The Journal of Immunology, 2002, 169: 271-276.
Copyright © 2002 by The American Association of Immunologists
Unraveling of the Polymorphic C
2-C3 Amplification and the Ke+Oz- Polymorphism in the Human Ig Locus
Mirjam van der Burg,
Barbara H. Barendregt,
Ellen J. van Gastel-Mol,
Talip Tümkaya,
Anton W. Langerak and
Jacques J. M. van Dongen1
Department of Immunology, Erasmus University Rotterdam/University Hospital Rotterdam, Rotterdam, The Netherlands
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Abstract
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Two polymorphisms of the human Ig
(IGL) locus
have been described. The first polymorphism concerns a single, 2- or
3-fold amplification of 5.4 kb of DNA in the C2-C3 region. The
second polymorphism is the
Mcg-Ke+Oz- isotype, which has
only been defined via serological analyses in Bence-Jones proteins of
multiple myeloma patients and was assumed to be encoded by a
polymorphic C2 segment because of its high homology with the
Mcg-Ke-Oz- C2 isotype. It has
been speculated that the
Mcg-Ke+Oz- isotype might be
encoded by a C gene segment of the amplified C2-C3 region. We
now unraveled both IGL gene polymorphisms. The
amplification polymorphism appeared to result from a duplication,
triplication, or quadruplication of a functional J-C2 region and is
likely to have originated from unequal crossing over of the J-C2 and
J-C3 region via a 2.2-kb homologous repeat. The amplification
polymorphism was found to result in the presence of one to five extra
functional J-C2 per genome regions, leading to decreased Ig
:Ig
ratios on normal peripheral blood B cells. Via sequence analysis, we
demonstrated that the Mcg-Ke+Oz-
isotype is encoded by a polymorphic C2 segment that differs from the
normal C2 gene segment at a single nucleotide position. This
polymorphism was identified in only 1.5% (2 of 134) of individuals
without J-C2 amplification polymorphism and was not found in the
J-C2 amplification polymorphism of 44 individuals, indicating that
the two IGL gene polymorphisms are not
linked.
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Introduction
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The human Ig
(IGL)2
locus is located on chromosome band 22q11.2 and spans a region of about
one megabase (1). The IGL locus contains 73–74
V gene segments, including 56–57 functional V segments, which
could be assigned to 11 subgroups based on nucleotide homology
(1, 2, 3, 4, 5, 6) (http://imgt.cnusc.fr:8104). Seven J-C gene
regions are located downstream of the V segments. Each C gene
segment is preceded by a J gene segment. Only four J-C gene
regions are functional: i.e., J-C1, J-C2, J-C3, and J-C7;
the regions J-C4, J-C5, and J-C6 are nonfunctional (pseudo)
gene regions (7, 8, 9). This is due to a deletion of 
1150
bp in the J-C4 region and the lack of some of the essential
nucleotides in the recombination signal sequence (RSS) (3)
of the J4 gene segment (7, 10). In the 3' end of the
C5 exon, 11 bp are deleted, and the RSS of the J5 segment also
lacks some of the essential nucleotides (7, 10). Finally,
the C6 exon contains a duplication of four nucleotides, which
results in a premature stop codon (7, 9). Rearrangements
of the J-C6 segment can occur, but they encode a truncated
Ig protein (11).
The four different functional types of Ig L chains have also been
identified in human serum using the serological isotype markers Mcg,
Kern (Ke), Oz, and Mcp (11, 12, 13, 14). These serological isotype
markers are based on amino acid differences found in the C regions
of various Bence-Jones proteins derived from multiple myeloma patients
as well as from Ig L chains isolated from intact Igs. The four
functional J-C gene regions, J-C1, J-C2, J-C3, and
J-C7, encode the isotypes
Mcg+Ke+Oz-,
Mcg-Ke-Oz-,
Mcg-Ke-Oz+,
and Mcp+, respectively. A fifth isotype, termed
Mcg-Ke+Oz-,
is highly homologous to
Mcg-Ke-Oz-
and is assumed to be encoded by a polymorphic C2 gene segment, but
this has not yet been confirmed by sequence analysis at the DNA
level.
