centre, University Hospital
and Department of Transfusion Medicine, Institute of Laboratory
Medicine, Lund, Sweden. E-mail: [email protected]
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Table
I.
Summaryofinformationon
genesandgeneproductsinthecurrentlyacknowledgedbloodgroupsystems.
ISBT
Name
ISBT
number
ISBT
system
symbol
Ch
romosome
loc
ation
ISGN
gene
symbol
Genbank
account
number*
Gene
product
Protein
type
Apparent
mass
(kDa)
Number
ofamino
acids
CD
number
Numberof
antigens
Cloni
ngreference
ABO
1
ABO
9q342
ABO
NM_
020469
a3GalNAcT,a3GalT
II
n.a.
354
4
Yama
motoetal(1990b))
MNS
2
MNS
4q282-q311
GYPA
NM_
002099
Glyco
phorinA
I
36
131
CD235a
43
SiebertandFukuda(1986)
GYPB
NM_
002100
Glyco
phorinB
I
24
72
CD235b
SiebertandFukuda(1987)
P
3
P1
22q112-ter
P1
a4GalT?
-
n.a.
1
Rh
4
RH
1p3613-p343
RHD
RHCE
NM_
016225
NM_
138618
RhD
RhCE
M-12
M-12
3032
417
417
CD240D
CD240CE
48
Aventetal(1990),
Cheri
f-Zaharetal(1990),
LeVa
nKimetal(1992),
Arceetal(1993),
Kajii
etal(1993)
Lutheran
5
LU
19q132
LU
NM_
005581
Luthe
ranglycoprotein(IgSF)
I
7885
597
CD239
19
Parso
nsetal(1995)
B-CA
M
(IgSF)
I
557
Kell
6
KEL
7q33
KEL
NM_
000420
Kellg
lycoprotein
II
93
732
CD258
24
Leeetal(1991)
Lewis
7
LE
19p133
FUT3
NM_
000149
a3/4F
ucT
II
n.a.
361
6
Kukowska-Latalloetal(1990)
Duffy
8
FY
1q21-q25
DARC
NM_
002036
DARC,
Duffyglycoprotein
M-7
3545
338
CD234
6
Chaudhurietal(1993)
Kidd
9
JK
18q11-q12
SLC14A1
NM_
015865
HUT,
Kiddglycoprotein
M-10
50
389
3
Olivesetal(1994)
Diego
10
DI
17q12-q21
SLC4A1
NM_
000342
AE-1,
Band3
M-14
90
911
CD233
21
Tanneretal(1988),
Luxe
tal(1989)
Yt
11
YT
7q22
ACHE
NM_
015831
Acety
lcholinesterase
GPI
160
557
2
Lietal(1991)
Xg
12
XG
Xp
2232
XG
NM_
175569
Xgglycoprotein
I
2229
180
CD99
2
Darlingetal(1986),
Ellisetal(1994)
Scianna
13
SC
1p34
ERMAP
NM_
018538
ERMAP(IgSF)
I
60
475
4
Yeet
al(2000)
Dombrock
14
DO
12p132-p121
ART4
NM_
021071
ADP-
ribosyltransferase4
GPI
5457
314
5
Gubinetal(2000)
Dombrockglycoprotein
Colton
15
CO
7p14
AQP1
NM_
000385
CHIP
,Aquaporin-1
M-6
28or50
269
3
PrestonandAgre(1991)
Landsteiner-
Wiener
16
LW
19p132-cen
ICAM4
NM_
022377
ICAM
-4
LWg
lycoprotein(IgSF)
I
42
241
CD242
3
Bailly
etal(1994)
Chido-
Rodgers
17
CH/RG
6p213
C4A
C4B
NM_
007293
NM_
000592
Complementfactor4A
Complementfactor4B
S S
n.a.
1741
1744
9
Yuet
al(1986),
Yu(1991)
Hh
18
H
19q133
FUT1
NM_
000148
a2FucT
II
n.a.
