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*
Wisconsin Regional Primate Research Center, University of Wisconsin, Madison, WI 53715;
HLA/Molecular Diagnostics Laboratory, Department of Pathology, University of Wisconsin, Madison, WI 53792
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Interestingly, HLA-E shares a number of characteristics with the mouse nonclassical MHC class Ib locus Qa-1. Both genes encode molecules that exhibit extensive tissue distribution (5, 6), low cell surface expression (5, 6), and limited polymorphism (5). HLA-E and Qa-1 also share unusual structural similarities within the putative peptide binding groove. Specifically, both loci are characterized by an alanine at position 67 and serines at positions 143 and 147 (5), replacements that are not found in human or mouse classical MHC class I molecules. Recent studies of peptide binding capacity have also shown that, like Qa-1 molecules (7), HLA-E can bind peptides derived from class I signal sequences (8). Taken together, the unusual and highly convergent features shared by the Qa-1 and HLA-E genes lend further support for the hypothesis that these nonclassical MHC class I molecules perform an important immunologic function that is perhaps regulated by the expression of other MHC class I molecules.
Among the nonhuman primates, both classical and nonclassical MHC class I genes have been identified. In apes and Old World monkeys, homologues of the classical HLA-A and -B loci are polymorphic, with a high rate of nonsynonymous substitution in the PBR (9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21). Homologues of the nonclassical HLA-E and -F loci have also been identified in orangutans (22) and macaques (21, 23, 24, 25). Recently, MHC-E orthologues were identified in gorillas, chimpanzees, and bonobos (26) and in vervet (green) monkeys (23). Like their human counterparts, the nonclassical MHC-E and -F genes in apes and Old World monkeys exhibit conservation of the codons encoding amino acids in the PBR, particularly with respect to the MHC-E locus (24). In the cotton-top tamarin, a New World primate, the classical MHC class I genes exhibit reduced polymorphism and limited sequence variation (27, 28). Furthermore, comparisons with human, chimpanzee, and macaque MHC-F cDNA sequences have revealed that the cotton-top tamarin MHC-F gene has accumulated more nonsynonymous than synonymous differences in the PBR (25).
To evaluate the level of conservation of the MHC-E locus throughout anthropoid primate evolution, we identified the homologue of the HLA-E locus in the cotton-top tamarin (Saguinus oedipus) and five other New World monkey species. Together, the species studied represent all extant platyrrhine clades (Cebidae, Atelidae, and Pitheciidae) (29). Our comparisons of platyrrhine and other primate MHC-E locus alleles demonstrate that this genetic locus is very ancient, and the majority of amino acids in the putative PBR have been conserved throughout anthropoid primate evolution.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A total of 10 New World monkeys, representing all extant platyrrhine clades (Cebidae, Atelidae, and Pitheciidae) (29), were studied. Four unrelated cotton-top tamarins (Saguinus oedipus), two unrelated common marmosets (Callithrix jacchus), and one owl monkey (Aotus trivirgatus) were analyzed using B lymphoblastoid cell lines. One of the cotton-top tamarins (So 100-75) and the owl monkey (At-666) were originally housed at the New England Regional Primate Research Center (Southborough, MA). The remaining three tamarins (So-1, So-5, and So-7) and the two marmosets (Cj-159 and Cj-181) were housed at the Wisconsin Regional Primate Research Center (Madison, WI). A blood sample from the white-faced saki monkey (Pithecia pithecia) was obtained from the Roger Williams Park Zoo (Providence, RI). Blood samples from one long-haired spider monkey (Ateles belzebuth) and one brown-headed spider monkey (A. fusciceps) were obtained from the Zoologico Santa Cruz (Mesitas del Colegio, Colombia).
RNA extraction, cDNA synthesis, and PCR
Total RNA was extracted from peripheral blood or lymphoblastoid
cell lines from all animals using RNAzol (Tel-Test, Inc., Friendswood,
TX). One microgram of the RNA was then used to synthesize cDNA with 1
µg of random hexamers (Promega, Madison, WI) and 50 U of SuperScript
II reverse transcriptase (Life Technologies, Gaithersburg, MD) in 20
µl of 1x PCR buffer (GeneAmp, Perkin-Elmer, Foster City, CA), 5 mM
MgCl2, 20 U of RNase inhibitor (Promega), and 1 mM of
each of the four deoxyribonucleotide triphosphates (dGTP, dATP, dTTP,
and dCTP; GeneAmp, Perkin-Elmer). The cDNA synthesis was conducted in a
Perkin-Elmer 9600 thermal cycler at room temperature for 10 min, at
42°C for 15 min, at 99°C for 5 min, and at 5°C for 5 min. PCR
amplification was then conducted using 25 pmol of the primers listed in
Table I
. The PCR mixture also included
1x PCR buffer, 2 mM MgCl2, 2.5 U of Taq polymerase
(Perkin-Elmer), and 20 µl of cDNA for a final volume of 100 µl. The
reactions were heated to 94°C for 2 min and then to cycling
conditions consisting of 30 rounds of 60-s denaturation at 94°C, 60-s
annealing at 60°C, and 90-s extension at 72°C. The reaction was
concluded with a 10-min final extension at 72°C.
