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Cutting Edge: Expansion of the KIR Locus by
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J Immunol 2003; 171:2192-2195; ;
doi: 10.4049/jimmunol.171.5.2192
http://www.jimmunol.org/content/171/5/2192
http://www.jimmunol.org/content/suppl/2003/08/15/171.5.2192.DC1
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Copyright © 2003 by The American Association of
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Supplementary
Material
Maureen P. Martin, Arman Bashirova, James Traherne, John
Trowsdale and Mary Carrington
OF
THE
JOURNAL IMMUNOLOGY
CUTTING EDGE
Cutting Edge: Expansion of the KIR Locus by Unequal
Crossing Over1
Maureen P. Martin,* Arman Bashirova,† James Traherne,‡ John Trowsdale,‡ and
Mary Carrington2*
iller Ig-like receptor (KIR)3 molecules regulate the activity of NK and some T cells through interaction
with specific HLA class I molecules on target cells. Because HLA class I alleles are under continuous selection pressure
from infectious disease morbidity and mortality, the KIR locus
must also evolve to maintain and enhance beneficial interactions with HLA class I (1). A model asserting rapid evolution of
the KIR locus is supported by the highly diverse nature of KIR
haplotypes in terms of number and types of genes present on a
given haplotype (2, 3). Segregation analysis within a limited
number of families (4 –7) has indicated remarkable diversity in
terms of the number and type of KIR genes present on independent KIR haplotypes (a compilation of distinct KIR haplotypes
can be seen at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db⫽
Books (8)). In general, KIR haplotypes contain 7–12 genes plus
two pseudogenes, although very short haplotypes that contain as
few as three or four genes have been observed infrequently (Ref. 3
and M. P. Martin, unpublished observations). The extent of KIR
gene/haplotype diversity has only been appreciated over recent
years, but already the influence of the presence/absence of specific
KIR genes has been implicated in human disease (9 –11).
K
The KIR genes map to 19q13.4 where they are arranged in a
head to tail fashion spanning a region of roughly 150 Kb (12,
13). KIR genes are generally 80 –90% identical, whereas allelic
variants of a single KIR gene tend to differ by 2% or less (14,
15). Except for a unique 14-kb sequence in the center of the
KIR gene cluster just upstream of the KIR2DL4 gene, intervening segments between adjacent KIR genes are consistently 2 kb
in length and are highly conserved (16). Three prototypic KIR
haplotypes have been sequenced in their entirety (5, 6), providing fundamental information regarding KIR gene order across
the cluster. Additional information regarding gene order has
been garnered from a sequence-specific priming (SSP) protocol
in which forward and reverse PCR primers were designed from
gene-specific segments near the 3⬘ end and 5⬘ end of each KIR
gene, respectively (3), which we will refer to as “intergenic SSPPCR.” By this approach, PCR products are produced only
when the forward primer recognizing the 3⬘ end of one gene
and the reverse primer recognizing the 5⬘ end of an immediately
adjacent gene are used, thereby defining the pairwise order of
KIR genes on that haplotype.
In this study, we describe an extended KIR haplotype in a
family that contains two copies of both KIR2DL4 and
KIR3DL1/S1, as well as a novel hybrid gene composed of half
KIR2DL5A and half KIR3DP1. All individuals with the extended haplotype have three copies of both KIR2DL4 and
KIR3DL1/S1, two of each on the extended haplotype and one
of each on the homologous haplotype. We propose that the extended haplotype was generated by unequal crossing over,
which represents a likely mechanism for the expansion and contraction of KIR haplotypes in general. Unequal crossing over
may potentially maintain flux in the physical order of KIR genes
within the set of KIR haplotypes present in a population.
Materials and Methods
KIR genotyping
Genomic DNA from a three-generation Center d’Etude du Polymorphisme
Humaine family was genotyped for presence or absence of the following KIR
genes: 2DL1, 2DL2, 2DL3, 2DL4, 2DL5, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5,
*Basic Research Program, Science Applications International Corporation-Frederick, and
†
Laboratory of Genomic Diversity, National Cancer Institute, Frederick, MD 21702; and
‡
Immunology Division, Department of Pathology, University of Cambridge, Cambridge,
United Kingdom
1
This work was supported with federal funds from the National Cancer Institute, National
Institutes of Health under contract no. NO1-CO-12400. The content of this publication
does not necessarily reflect the views orpolicies of the Department of Health and Human
Services, nor does mention of trade names, commercial products, or organizations imply
endorsement by the U.S. Government.
Received for publication May 28, 2003. Accepted for publication July 11, 2003.
2
Address correspondence and reprint requests to Dr. Mary Carrington, National Cancer
Institute, P.O. Box B, Frederick, MD 21702. E-mail address: [email protected]
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
Copyright © 2003 by The American Association of Immunologists, Inc.