365
CD173
1
Kelly
etal(1994)
Kx
19
XK
Xp
211
XK
NM_
021083
Xkglycoprotein
M-10
37
444
1
Hoetal(1994)
Gerbich
20
GE
2q14-q21
GYPC
NM_
002101
GPC
I
32
128
CD236R
7
Colin
etal(1986)
GPD
I
23
107
CD236
Cromer
21
CROM
1q32
DAF
NM_
000574
DAF
GPI
70
347
CD55
12
Caras
etal(1987),
Medo
fetal(1987)
Knops
22
KN
1q32
CR1
NM_
000573
CR1
I
170280
1998
CD35
8
Wongetal(1989)
Indian
23
IN
11p13
CD44
NM_
000610
Herm
esantigen
I
80
341
CD44
2
GoldsteinandButcher(1990),
Harn
etal(1991)
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Table
1.
(continued)
ISBT
Name
ISBT
number
ISBT
system
symbol
Ch
romosome
loc
ation
ISGN
gene
symbol
Genbank
account
number*
Geneproduct
Protein
type
Apparent
mass
(kDa
)
Number
ofamino
acids
CD
number
Numberof
antigens
Cloningreference
Ok
24
OK
19p133
BSG
NM_
001728
Neurothelin,
basigin
I
356
9
248
CD147
1
Guoetal(1998)
Raph
25
RAPH
11p155
MER2
NM_
004357
MER2
M-4
40
253
CD151
1
Hasegawaetal(1996)
JMH
26
JMH
15q223-q23
SEMA7A
NM_
003612
H-Sema-L
GPI
758
0
656
CD108
1
Yamadaetal(1999)
I
27
I
6p24
GCNT2
NM_
145649
b6GlcNAcT
II
n.a.
400
1
Bierhuizenetal(1993)
Globoside
28
GLOB
3q25
B3GALT3**
NM_
033169
b3GalNAcT1,Psynthase
II
n.a.
331
1
Amadoetal(1998)
GIL
29
GIL
9p13
AQP3
NM_
004925
Aquaporin-3
M-6
45
292
1
Inaseetal(1995)
*SeveraldifferentGenBankentriesmay
existforeachsystem;n.a.,notapplicable.Mostaccessionnumbersgivenwereretrievedfrom
http://www.gene.ucl.ac.uk/cgi-bin/nomenclature/searchgenes.p
linJuly
2003.
TypeIandIIaresinglemembranepa
ssmoleculeswiththeiramino-orcarboxyterm
inalsoutsidethecell(insidetheGolgiforgly
cosyltransferases)respectively.
M-nisamultimembranepassmolecule
thattraversesthemembranentimes;G
PIisamoleculeanchoredtotheRBCmemb
raneviaaglycosylphosphatidylinositollink;S
isamoleculethatisfoundinitssolubleform
inplasmabuthasbeen
adsorbedtotheRBCmembraneandc
ovalentlyboundtolysineresidues.
Insomeinstancesthenumberofaminoacidsgivenmayvarybetweendifferentva
riants/formsofthemolecule.
Whilsttheprimarygeneproductistheglycosyltransferasegiven,thebloodgroup
antigensarecarriedbycarbohydratestructuresonglycoproteinsand/orglycolipids.
ThesizegivencorrespondstothefulllengthofC4.ObservethattheC4dfragmen
tonlyisadsorbedandboundtotheRBCandcarriestheCH/RGantigens.
**Currentgenenamebasedontheerr
oneousassignmentofthegeneproductasab3-galactosyltransferase.
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ment of these antigens to a specific blood group system.
However, there are exceptions in both cases. For example, the
gene responsible for expression of P1 antigen in the P blood
group system has not been identified. Despite this, it has been
acknowledged as a system of its own since it was declared
independent of all other blood group systems. The opposite is
true for the Pk blood group antigen, currently residing in
collection 209. The locus responsible for Pk blood group
antigen expression was unambiguously shown to be a 4-a-
galactosyltransferase gene (A4GALT) on the long arm of
chromosome 22 (Steffensen et al, 2000). However, since its
relation to the P blood group system (also coded for by a locus
on the long arm of chromosome 22 according to family
studies) is unclear, it remains in the GLOB collection until this
issue has been resolved.