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In preparation for direct sequencing, PCR products from the 5'LPXI/SOER1 and SOEF2/SOENDR2 amplifications of cDNA from animal S. oedipus 100-75 were electrophoresed on a 1% agarose gel. The appropriately sized bands were excised and purified using the Qiaex Gel Extraction Kit (Qiagen, Inc., Chatsworth, CA). Fifty to one hundred nanograms of each purified PCR product was sequenced using the Taq DyeDeoxy Terminator Cycle Sequencing Kit (Perkin-Elmer). All samples were sequenced in both directions using the forward and reverse PCR primers and subsequently run on a 4.75% polyacrylamide gel using an ABI 373 automated sequencer.
Denaturing gradient gel electrophoresis (DGGE)
Optimal conditions for separation of platyrrhine MHC-E locus alleles using DGGE were initially established by separating MHC class I alleles of the cotton-top tamarin on a perpendicular denaturing gradient as described by Myers and co-workers (30) and Scheffield and co-workers (31). Briefly, 100 µl of the GC-clamped PCR product was electrophoresed in an 8% acrylamide (37.5/1, acrylamide/bisacrylamide) gel with an increasing gradient from 0 to 80% denaturant (100% denaturant = 7 M urea and 40% formamide). Perpendicular DGGEs were run on a Bio-Rad D-GENE (Bio-Rad, Richmond, CA) apparatus in 1x TAE buffer at 60°C constant temperature. Samples were electrophoresed for 3.5 h at 300 constant V. Following electrophoresis, the perpendicular gel was silver stained according to a method described by Bassam and co-workers (32), and the optimum gradient conditions were identified.
To separate the MHC-E locus alleles, 1 to 5 µl of the EA1MID/A3 MID+GC-clamped PCR products were mixed with 3x loading buffer and electrophoresed on a 50 to 65% parallel denaturing gradient according to a method described by Myers and co-workers (30). As described for perpendicular DGGE, the 8% acrylamide gel was electrophoresed in a Bio-Rad D-GENE apparatus in 1x TAE buffer at 60°C constant temperature. MHC-E PCR products were electrophoresed for 3.75 h at 300 constant V. Individual bands on the parallel DGGE gels were visualized using SYBR-Green stain (Molecular Probes, Eugene, OR) and UV illumination. Individual gel plugs were removed from the visualized bands using wide-bore pipette tips, and the DNA was eluted in 50 µl of distilled water at room temperature overnight.
Direct sequencing of platyrrhine E-locus alleles
To generate PCR product for fluorescent-based sequencing, a
5-µl aliquot of the eluate was amplified using the primer pairs EA1
MIDRM13 and A3 MIDM13 (Table I
C). DNA was reamplified
in 50 µl of 1x PCR buffer (Perkin-Elmer); 2.0 mM MgCl2;
2.5 mM of each dGTP, dATP, dTTP, and dCTP; 12.5 pmol of each primer;
and 1.25 U of Taq polymerase. Cycling conditions consisted of 30 cycles
of 20-s denaturation at 94°C, 30-s annealing at 65°C, and 36-s
extension at 72°C, followed by a 10-min extension at 72°C.
In preparation for sequencing, 5 µl of each PCR product was incubated for 15 min at 37°C with 2 U of shrimp alkaline phosphatase and 10 U of exonuclease I (ExoI) to remove unincorporated dNTPs and residual single-stranded PCR primers, respectively (U.S. Biochemical Corp., Cleveland, OH). The shrimp alkaline phosphatase and ExoI enzymes were then inactivated with a 15-min incubation at 80°C, and the entire 7-µl reaction was diluted with 28 µl of distilled water. Five microliters of the diluted enzyme-treated PCR product was then sequenced using the Taq DyeDeoxy Terminator Cycle Sequencing Kit (Perkin-Elmer). Samples were run on a 4.75% polyacrylamide gel using an ABI 373 automated sequencer (Applied Biosystems, Foster City, CA). All reamplified DGGE bands were sequenced in both directions using the sequencing primers, -21 M13 and reverse M13 (33).