The human IGL locus also contains an 5.4-kb amplification
polymorphism in the C2-C3 region. As the amplified region can be
present once, twice, or three times; this amplification might result in
up to 10 J-C gene regions per allele (3, 15, 16, 17). The
polymorphic C2-C3 amplifications can be identified via Southern
blot (SB) analysis as EcoRI fragments of 13.7, 19.1, or 24.5
kb, representing one, two, or three amplifications, respectively
(15, 18). In the absence of an IGL
amplification polymorphism, only an 8.3-kb EcoRI fragment is
detected. In HindIII-digested DNA, the IGL
polymorphism is visible as a 5.4-kb fragment, independent of the number
of amplified regions (18). It has been reported that the
frequency of the C2-C3 amplification polymorphism varies between
populations in different geographical areas (3, 16, 17),
but this polymorphism has not been fully characterized in detail.
Here we studied both the C2-C3 amplification polymorphism and the
Mcg-Ke+Oz-
polymorphism. Our aim was to investigate whether the
Mcg-Ke+Oz-
isotype is encoded by a polymorphic C2 gene segment and whether the
C segment encoding this isotype is located on the amplified
C2-C3 fragment, implying that the two IGL
polymorphisms might be linked, as speculated previously (8, 14). Furthermore, we assessed the structure of the C2-C3
amplification polymorphism and determined whether the amplified region
contains functional J-C segments that might lead to higher
frequencies of Ig protein expression.
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Materials and Methods
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Cell samples
Peripheral blood (PB) samples were obtained from 96 healthy
individuals. The expression of Ig and Ig on PB B cells was
determined via Ig/CD19 and Ig/CD19 two-color immunofluorescence
in 69 cases. DNA was isolated from the granulocytes of all 96 healthy
individuals using phenol/chloroform extraction (18). In
addition, DNA samples from 82 precursor-precursor B cell acute
lymphoblastic leukemia samples and Ig+
B cell chronic lymphocytic leukemia with both IGL alleles in
germline configuration were analyzed for the presence of the
Mcg-Ke+Oz-
polymorphism (19, 20).
Southern blot analysis
Fifteen micrograms of DNA from 80 healthy controls (60 of
Caucasoid origin and 20 of Chinese origin) was digested with
EcoRI (Life Technologies, Gaithersburg, MD), separated in
0.7% agarose gels, and transferred by vacuum blotting to Nytran-13N
nylon membranes (Schleicher & Schuell, Dassel, Germany)
(18). The filters were hybridized with the
32P-labeled -IVS probe (15).
PCR analysis and fluorescent sequencing of the amplified
C2-C3 region
Specific PCR primers for the C2-C3 amplification
polymorphism (IGLamp-F and IGLamp-R) were
designed using the OLIGO 6.2 software program (Dr. W. Rychlik,
Molecular Biology Insights, Cascade, CO; Table I
). PCR analysis was performed with the
Expand Long Template PCR System (Roche Diagnostics, Mannheim, Germany)
according to the manufacturer’s instructions. PCR products were
analyzed on a 1% agarose gel and purified using a PCR purification kit
(Qiagen, Hilden, Germany) before fluorescent sequencing. PCR products
were sequenced on an ABI 377 fluorescent cycle sequencer (PE Applied
Biosystems, Foster City, CA) with Big Dyes (PE Applied Biosystems)
according to the manufacturer’s instructions. The original PCR primers
were used as sequence primers, and subsequently new sequence primers
were designed in the newly sequenced regions. An extra PCR was
performed using the primers Up-F and Down-R to sequence the gap between
the primers IGLamp-R and IGLamp-F (see also Table I and Fig. 2B). The IGL gene sequence (accession
no. X51755) was used as the reference sequence. Pairwise alignment
algorithms were used from EMBL, European Bioinformatics Institute
(Cambridge, U.K.; http://www.ebi.ac.uk/emboss/align/).
Analysis of the C2 gene region for the presence of the
Mcg-Ke+Oz- polymorphism
The C2 region was amplified by PCR with the primers C2-F
and C2-R (Table I
) using the TaqGold amplification system (PE
Applied Biosystems). The obtained PCR products were sequenced with the
C2-F primer and/or the C2-Rseq primer (Table I) as described
above.