Molecular mechanisms that generate bloodgroup diversity
Diversity in the human genome arises through a number of
different mechanisms (Table III) but the most common is the
SNP. SNPs are predicted to account for much of the diversity
observed between subjects of the same or even closely related
species. The 142 million SNPs originally reported in a genomic
map of human genetic variation was just a first hint of the true
number of SNPs (Sachidanandamet al, 2001). Since the initial
sequencing and mapping of the human genome, the number of
SNPs reported has grown exponentially and over 2 million
SNPs have been identified and validated (http://www.ncbi.-
nih.gov/SNP/index.html).
SNPs in exon sequences
The SNPs can be silent or affect the translated gene product,
either as missense mutations, or non-sense mutations. Single
amino acid substitutions resulting from missense mutations in
exon sequences are common. Accordingly, it is not surprising
that it has been estimated that two thirds of all blood group
antigens are defined by missense SNPs in blood group genes
(Reid & Yazdanbakhsh, 1998). SNPs associated with some
important pairs of antithetical antigens are listed in Table II.
Non-sense SNPs are those that cause an immediate (and
premature) stop codon e.g., a T>A mutation in the FY gene
occurring at different points in three unrelated people of the
Fy(ab) phenotype resulted in the substitution of tryptophan
by a premature stop codon (Rios et al, 2000a). The mutationsat nucleotide 287, 407 or 408 demonstrate the effect of
premature stop codons on protein synthesis, since there was no
detectable Duffy protein present on the RBCs.
SNPs cannot only alter the antigen expressed by a certain
blood group molecule but also modify the number of copies
expressed in the RBC membrane. This is well illustrated by the
many RHD alleles in which a SNP results in weakened
expression of the D antigen. Indeed, a single nucleotide change
can have a profound effect on the amount of D antigen
expressed at the RBC surface, reducing the amount by as much
Table II. Single nucleotide polymorphisms (SNPs) associated with selected antigens in some important blood group systems.
System symbol Antige n 1 Critical SNP (amino acid change) Antigen 2 Reference
ABO A C796A, G803C* (Leu266Met, Gly168Ala) B Yamamoto et al(1990a)
MNS M C59T, G71A, T72G (Ser1Leu, Gly5Glu) N Siebert and Fukuda (1986)
S T143C (Met29Thr) s Siebert and Fukuda (1987)
RH C T307C* (Ser103Pro) c Mouro et al (1993), Simseket al(1994)
E C676G (Pro226Ala) e Mouro et al (1993), Simseket al(1994)
LU Lua A252G (His77Arg) Lub El Nemer et al (1997), Parsons et al(1997)
Aua A1637G (Thr539Ala) Aub Parsons et al(1997)
KEL K1 T698C (Met193Thr) K2 Lee et al(1995)
Kpa T961C (Trp281Arg) Kpb Lee et al(1996)
FY Fy a G125A (Gly42Asp) Fy b Chaudhuri et al (1995), Iwamoto et al(1995),
Mallinson et al (1995), Tournamille et al(1995b)
JK Jk a G838A Asp280Asn Jk b Olives et al(1997)
DI Dia C2561T (Leu854Pro) Dib Bruce et al(1994)
Wra G1972A Glu658Lys Wrb Bruce et al(1995)
YT Yta C1057A (His353Asn) Ytb Bartels et al(1993)
SC Sc1 G169A (Gly57Arg) Sc2 Wagner et al(2003)
DO Doa A793G (Asn265Asp) Dob Gubin et al(2000)
CO Co
a
C134T (Ala45Val) Co
b
Smith et al(1994)LW LWa A308G (Gln70Arg) LWb Hermand et al(1995)
CROM Tca G155T (Arg18Leu) Tcb Lublin et al(2000)
IN Ina C252G (Pro46Arg) Inb Telen et al(1996)
*Additional missense mutations that differ between these alleles can occur.
Another missense mutation at this position encodes a blood group antigen of very low prevalence that is antithetical to antigen 1 and antigen 2.