Sequence analysis and phylogenetic trees
The Saoe-E locus allele was initially identified by alignment to a database of primate MHC class I alleles previously identified using cloning and sequencing methods. The full-length sequence was subsequently compared with known classical and nonclassical MHC class I primate alleles in a phylogenetic tree constructed by the neighbor-joining method based upon distances estimated by the Jukes and Cantor method (34) using the computer program MEGA, version 1.02 (35). The analysis was conducted using 1042 nucleotides of the full-length sequence. Bootstrap analyses (36) using 500 replications were performed to determine the significance of MHC-E locus assignment. A second neighbor-joining analysis using 433 nucleotides was conducted using the cotton-top tamarin and other new platyrrhine MHC-E locus alleles described herein.
Patterns of nucleotide substitution
Patterns of nucleotide substitution in classical and nonclassical MHC class I genes were examined by calculating the number of nucleotide substitutions per synonymous (ds) and nonsynonymous (dN) sites (37). Pairwise comparisons were made between HLA-E and -F loci and chimpanzee, orangutan, macaque, and cotton-top tamarin MHC-E and -F loci, respectively. To illustrate the typical pattern of nucleotide substitution in classical MHC class I genes, ds and dN were compared in human, chimpanzee, gorilla, orangutan, gibbon and macaque MHC-B orthologues. We also calculated ds and dN for 11 different Saoe-G alleles that represent a minimum of three different paralogous classical MHC class I loci. The mean ds and dN were calculated by the method of Nei and Jin (38), and statistical significance was determined using a t test.
We also compared patterns of nucleotide substitution between MHC
class I genes and functional non-MHC type I IFN genes, IFN-
and
IFN-ß. Using a method described by Nei and Gojobori (37), we
estimated the proportion of synonymous nucleotide substitutions per
synonymous site (pS) and the proportion
of nonsynonymous nucleotide substitutions per nonsynonymous site
(pN) in the PBR and non-PBR for pairwise
comparisons of primate MHC-A, -B, -E,
and -F orthologues. For comparative purposes, the same
method was used to evaluate patterns of nucleotide substitution in the
receptor binding regions and non-receptor binding regions of mammalian
IFN- and IFN-ß alleles. As suggested by Hughes (39), the estimates
of pS and pN were not
corrected for multiple hits because the correction is not applicable to
short domains when the nucleotide sequences are distantly related.
MHC-E nomenclature
Official locus and allele names were given in accordance with the rules designated by the nonhuman primate MHC nomenclature committee (40). New sequences have been deposited in GenBank (AF004918 through AF004925).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine the degree of conservation of the
MHC-E locus in primates, we designed primers to amplify
MHC-E in cotton-top tamarins (Table IA).
With the 5'LPXI/SOER1 and SOEF2/SOENDR2 primers, we PCR-amplified two
overlapping cDNA fragments representing the full-length cotton-top
tamarin MHC-E gene (Fig. 1A). Direct sequencing
of MHC-E cDNAs from four unrelated tamarins revealed that
the sequence was identical in all individuals.
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The predicted amino acid sequence of the cotton-top tamarin
cDNA, Saoe-E*01, is shown in Figure 2. Interestingly, the
Saoe-E*01 sequence shares unique characteristics with the
HLA-E alleles. For example, like the MHC-E
sequences described for humans and the orangutan, Saoe-E*01
contains a deletion in exon 7 that may result in a shortened
cytoplasmic domain. Surprisingly, this same deletion has not been
observed in the MHC-E alleles of macaques. However, both the
rhesus macaque allele, Mamu-E*05, and the cotton-top
tamarin, Saoe-E*01, have a three-nucleotide deletion in the
transmembrane region that is absent in HLA-E,
Popy-E, and Mafa-E.
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). These five residues (positions 65, 73, 82, 149, and 170) form
portions of the -helixes and include one TCR contact residue
(position 65) (41) and one C peptide-binding pocket residue (position
73) (42).