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Results
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Southern blot analysis of the C2-C3 amplification
polymorphism in Caucasoid and Chinese individuals
The IGL locus of 80 healthy controls (60 of Caucasoid
origin and 20 of Chinese origin) was analyzed with respect to the
number of amplifications using the -IVS probe in combination with
EcoRI digests (Fig. 1A). Examples of Southern blot
results for two individuals without a C2-C3 amplification
polymorphism and four individuals with amplification polymorphisms are
shown in Fig. 1B. Seventy-two percent of the Caucasians did
not have the C2-C3 amplification polymorphism, in contrast to
only 15% of the Chinese individuals (Table II). The IGL locus of
individuals without a C2-C3 amplification polymorphism on both
alleles is described as
P0/P0. In the group of
Caucasoid individuals the frequency of monoallelic amplifications was
7, 15, and 7% for one, two, or three amplifications, respectively
(P0/P1,
P0/P2, and
P0/P3). These percentages
were comparable to the percentages in the Chinese individuals. However,
55% of the Chinese individuals had biallelic amplifications
(P1/P2,
P1/P3,
P2/P2, and
P2/P3), which were not
observed in the Caucasoid individuals.
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FIGURE 1. Detection of the IGL amplification polymorphism of the
C2-C3 region. A, Schematic representation of the
IGL locus with the amplification polymorphism of the
C2-C3 region. The EcoRI restriction sites, the
position of the -IVS probe, and the relevant restriction fragments
are indicated. In cases without an IGL amplification
polymorphism (P0) the -IVS probe detects an 8.3-kb band.
Dependent on the number of amplified regions (P1,
P2, or P3), a 13.7-, 19.1-, or 24.5-kb band is
detected, respectively. B, Southern blot analysis of
EcoRI-digested DNA of six healthy controls with the
-IVS probe. Lanes 1 and 2, No
IGL amplification polymorphism on both alleles
(P0/P0); lanes 3,
4, and 6, one allele without
IGL amplification polymorphism together with a
polymorphic allele, P0/P1,
P0/P2, and P0/P2,
respectively; lane 5, two polymorphic alleles
(P2/P3).
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Table II. Configuration of the IGL locus with
respect to the number of IGL amplifications as determined by
Southern blot analysis
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Sequencing strategy of the C2-C3 amplification polymorphism
To date, the polymorphic C2-C3 amplification has never been
sequenced, probably because of the complexity of the IGL
locus, especially because of the high homology between the J-C2
region and the J-C3 region. The primers (IGLamp-F and
IGLamp-R) were designed tail-to-tail, just upstream of the
HindIII restriction site, such that in situations without
polymorphic C2-C3 amplifications
(P0/P0), no PCR product is
formed (Fig. 2, A and
C). In cases with a polymorphic amplification, a PCR product
of 5.4 kb was generated, independent of the number of amplifications
(Fig. 2, B and C). The size of the PCR product
was comparable to the size of the amplified region, as it was
determined via Southern blot analysis using HindIII digests
(18). The amount of PCR product was quantified using
semiquantitative PCR with sampling after different cycles (7, 10, 13,
16, 19, and 22 cycles), followed by hybridization with the
J-C2-specific IGLC2D probe (19). The
hybridization signals obtained correlated with the number of
amplifications as determined via Southern blot analysis (data not
shown). This result implies that in the case of multiple C2-C3
regions, all regions were represented in the sequence analysis. The
5.4-kb PCR product of four individuals with the genotypes
P1/P2,
P2/P2,
P2/P2, and
P0/P3 were completely
sequenced. Sequence analysis was started with the IGLamp-F
and IGLamp-R primers. Subsequently, sequence primers were
designed in the newly generated sequence ("gene walking"). Finally,
an extra primer set was designed to analyze the region between the two
primers IGLamp-R and IGLamp-F by PCR and
sequencing. The forward primer (Up-F) was designed in the newly
generated sequence and the reverse primer (Down-R) downstream of the
IGLamp-F primer (Fig. 2B). These primers also
annealed in the homologous region just downstream of the J-C2 region
(Fig. 2B). The total sequenced region is indicated in Fig. 2B.