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as 100-fold (Wagner et al, 1999, 2000). Another interesting
example is the Fyx phenotype, in which a missense mutation
that encodes an amino acid change in an intracellular loop of
the molecule results in less Duffy glycoprotein on the cell
surface (Olsson et al, 1998; Parasol et al, 1998; Tournamille
et al, 1998). The SNP that encodes the Kpa polymorphism not
only results in the altered antigen specificity but also affects
trafficking of the Kell glycoprotein to the RBC surface so that
there is a reduced expression of Kell in the cell membrane
whilst increased amounts can be found intracellularly (Ya-
zdanbakhshet al, 1999).
Evolutionary pressure from various pathogens is generally
thought to be responsible for the generation of genetic
variants, the host effects of which determine whether or not
they will survive over time. This has been discussed with a
main focus on microbial pathogens, e.g. relating to the
differences in carbohydrates expressed on cell surfaces
(Gagneux & Varki, 1999) but there is also strong evidence
for the role of malaria on the genetic variants of some of the
integral RBC membrane proteins, such as the Duffy glycopro-
tein and the RBC anion exchanger (AE1; band 3) (Milleret al,1976; Bruce & Tanner, 1999).
SNPs in introns and regulatory regions
The splice sites are crucial for exon fusion when the introns are
removed by the splicing machinery of the cell during the
maturation of hnRNA to mRNA. Mutations that affect the
invariant GT at +1 and +2 of the 5-donor splice site or
the invariant AG at 1 and 2 of the 3-receptor splice site
will cause skipping of the preceding or succeeding exons
respectively. Mutations of the less conserved nucleotides of the
splice site recognition sequence can also affect exon processing
and cause exon skipping. The Jknull phenotype in Polynesians
(Irshaidet al, 2000) and some K0phenotypes (Lee et al, 2001)
are examples of how this phenomenon can alter the RBC
phenotype. Individuals whose RBCs carry null phenotypes,
such as the Jknull and K0 phenotypes, are at risk of immun-
ization by blood transfusion or pregnancy and once immun-
ized, will require the provision of rare blood for any further
transfusion therapy. The SsU+w phenotype in African-
Americans also arises from exon-skipping events due either to
a mutation in the intron 5 splice site or to mutations in exon 5
that activate a cryptic splice site (Storryet al, 2003). The SNP
responsible for the Dr(a) phenotype in the Cromer blood
group system, also creates a cryptic splice site in the DAFgene
that is used preferentially (Lublin et al, 1991). The product of
the alternative splicing is not found on the RBC surface and
consequently, Dr(a) RBCs express only 40% of normal levels
of DAF.
The SNPs that occur in the regulatory elements, such as the
promoter or enhancer regions of blood group genes, canmodify or abolish antigen expression. A well-known example
of such modification is the altered tissue distribution of the
Duffy blood group antigens commonly found in individuals of
African origin. A disruption of the GATA-1 motif in the
promoter region of the FY*B gene by a single nucleotide
substitution abolishes erythroid expression whilst the molecule
is expressed normally in other tissues (Tournamille et al,
1995a). This mutation is a perfect illustration of evolutionary
pressure exerted by a pathogen since the Duffy protein is the
exclusive receptor on mature RBCs for the malarial parasite,
Table III. Molecular mechanisms that generate diversity in blood group genes.
Type of change Molecular mechanism Example of gene event Phenotypic consequence
Antithetical antigen Missense SNP KEL 698C>T K2fiK1 antigen
Novel antigen Missense SNP GYPB161G>A Mit+
Equal crossover between homologous genes GYP(B-A) Ss+wU, Dantu+
DNA conversion between homologous genes RH(D-CE-D) DVI, BARC+
Exon duplication GYPC.Lsa Ls(a+)
Reduced amount of
expected antigen
Missense SNP ABO646T>A Ax
FY298C>T Fy x
CROM596C>T Dr(a)
Splice site mutation GYPB intron 5 +5g>t SsU+w
XK intron 2 +5g>a McLeod phenotype:
weakened Kell antigens
No protein product Non-se nse SNP DO 442T>C Gy(a)
Nucleotide deletion RHAG 1086delA RhnullCO 232delG Co(ab)
Mutation in transcription motif FY46T>C Fy(ab)
Splice site mutation DO intron 1 2a>g Gy(a)
Gene deletion DRHD D
D
GYPA En(a)Modifying gene In(LU) Lu(ab)
*SNP, single nucleotide polymorphism; D, deletion.