Consistent with previous analyses of patterns of synonymous
substitutions within the putative PBR of MHC-E alleles in
other primates, comparisons between Saoe-E*01 and
HLA-E*01 demonstrate that the number of synonymous
(dS) nucleotide substitutions was
significantly greater than the number of nonsynonymous
(dN) substitutions (Table II). The dS
values, in changes per 100 synonymous sites, and
dN values, in changes per 100 nonsynonymous
sites, between Saoe-E*01 and HLA-E*01 in the PBR
are 33.0 ± 11.0 and 6.7 ± 2.3, respectively. In non-PBR
sites the values for dS are 2 to 5 times greater
than the dN values in the same region. Analysis
of the PBR sites of classical MHC class I molecules encoded by the
MHC-B or Saoe-G loci demonstrates that
dN is significantly greater than
dS (Table II). Thus, in contrast to the low
dS/dN ratio reported for
PBR vs non-PBR sites in homologues of the classical MHC class I loci,
the dS/dN ratios for PBR
sites in MHC-E alleles are extraordinarily high. The high
dS/dN ratios reported for
the PBR of MHC-E alleles, however, is not observed when the
PBR of another nonclassical MHC class I locus present in humans, rhesus
macaques, and cotton-top tamarins (HLA-F,
Mamu-F, and Saoe-F, respectively) is analyzed.
Instead, the dS/dN ratios
for the comparison between human and rhesus macaque PBR and between
human and cotton-top PBR are 1.1 and 0.38, respectively (Table II).
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To identify MHC-E genes in other New World monkey
species, a second set of PCR primers was designed to amplify the most
polymorphic portions of exons 2, 3, and 4 of MHC-E genes
(Fig. 1B and Table IB). Following reverse
transcription-PCR amplification with the EA1MID and A3MID+GC-clamped
primers, we analyzed our 510-bp PCR product using DGGE. Because each
allele at a particular locus is the same length, individual alleles
cannot be discriminated on agarose gels. Instead, alleles can be
separated on a denaturing gradient gel according to differences in
sequence composition. When DNA fragments are electrophoresed through an
increasing gradient of denaturants composed of urea and formamide, the
two DNA strands of each allele dissociate at different rates because of
sequence-specific differences in denaturation. As a consequence, each
allele migrates at a unique rate through the gel. To maximize the
separation of alleles that differ by only one or two nucleotide
substitutions, a G+C-rich sequence (GC-clamp) is attached to the PCR
product during amplification (31). The optimum denaturing gradient for
each PCR product can then be determined by analyzing DNA fragments with
a perpendicular denaturing gradient according to a method described by
Myers and co-workers (30). Once the optimum gradient is identified, PCR
products can be electrophoresed on an appropriate parallel denaturing
gradient (30). Perpendicular DGGE analysis of MHC class I genes in
cotton-top tamarins using perpendicular DGGE indicated that the optimal
denaturing gradient for separation of our reverse transcription-PCR
products was 50 to 65%.
Parallel DGGE analysis of MHC-E locus cDNAs in New World
monkeys on a 50 to 65% denaturing gradient revealed one or two
MHC-E alleles in each species. Figure 3 shows the pattern of homoduplexes and,
in two cases, heteroduplexes identified in our DGGE analysis of 10 New
World monkeys. In the common marmosets and the brown-headed spider
monkey, two different alleles were identified for each individual. For
these samples, heteroduplex bands were also formed during the PCR when
complementary strands from the two alleles hybridized. The heteroduplex
bands exhibited less fluorescence and migrated at higher positions in
the gradient gel. Only one MHC-E locus sequence was
identified in our four unrelated cotton-top tamarins, the owl monkey,
the long-haired spider monkey, and the white-faced saki monkey.
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). In the Callitrichidae, both cotton-top tamarins
and common marmosets possessed nearly identical MHC-E cDNAs
within the region studied. Specifically, Saoe-E*01 and the
Caja-E*01 and -E*02 alleles differed by one and
two amino acids, respectively. Furthermore, all three cDNAs were
identical in the 36 peptide binding sites examined in the DGGE
analysis. The majority of residues in the PBR of the owl monkey
(Aotr-E*01) and spider monkeys
(Atfu-E*01, E*02, and
Atbe-E*01) were also conserved. However, it is
noteworthy that these four sequences are distinguished by an alanine,
rather than a serine, at position 147. The white-faced saki monkey
cDNA, Pipi-E*01, shared more common substitutions with the
MHC-E sequences of humans, apes, and Old World monkeys than
with the New World monkeys included in this study.
A gene tree of the full-length Saoe-E*01 cDNA and MHC class
I alleles from Old World monkeys, apes, and humans was performed to
evaluate the relationship between Saoe-E*01 and other
primate MHC class I genes. Figure 4
demonstrates that Saoe-E*01 is orthologous to
HLA-E. A second analysis of the new platyrrhine
MHC-E alleles clusters all the new E locus
alleles together based upon sequence from the middle of exon 2 through
the middle of exon 4 (Fig. 5).