Structure of the C2-C3 amplification polymorphism
The region of the IGLamp-F IGLamp-R product
together with the extended region that fills the gap between the ends
of the two primers was further analyzed for the presence of restriction
sites (Fig. 3A, white area).
This sequence was subsequently aligned with the standard IGL
gene sequence (P0) to determine the structure of
the amplification. The first 2.5 kb of the sequenced region appeared to
be homologous to the region downstream of C2 gene segment (Fig. 3A, dotted lines) with 99.3% homology. The second part of
the sequenced region (2.9 kb) shared the highest homology with the
J-C2 region (Fig. 3A, dashed lines), which was also
99.3%. It should be noted that there is a highly homologous region of
2.2 kb between the J-C2 and J-C3 regions, with a similarity of
98.7%. These homologous regions are indicated as gray areas. Fig. 3A represents the experimental approach for characterization
of the IGL amplification, but does not reflect the
mechanism. In Fig. 3B the actual positioning of the
amplification polymorphism is depicted in the total structure of a
P1 allele. The amplified region starts with a
2.2-kb homologous region and ends just before the 2.2-kb homologous
region of J-C3.
Due to the polymorphic amplification, a new HindIII is
generated (Fig. 3B). SB analysis of
HindIII-digested DNA from individuals with the amplification
polymorphism will therefore show the 5.4-kb polymorphic
HindIII fragment when using the -IVS probe. Consequently,
two and three (identical) repeats of the amplified region
(P2 or P3) also result in
5.4-kb HindIII restriction fragments.
Sequence analysis of the J-C region within the
IGL amplification polymorphism
The J-C region of the amplified IGL region shares
the highest homology with the J-C2 region. The J2amp gene segment
is identical with the J2 except for one amino acid (Fig. 4). The RSS of the J2amp was compared
with the RSS of the seven other RSS and appeared to be identical with
that of J2 and J3; it contained all essential nucleotides (Table III). The donor and acceptor splice sites
of the J-C2amp region were intact. The C2amp gene segment was
completely identical with the C2 gene segment and also coded for the
Mcg-Ke-Oz-
(Table IV, comparison to all isotypes).
Therefore, the IGL amplification polymorphism does not
encode the
Mcg-Ke+Oz-
polymorphism and constitutes a different IGL polymorphism.
Based on these data we conclude that the J-C2amp region is
functional. This conclusion was supported by homology search of the
J2amp segment using nucleotide BLAST
(http://www.ncbi.nlm.nih.gov/BLAST), which resulted in a perfect match
with >15 sequences of human mRNA for Ig chains.
Effect of the number of IGL amplifications on the
Ig:Ig ratio on PB B cells
As sequence analysis of the J-C region on the IGL
amplification showed that this region can undergo gene rearrangements
and can be expressed, we studied the effect of the number of functional
J-C regions on the frequency of Ig-positive B lymphocytes, by
determining the Ig:Ig ratio on normal PB B cells. The combined
Southern blot and Ig:Ig ratio data are summarized in Table V. The human IGL locus
contains four functional J-C regions, meaning that in cases without
IGL amplification polymorphisms
(P0/P0) a total of eight
functional J-C regions are present. In cases with the IGL
amplification polymorphism, every amplified region represents one
additional functional J-C region. The Ig:Ig ratio of cases
with an amplification (resulting in 9–13 functional J-C gene
regions) was significantly lower than the Ig:Ig ratio of cases
without amplification (8 J-C gene regions): 1.37 ± 0.18 vs
1.56 ± 0.26 (by t test, p < 0.001).
One additional J-C gene region appeared to be sufficient for a
decrease in the Ig:Ig ratio (Table V).
Frequency of Mcg-Ke+Oz- C2
polymorphism
The sequence data demonstrated that the IGL
amplification polymorphism does not coincide with the
Mcg-Ke+Oz-
polymorphism. Therefore, it is most likely that the
Mcg-Ke+Oz-
polymorphism is encoded by a polymorphic C2 gene segment. This
implies that at the DNA level the codon AGC for serine (S) at position
152 must be changed in GGC for glycine (G), which is the serological
marker Ke+. The C2 region of 178 individuals
was analyzed for the presence of the
Mcg-Ke+Oz-
polymorphism. The group consisted of 96 healthy controls (granulocyte
DNA) as well as 82 precursor B cell acute lymphoblastic leukemia
and Ig+ B cell chronic lymphocytic leukemia
samples, without IGL gene rearrangements, as determined by
Southern blot analysis (19, 20). All samples were first
screened with the IGLamp-F and IGLamp-R primers
to define cases with the IGL amplification polymorphism.