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Plasmodium vivax (Miller et al, 1976). The Duffy protein is
absent from the RBCs of up to 100% of native West Africans
and consequently, these individuals are protected fromP. vivax
infection. Furthermore, the same evolutionary pressure is
proposed to have driven the identical mutation in the GATA-1
sequences of the FY*A allele in a Papua New Guinean
population but, interestingly, the mutation is thought to be a
much more recent and unlinked event (Zimmerman et al,
1999).
Other mechanisms that contribute to blood group diversity
While single nucleotide changes can have far-reaching conse-
quences on gene product expression and function, there are
also other mechanisms that contribute to diversity. Gene
rearrangements due to recombination or gene conversions
between homologous genes, such as those encoding the Rh and
MNS blood group systems, can affect blood group expression
in many different ways (Blumenfeld & Huang, 1997; Avent,
2001). Surprisingly, the same is true for ABO where only a
single gene locus results in multiple hybrid alleles, giving rise to
unexpected phenotypes (Fig 1) (Olsson & Chester, 2001).
Recombination between the two homologous genes in the Rhand MNS blood group systems is common and can lead to
many different kinds of phenotype. Examples of exchange
between homologous genes in trans are common in the MNS
system where hybrids of GPA and GPB are created by unequal
crossover or gene conversion events (Fig 2A) (Blumenfeld &
Huang, 1997). New antigens arise as a result of the novel
amino acid sequences generated by the hybrid genes. The
hybrid molecules that carry unusual phenotypes in the Rh
blood group system are thought to be generated by crossover
between the RHD and RHCE genes in cis (Fig 2B) (Wagner
et al, 2001), that may alter or abolish the expression of
expected antigens and create novel antigens/phenotypes. For
example, the partial D phenotype, DVI type I, results from a
RH(D-CE-D) hybrid in which exons 4 and 5 of RHD are
replaced by the corresponding exons of an RHcEallele (Avent
et al, 1997; Huang, 1997). The hybrid protein expresses a
qualitatively and quantitatively altered D antigen. A similar
exchange of RHD with exons 4, 5 and 6 of an RHCe allele
produces a hybrid protein with a qualitatively identical D
antigen, as determined by monoclonal antibody studies;
however, more copies of the D antigen are present and these
RBCs also express the low incidence antigen, BARC (Mouro
et al, 1994; Tippett et al, 1996).
Non-sense mutations, such as nucleotide deletions or
insertions, often abolish or decrease blood group expression
by causing a shift in the open reading frame of the sequence
such that the amino acids encoded after the mutation are
completely different. For example, in the ABO system, two
different single nucleotide deletions in the consensus A1
sequence have been shown to account for the common O and
A2 blood groups. These are illustrated in Fig 3 (Yamamoto
et al, 1990a, 1992).
Not surprisingly, the deletion of whole genes or parts ofgenes can result in loss of blood group antigen expression as
exemplified by the following reports concerning the MNS
(Huanget al, 1987; Rahuelet al, 1988), RH (Wagner & Flegel,
2000), JK (Irshaid et al, 2002), H (Koda et al, 1997) and GE
(Colinet al, 1989) blood group systems.
Duplication of genetic material can result in the formation of
a novel antigen, for example, the nucleotide sequence created
by the exon 3-exon 3 duplication in the GYPC.Lsa variant gene
encodes the Lsa antigen (Reid et al, 1994). Conversely, a
duplication event may result in the loss of an existing antigen.