3
Abbreviations used in this paper: KIR, killer Ig-like receptor; SSP, sequence specific
priming.
0022-1767/03/$02.00
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The killer Ig-like receptor (KIR) genes have high sequence
similarity and are organized in a head-to-tail fashion.
These properties may enhance misalignment of homologous chromosomes during synapsis preceding meiotic recombination, resulting in unequal crossing over. We have
identified an extended KIR haplotype that contains a
novel hybrid gene and two copies of each of two previously
described KIR genes. A parsimonious mechanism for the
derivation of this haplotype invokes unequal crossing over
between two known ancestral KIR haplotypes. These data
raise the possibility that unequal crossing over may be responsible in part for the expansion/contraction of KIR
haplotypes as well as other homologous gene families that
map in tandem. The Journal of Immunology, 2003,
171: 2192–2195.
The Journal of Immunology
2193
Table I. Gene dosage determination of KIR2DL4 at the genomic level using
quantitative real-time multiplex PCR
Genotype
Genomic Copy
Number
Mean Relative Ratio
(SD)
bd
bc
ac
ab
cd
dg
ch
2
3
3
2
3
2
3
1.0 (0.01)
1.6 (0.1)
1.6 (0.04)
1.0 (0.04)
1.6 (0.06)
1.1 (0.08)
1.6 (0.06)
KIR haplotype determination
KIR haplotypes were determined by segregation analysis in the family (see Fig.
2). Because it was not always possible to define precisely the gene content of the
Determination of KIR gene order; intergenic SSP-PCR
Order of the genes on the c haplotype (see Fig. 1B) was determined by sequencing products derived from PCR in which forward primers recognized the 3⬘ end
and reverse primers recognized the 5⬘ end of the various KIR genes (primers and
annealing temperatures are provided in supplemental Tables I and II). In some
cases it was necessary to reamplify the initial PCR product because yield of the
amplicon was inadequate for sequencing. In these cases, an internal primer was
used in reamplification. KIR gene sequences are based on the alignment provided in http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db ⫽ Books.
Identification of KIR alleles
KIR genes that were suspected to be duplicated on haplotype c (see Fig. 2) were
sequenced for allelic determination. The PCR product derived from exons 3–5
of 2DL4 was also cloned for sequencing because it was not possible to assign
alleles after direct sequencing. The amplified product was cloned into the expression vector pcDNA2.1-TOPO (Invitrogen) and eight clones were sequenced. Primers used for sequencing of 2DL4 and 3DL1 are provided in supplemental Table II. Primers were designed to amplify all known alleles of the
genes. The primers used for amplification and sequencing of the hybrid
2DL5A/3DP1 gene are provided in supplemental Tables I and II. The amplified
products were purified using the Qiaquick PCR purification kit (Qiagen, Valencia, CA). Cycle sequencing was performed using the ABI BigDye Terminator Cycle Sequencing Ready Reaction kit (Applied Biosystems, Foster City,
CA), followed by isopropanol precipitation. The samples were then run on an
ABI 377 sequencer. Allele nomenclature is derived from Ref. 17.
Determination of 2DL4 copy number
Simultaneous detection of the target KIR2DL4 sequence and an internal singlecopy gene control in the same sample material was achieved by dual-color detection using the Lightcycler (Roche Diagnostic Systems, Indianapolis, IN).
FIGURE 1. A recombinant gene product and its derivation. A, The KIR2DL5A/3DP1 gene is a product of recombination between KIR2DL5A (AF217485) and
KIR3DP1 (AL133414). Nucleotide positions that differ between AF217485 and AL133414 are shown. B, The proposed ancestral haplotypes from which
KIR2DL5A/3DP1 was derived have been observed previously in family studies and their frequencies are provided (4 –7). The gene content and order on these
ancestral haplotypes, joined as shown and forming the expanded haplotype, correspond precisely with those determined for haplotype c (see Fig. 2). Distinct alleles
of the duplicated genes are indicated by superscript a and b. Both alleles of each duplicated gene have been observed previously.