Twenty-five percent of cases (44 of 178) appeared to have the
IGL amplification polymorphism. In cases without the
IGL amplification polymorphism, the C2 region was
analyzed by PCR and sequencing. The C2amp regions of individuals
with the IGL amplification polymorphism were also sequenced.
For this purpose the PCR products generated with the
IGLamp-F and IGLamp-R primers were sequenced with
those generated with the C2-F and C2-Rseq primers.
In two of the 134 analyzed
P0/P0 cases (1.5%) a
heterozygous peak of nucleotides A and G was observed in the codon
encoding the serological marker Ke. This implies that these individuals
are heterozygous for the
Mcg-Ke+Oz-
polymorphism. In the C2amp region of the 44 individuals with an
IGL amplification polymorphism we did not detect the
Mcg-Ke+Oz-
polymorphism, indicating that the two polymorphisms are not linked.
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Discussion
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Two polymorphisms have been described in the human IGL
locus. However, they have never been sequenced at the DNA level. The
first polymorphism concerns an IGL amplification
polymorphism of 5.4 kb of DNA in the C2-C3 region. The second
polymorphism is the
Mcg-Ke+Oz-
isotype, which was only known from serological analyses of Bence-Jones
proteins of multiple myeloma patients (11, 12, 13, 14). Due to the
high homology with the
Mcg-Ke-Oz-
isotype, which is encoded by the J-C2 region, it was proposed that
the
Mcg-Ke+Oz-
polymorphism is encoded by a polymorphic J-C2 region that differs
from the normal J-C2 region at a single nucleotide position. It has
been speculated that the two polymorphisms might be linked in such a
way that the C region on the polymorphic amplification encodes the
isotype
Mcg-Ke+Oz-
(8, 14).
In this study we were able to sequence the 5.4-kb IGL
amplification polymorphism. The IGL amplification
polymorphism shares a homology of >99% with the J-C2 region. The
first 2.5 kb of the amplification, containing the J and C gene
segments, coincides with a 2.2-kb region, which is also highly
homologous to a 2.2-kb region in the J-C3 cluster (98% homology;
Fig. 3B). Taub et al. (15) proposed in
1983 a mechanism for the generation of this IGL
polymorphism. Based on SB data and restriction fragment analysis, they
proposed unequal crossing over between two 8-kb EcoRI
allelic fragments through homologous recombination between two large
homologous repeats. Our sequence information of the polymorphic
IGL amplification together with the germline sequence of the
complete IGL locus show that the homologous regions are 5.4
kb apart in the germline (P0) situation.
Therefore, we confirm that the amplification probably occurred during
meiosis via unequal homologous recombination between the two 2.2-kb
homologous J-C2 and J-C3 regions.
The C2 and C3 gene region might be susceptible to duplication,
because of its high homology, but especially because of the two
homologous J-C regions of 2.2 kb. The maximum number of
amplifications is three, which suggests that the region is indeed
susceptible to duplication, but this phenomenon apparently has its
limitations. The different amplification variants appeared to be
exactly identical. No differences were observed in multiple
amplifications on the same allele, which suggests that during evolution
the various amplifications occurred simultaneously or shortly after
each other.
The J-C region of the polymorphic amplification appeared to have the
highest homology with the J-C2 region and contained all essential
elements required for recombination and expression, i.e., a functional
RSS, intact donor and acceptor splice-sites, as well as functional J
and C gene regions. Since the amplified J-C2 region does not
encode the
Mcg-Ke+Oz-
isotype, we concluded that the human IGL locus has two
separate polymorphisms.
As known from literature, the IGL amplification polymorphism
is found up to three times per allele (15, 18). Our
sequence analysis showed that this polymorphism concerns identical
amplifications, implying that in cases with a P2
amplification the first amplified region does not differ from the
second. Screening of healthy controls showed that the frequency of the
IGL amplification was 28% in Caucasoid individuals and
involved only one allele. In Chinese individuals the frequency was much
higher (85%) and involved both alleles in the majority of cases.