Fig 1. Hybrid genes arising from crossover events between ABO genes have been shown to give rise to more or less unexpected phenotypes. In this
example, a crossover in intron 6 between an O1v allele and aBallele to generate aBO1v hybrid was shown to be one molecular mechanism behind the
Ax
phenotype (Olsson & Chester, 1998). Weak A antigen expression occurs because exon 7 of the O1v allele encodes A transferase activity that is
normally silenced by the presence of 261delG in exon 6. Since exon 6 is derived from the Ballele without this deletion in the hybrid, enzyme activity is
restored. The corresponding product of the crossover would be expected to encode a non-functional protein since the 261delG mutation is present in
exon 6. Indeed, such an allele was reported to be common in Brazilian blacks (Olsson et al, 1997) and has since been found in Blacks of several
different geographic origins (unpublished observations). Note that the introns are not drawn to scale.
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The best example of this is the 37 bp nucleotide duplication
that occurs at the intron 3/exon 4 border in the RHD
pseudogene (Singleton et al, 2000). The duplication results in
an alteration of the reading frame and an eventual premature
stop codon so that no RhD protein is found on the RBCs.
In theABOgene, a 43 bp minisatellite motif 4 kbp upstreamfrom exon 1, with the ability to bind the transcription factor
CBF/NF-Y has been suggested to govern transcription in an
enhancer-like way (Kominato et al, 1997). Allele-related vari-
ation in the number of repeats was observed in samples of
different ABO genotypes: A1 and O2 alleles having one copy
only while A2, B, O1 and O1v alleles had four copies (Irshaid
et al, 1999). In an experimental model, four repeats (associated
with the common A2, B and O1/O1v alleles) produced
approximately 100 times more mRNA than a single repeat
(found in A1 andO2 alleles) (Yu et al, 2000).
Blood group genes that control carbohydrate antigens
All genes encode proteins but not all blood group genes encode
blood-group-carrying proteins. The reason, of course, is that
not all blood groups antigens are of protein nature. This
apparent anomaly was indeed confusing to the pioneers whohad elucidated the biochemical basis of blood groups like
ABO, H and Lewis. On one hand, DNA was supposed to code
for proteins but, on the other hand, these carbohydrate blood
groups were definitely inherited characters. The solution came
when Watkins hypothesized that the genes encoded blood-
group-specific glycosyltransferases (Watkins, 1974). This hypo-
thesis held true, although today researchers still struggle to
clarify the genetic heterogeneity underlying variant carbohy-
drate blood groups. In theory, any mutation that changes the
enzymatic properties of the primary gene product including
Fig 2. Mechanisms that generate hybrid genes
in the MNS and Rh blood group systems. (A)
DNA exchange between the GYPA and GYPB
genes intrans, either by unequal crossover or by
gene conversion, creates novel sequences that
are recognized as blood group antigens. (B)Crossover of the RHgenes in cis creates hybrid
genes that have altered expression of expected
antigens and may create novel antigens. SMPis
an unrelated gene. Genes are illustrated in a
53 direction unless noted otherwise. Novel
sequences are indicated by the parenthesis.
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activity, substrate and acceptor preference may cause, e.g. a
weak A or B subgroup (Chester & Olsson, 2001). The null
phenotypes O, p, or Bombay result from the inheritance of two
inactive alleles of the respective glycosyltransferase gene. In all
three genes, inactivating mutations have been found through-
out the coding sequence. For ABO, however, a single-
nucleotide deletion is the predominant cause of the blood
group O phenotype whilst other causes are infrequent or rare.
Currently, the number of alleles at the ABO locus approaches a
hundred and reaches a degree of complexity due to point
mutations and hybrid allele formation that is only matched by
theRHand MNS loci.
Heterogeneity of null phenotypes
By comparison with theABO locus, most of the protein-based
systems are relatively simple and a polymorphism defined at
the genetic level can almost always be correlated with the
expression of a certain blood group antigen. However, in
genomic DNA-based analysis, the interpretation of results can
be confounded by the existence of null phenotypes. Clearly,
any mutation in the gene that results in the failure of the
antigen-carrying molecule to be expressed at the RBC surface
will, in fact, be a null mutation. Because some of these
mutations occur relatively commonly, it is important toinclude their detection together with assays for common
phenotype prediction in order to avoid false positive results.