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3DL1, 3DL2, 3DL3, 3DS1, 2DP1, and 3DP1. Genotyping was performed using PCR amplification with two pairs of locus-specific primers (PCR-SSP) as
previously described (10). Internal control primers that amplify a 796-bp fragment of the third intron of DRB1 were also included in each PCR to validate
proper amplifications. Additional primers that recognize 3DP1 and 2DS4, respectively, are as follows: 3DP1F, 5⬘-GCAGCACCATGTCGCTCATG-3⬘;
3DP1R, 5⬘-AACGGTGTTTCGGAATAC-3⬘; 3DP1⌬exon 2F, 5⬘CAGGGGGCCTGGCCACATGA-3⬘;
2DS4vF,
5⬘-GTTCAGGCAG
GAGAGAAT-3⬘; 2DS4vR, 5⬘-GTTTGACCACTCGTAGGGAGC. Amplification was performed in a volume of 10 ␮l containing 200 ␮M dNTP, 500
nM primer, 1.5 mM MgCl2, 20 mM Tris-HCl (pH 8.4), 50 mM KCl, and
0.5U Platinum TaqDNA polymerase (Invitrogen, Carlsbad, CA), and 20 ng of
DNA. Cycling was performed as follows: 2 min at 94°C; 5 cycles of 94°C for
15 s, 65°C for 15 s, 72°C for 30 s; 21 cycles of 94°C for 15 s, 60°C for 15 s, 72°C
for 30 s; 4 cycles of 94°C for 15 s, 55°C for 1 min, 72°C for 2 min, and a final
extension step of 10 min at 72°C. PCR products were electrophoresed in 1.5%
agarose gels containing ethidium bromide, and predicted size products were
visualized under UV light.
haplotypes using segregation analysis, several assumptions were made in determining the haplotypes based on published gene frequencies and patterns of
linkage disequilibrium between pairs of KIR genes: 1) 3DL3, 3DP1, 2DL4, and
3DL2 are present on all haplotypes, 2) if 2DL1 is present, 2DP1 is always
present, 3) 3DS1 segregates as an allele of 3DL1, 4) 2DL2 and 2DL3 segregate
as alleles of a single locus.
2194
CUTTING EDGE: EXPANSION OF THE KIR LOCUS BY UNEQUAL CROSSING OVER
The KIR2DL4 forward and reverse PCR primers, sited within exon 3, were
5⬘-TCAGGA CAAGCCCTTCTG-3⬘ and 5⬘-ACC CCATCT TTCTTG TA
CAGTG-3⬘, respectively. The penultimate nucleotide of the reverse primer
(underlined) is a mismatch to all KIR gene sequences to prevent nonspecific
priming. The KIR2DL4 hybridization probes were 5⬘-CTGTGGTGCCT
CAAGGAGG-fluorescein-3⬘ and 5⬘-Red640-ACGTGACTCTTCGGTGT
CAC-phosphate-3⬘. A proprietary internal control (␤-globin gene; Roche Diagnostic Systems) was used. Final concentrations in 20-␮l reaction volumes
were 1⫻ FastStart Reaction Mix (Roche Diagnostic Systems), 5 mM MgCl2,
0.5 ng/␮l DNA template, 500 nM of each primer, 0.1 ␮M of each fluorescein
probe, and 0.2 ␮M of each Red fluorophore probe. Cycling was performed as
follows: 10 min at 95°C followed by 45 cycles of 95°C for 3 s, 62°C for 5 s, and
72°C for 8 s. The results of duplicate experiments are expressed as the mean
relative ratio of KIR2DL4 to the reference gene (Relative Quantification Software (Roche Diagnostic Systems) using a precreated coefficient file) with SDs
(Table I). All samples were tested blindly.
Results and Discussion
While performing segregation analysis of KIR genes/haplotypes
in a battery of Center d’Etude du Polymorphisme Humaine
families, we identified a novel KIR gene sequence (termed
KIR2DL5A/3DP1) that, in the 5⬘ region, is identical to the gene
KIR2DL5A (accession no. AF217485), but is identical to another gene, the KIR3DP1 pseudogene (accession no.
AL133414), from intron 2 to the end of the gene (Fig. 1A; the
novel sequence has been submitted to GenBank). We hypothesized that KIR2DL5A/3DP1 was derived by an unequal crossover between an ancestral KIR2DL5A gene (KIR2DL5A maps
to the telomeric half of the KIR gene complex; Ref. 3) and an
FIGURE 3. The origin of KIR2DL5B. The KIR2DL5B gene (AF217486) appears to be the reciprocal of the novel hybrid gene KIR2DL5A/3DP1, derived from
an unequal crossover event between KIR3DP1 (AL133414) and KIR2DL5A (AF217485). Nucleotide positions that differ among the genes are shown.
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FIGURE 2. Segregation of the haplotype containing KIR2DL5A/3DP1 in a
Center d’Etude du Polymorphisme Humaine family. KIR haplotypes were determined by segregation analysis in all members of a three-generation family.