As the polymorphic amplified regions contain functional J-C2
regions, we investigated the effect of the total number of J-C
regions on the frequency of Ig+ B lymphocytes
by studying the distribution between Ig and Ig L chain expression
(Ig:Ig ratio). The presence of additional functional J-C gene
regions resulted in decreased Ig:Ig ratios of blood B lymphocytes
compared with individuals without the J-C2 amplification. One
additional J-C gene region was sufficient to decrease the
Ig:Ig ratio, suggesting that this effect is dominant and that the
addition of extra J-C gene regions has little effect on the
Ig:Ig ratio.
The Ig:Ig ratio can be decreased by extra copies of J-C
regions as well as by a decrease in Ig (IGK) gene copies.
In a patient with a heterozygous de novo deletion of chromosome 2
region p11.2p13, including the IGK locus (2p12), the
Ig:Ig ratio was strongly decreased to 0.7 (21). This
decrease is stronger than that found in individuals with extra J-C
regions. This difference in effect on the Ig:Ig ratio can be
explained by the fact that Ig L chain rearrangements take place in an
ordered fashion, starting with rearrangements in the IGK
locus, followed by IGL gene rearrangements, if no functional
IGK rearrangement took place (20). If there is
only one IGK allele, the chance of a functional
rearrangement resulting in Ig expression is 50% reduced.
Consequently, the rearrangement process will shift to the
IGL locus in an earlier stage, which is in line with a
reduction of the Ig:Ig ratio from 1.4 to 0.7. In contrast, there
is a limited time period or a limited number of attempts for acquiring
functional Ig gene rearrangements (22, 23). If the B cell
is not able to generate an Ig molecule within that time frame or that
number of attempts, the cell will die by apoptosis (22, 23). Finally, the presence of multiple functional J-C regions
also implies that consecutive IGL rearrangements with
V-J replacements can occur on one allele.
The polymorphic
Mcg-Ke+Oz-
isotype is the second type of IGL polymorphism and was only
known from serological analyses. Our sequencing data now show that this
isotype is encoded by a polymorphic C2 gene segment. The polymorphic
C2 region was detected in only two individuals, who were both
heterozygous for this IGL polymorphism. The reported
frequency of the
Mcg-Ke+Oz-
polymorphism in 70 multiple myeloma patients was 6% (13, 19, 24), which exceeds the frequency of 1.5% in the 134 analyzed
individuals who did not carry the IGL amplification
polymorphism. However, this difference is not statistically significant
(by 
2 test, p > 0.05). No
Mcg-Ke+Oz-
polymorphism was detected in the J-C2 amplification polymorphism of
44 individuals, but this might be due to the low number of analyzed
cases. Nevertheless, the data obtained indicate that the J-C2
amplification polymorphism and the C2 polymorphism are independent.
The two polymorphisms might theoretically be present in one individual,
but the frequency of such an event will be low (<0.5%).
In conclusion, two separate polymorphisms in the human IGL
locus exist: the IGL amplification polymorphism and the
C2 polymorphism, resulting in the
Mcg-Ke+Oz-
isotype. Both polymorphisms involve the C2 region, but they are not
linked, although they might theoretically both be present in one
individual. The presence of the IGL amplification
polymorphism results in the presence of extra functional J-C
regions, which appeared to decrease the Ig:Ig ratio of normal
blood B lymphocytes.
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Acknowledgments
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We thank Prof. Dr. R. Benner for his continuous support.
We acknowledge Dr. Jeroen G. Noordzij for technical support
and Tar van Os for making the figures.
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Footnotes
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1 Address correspondence and reprint requests to Prof. Jacques J. M. van Dongen, Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail address: vandongen{at}immu.fgg.eur.nl 
2 Abbreviations used in this paper: IGL, Ig; IGK, Ig; PB, peripheral blood; RSS, recombination signal sequence; SB, Southern blot.
Received for publication January 18, 2002.
Accepted for publication May 1, 2002.
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Nucleic Acids Res.,
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Abstract
Introduction
G).