For example, it is necessary to test for the GATA-1 mutation in
the FY gene described above, when determining Fya and Fyb
antigen status but not for the other very rare mutations that
result in the Fy(ab) phenotype. Similarly, in the Nordic
population, it should be considered to include detection of
the 871T>C mutation in the JKgene that is the basis for the
Jk(ab) phenotype in the Finnish people (Irshaid et al, 2000).
The heterogeneity of the molecular bases of these phenotypes is
a major problem for all DNA-based prediction of blood
groups.
Most null blood group phenotypes are the result of
molecular changes in the gene that encodes the carrier
molecule. However, there are important interactions between
proteins at the cell surface and with the cytoskeleton and
therefore mutations that change the expression of an interact-
ive protein can affect the proteins around it. Mutations in
RHAG that stop the expression of the Rh-associated glyco-
protein (RhAG) also prevent the expression of the RhD and
RhCE proteins the so-called regulator type of Rhnullphenotype (reviewed in Daniels, 2002). Similarly, mutations
leading to the absence of the XK protein in the red cell
membrane results in the weakened expression of Kell blood
group antigens (Daneket al, 2001; Russo et al, 2002).
Future perspectives
Today, almost all of the genes underlying expression of the
human blood group systems have been cloned and the
polymorphisms responsible for the phenotypes encountered
in different individuals and populations clarified. A challenge
that remains for the future is to investigate and understand the
genetics of antigens in the blood group collections and series
since our experience tells us that they are likely to be carried onfunctional molecules.
The increasing knowledge of the genes encoding blood
group antigens has relevance in the clinical laboratory.
Genomic typing assays for fetal RBC phenotype prediction to
determine the risk to a foetus of haemolytic disease of the
newborn are now standard of care. Much of this testing is
performed on DNA isolated from amniotic fluid; however, in
the last few years, more sensitive quantitative PCR techniques
have permitted the identification of fetal RHD alleles from
DNA isolated from maternal plasma (Lo et al, 1998; Lo, 2001;
Fig 3. A single nucleotide deletion in the coding region of a gene can alter the open reading frame. For example, in the ABO blood group system, the
deletion of 261G in the consensus sequence (A1 allele) results in a frameshift and a subsequent introduction of a premature stop codon (O1 allele).
The truncated protein that is encoded is inactive. Conversely, the A2 allele results from the deletion of 1061C, and instead, the open reading frame is
elongated. The glycosyltransferase encoded by this gene consists of 21 additional amino acids and is less efficient, as determined by the presence of
fewer A antigens on the RBCs of group A2 people. In addition, it appears to be unable to synthesize the A1 antigen. Asterisks (*) represent stop
codons. The grey shading indicates nucleotides that are transcribed normally; the white boxes indicate a nucleotide sequence that is not transcribed as
a result of the nucleotide deletion at position 261; the hatched box represents the additional nucleotide sequence that is transcribed as a result of the
nucleotide deletion at 1061.
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van der Schoot et al, 2003). Although there are some current
limitations to the technique, the advantages of this non-
invasive method are obvious. Other applications of blood
group genotyping have included testing samples from multiply
transfused patients that are either immunized, or at risk of
being immunized, to one or more blood group antigens (Reid
et al, 2000). Patient groups, such as those with Sickle Cell
Disease or other transfusion-dependent haemoglobinopathies,
can benefit from better antigen-matched blood (Reed &
Vichinsky, 2001). Genotyping is also useful in other serological
situations where the RBC phenotype cannot be accurately
determined (Rios et al, 2000b).
The potential for testing blood donor samples on a large
scale is clear to all in the field, but current techniques are both
laborious and expensive. However, automation of SNP detec-
tion, as a faster and easier way to type blood donors, is a
much-discussed issue and there are several techniques being
evaluated.
Lastly, the knowledge gained from the identification of
blood group genes leads to a better understanding of therelationship between blood group differences and subtle
functional differences in the molecules that carry the antigens.
The molecular genetics of blood groups may also help us to
better understand the functionality of the RBC at large, e.g.
moderation of the intracellular environment for invading
parasites, plasticity of the RBC membrane in the circulation
during stress, or the role of the circulating RBC in haemostasis.
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