Allele designations correspond to HGNC nomenclature (http://www.gene.
ucl.ac.uk/nomenclature/genefamily/kir.html). The position of the duplicated
block is shown by brackets and an arrow.
ancestral KIR3DP1 gene (KIR3DP1 maps to the centromeric
half of the complex; Ref. 3). The ancestral KIR haplotypes in the
model shown in Fig. 1B have been observed at frequencies of
3.5 (red haplotype) and 14% (blue haplotype) in family studies
(3–5, 7). These haplotypes were chosen for the model because
gene composition on the respective red centromeric and blue
telomeric halves of the haplotypes corresponds precisely with
those on the observed extended haplotype. We propose that
during synapsis, misalignment of KIR genes on the two parental
homologous chromosomes occurred, resulting in crossing over
between the KIR2DL5A and KIR3DP1 genes. The progeny
haplotype containing the observed novel hybrid gene,
KIR2DL5A/3DP1, should theoretically contain two copies of
both KIR2DL4 and KIR3DL1/S1.
KIR2DL5A/3DP1 was identified in a three generation Center
d’Etude du Polymorphisme Humaine family. Extensive cloning,
sequencing, and segregation analysis of KIR genes in the family indicated that two known alleles of both KIR2DL4 (X97229,
AF034773) and KIR3DL1/S1 (AF262969, AF022044) segregated
on the c haplotype, whereas a single distinct allele of each of these
loci segregated on each of the a, b, and d haplotypes (Fig. 2). Using
a quantitative PCR technique to measure gene dosage, we confirmed that individuals with the c haplotype had three copies of
KIR2DL4, and those without the c haplotype had two copies of this
gene (Table I). The order of the genes on the c haplotype was then
determined by sequencing products derived from PCR in which
forward primers recognized the 3⬘ end and the reverse primers recognized the 5⬘ end of the various KIR genes. Every sequence obtained supported the order of genes shown on the extended haplotype in Fig. 1B. Primer sequences used in this study and sequence
of informative variant sites that allowed determination of gene order are provided in supplemental Tables I and II.
The gene duplication, gene order, and novel hybrid
KIR2DL5A/3DP1 gene that characterize haplotype c strongly
indicate that the mechanism by which this haplotype was derived involved unequal crossing over between two well-defined
KIR haplotypes. We propose that this mechanism represents a
common means by which expansion and contraction of KIR
haplotypes occur, facilitating rapid evolution of the KIR gene
complex. The truncated KIR haplotype that also would have
been produced by the recombination event depicted in Fig. 1B
has not been observed in any family studies published to date
(3–7). However, the sequence of the hybrid gene in this putative haplotype, KIR3DP1/2DL5A (Fig. 3), is virtually identical
to the gene KIR2DL5B (7) (AF217486). It follows that the
truncated haplotype (or one similar to it) containing a hybrid
KIR3DP1/2DL5A (i.e., KIR2DL5B) gene has been generated
The Journal of Immunology
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previously and has circulated in the population. KIR2DL5A
and KIR2DL5B are highly homologous but distinct genes that
are sometimes located on the same haplotype (6, 7), indicating
that an unequal recombination event occurred subsequent to
that which gave rise to KIR2DL5B, placing KIR2DL5A and
KIR2DL5B on a single haplotype. Interestingly, of the three defined KIR2DL5B alleles, two alleles, including the most common one, are not expressed due to a mutation in their promoter
region (18), partially reverting this gene to the pseudogene status of its ancestor KIR3DP1 and hybrid counterpart
KIR2DL5A/3DP1.
The KIR region does not fit comfortably with traditional genetic models (6, 15). Several distinct KIR genes, such as
KIR2DL5A and KIR2DL5B, are highly related and because KIR
haplotypes can have different numbers of loci, the distinction
between genes and alleles is not always clear. KIR2DL4 and
KIR3DL1/S1 are present on virtually all KIR haplotypes (3) and
both genes have several alleles that are fairly evenly distributed
(M. Carrington, unpublished observations). Although no functional significance has been assigned to the genetic variability at
either of these loci, distinct beneficial phenotypes conferred by
specific allotypes may exist, resulting in some level of balancing
selection. KIR typing methods used currently distinguish only
between presence and absence of each gene, and do not provide
information regarding gene copy number. Thus, the frequency
of individuals who have three (or more) copies of a single gene
is not known and will require measurement of gene dosage, as
described for KIR2DL4 in this report (Table I). If indeed the
polymorphism at these loci is functionally significant, those individuals with three alleles are not encompassed by conventional genetic paradigms and “heterozygote advantage” is an inadequate description. Perhaps the term “polyzygote advantage”
would more appropriately describe the polyallelic phenomenon
observed within the KIR locus of some individuals. MHC haplotypes can contain one to three related copies of DRB sequences and provide another, albeit moderate, example of this
phenomenon (19).
Evolution of tandem arrays of homologous genes might often
occur through a mechanism involving unequal crossing over
(20), which may underlie the “birth and death” of clustered
genes (21). The mouse ly-49 region, the functional equivalent
of KIR, behaves in a similar manner (22). Functional consequences of expanded (or truncated) KIR haplotypes in viral infections and cancer are quite plausible, and their characterization may illuminate our understanding of gene dosage effects in
human disease.
2195