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To examine the extent to which MHC-E genes have been
subject to purifying selection, we compared patterns of nucleotide
substitution for MHC-A, -B, and -E
alleles in primates, and IFN- and IFN-ß
genes in mammals (Fig. 6). Like MHC class
I genes, IFN- and IFN-ß genes possess
distinct binding domains that may be subject to different selective
pressures than the remainder of the mature protein. The patterns of
nucleotide substitution were examined by estimating the proportion of
synonymous nucleotide substitution per synonymous site and the
proportion of nonsynonymous nucleotide substitution per nonsynonymous
site, pS and pN,
respectively (37). In the case of MHC-A and MHC-B
loci, mean pS exceeds mean
pN in non-PBR sites. This pattern is seen in
gene regions where purifying selection acts to eliminate a substantial
portion of nonsynonymous mutations. On the other hand, the
pS/pN ratio is very low
in the PBR sites of MHC-A and MHC-B alleles,
where positive selection maintains diversity. The MHC-F
locus in primates exhibits a very low
pS/pN ratio in the PBR
and an extraordinarily high
pS/pN ratio in the
non-PBR sites. In contrast to the pattern of classical MHC class I
genes and MHC-F, a high
pS/pN ratio is found in
both PBR and non-PBR sites of MHC-E alleles. Notably, a high
pS/pN ratio is also found
in the binding sites of type I IFN- and IFN-ß genes, where strong
purifying selection acts to conserve the receptor binding region
(38).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recent studies of diverse human populations describe the presence
of two HLA-E alleles that differ by a single base pair
substitution in exon 3, resulting in an amino acid change from arginine
(R) to glycine (G) at position 107 (26, 44), which is found in the loop
between the ß-pleated sheet and the -helix segments of the peptide
binding groove (45). In Hutterites, African-Americans, and Hispanics,
these two HLA-E alleles are found in nearly equal frequency,
and it has been suggested that functional differences between the
alleles may exist (44). Among all nonhuman primates studied to date,
only glycine is found at position 107. However, the number of nonhuman
primate samples that have been analyzed remains too small to draw any
conclusions regarding functional differences between alleles within the
same species. Nevertheless, our demonstration that the PBR is well
conserved among primates suggests that the MHC-E molecule
serves a critical immunologic function that is probably related to
peptide binding. This unusual conservation of the PBR of
MHC-E combined with its limited polymorphism may be related
to the role of MHC-E molecules in the regulation of NK cell
activity.
Previously, molecular cloning and expression studies of MHC genes in the cotton-top tamarin have shown that the limited polymorphism and variability in the classical MHC class I genes of this species are due, at least in part, to rapid turnover of MHC class I loci. There is evidence for duplication of expressed MHC class I genes (27, 46) and recent inactivation of other MHC class I genes (47). Additionally, a small founder population may have contributed to fixation of newly arisen MHC class I genes (28). Even the HLA-F orthologue in the cotton-top tamarin has accumulated a large number of nonsynonymous substitutions, suggesting that this locus is not as well conserved in cotton-top tamarins as it is in Old World monkeys, apes, and humans. Despite the phylogenetic distance between humans and tamarins and the high rate of gene turnover in the callitrichids, the cotton-top tamarin MHC-E locus has remained remarkably intact and highly conserved. Thus, it is likely that purifying selective pressures have maintained the MHC-E locus throughout anthropoid primate evolution.
Interestingly, the nature and intensity of selective forces acting on the codons encoding the PBR are not identical in all MHC class I genes. While the accumulation of nonsynonymous nucleotide substitutions and the high degree of polymorphism in the codons encoding the PBR of classical MHC class I genes appear to have been driven by positive or diversifying selection (2), the high rate of synonymous nucleotide substitutions relative to the low rate of nonsynonymous nucleotide substitutions in the PBR of primate MHC-E alleles appears to be the consequence of purifying selection. Thus, the high rate of nonsynonymous nucleotide substitution in the PBR that is characteristic of most MHC class I molecules is absent in primate MHC-E genes. Instead, most of the variability reported for human, ape, and monkey MHC-E locus alleles is found in regions outside the PBR.
Although unusual with respect to the pattern of primate MHC class
I gene evolution, the evolutionary history of MHC-E genes is
remarkably similar to the evolution of non-MHC genes that remain highly
conserved due to important functional constraints. Purifying selection
has eliminated disadvantageous nonsynonymous substitutions in the
ß-strand-encoding region of primate ß2m (48). The
highly conserved reactive center region of 1-proteinase
inhibitors, which control neutrophil elastase activity within the
circulation, has also been maintained through purifying selection in
primates (49). Additionally, a parallel can be drawn between the
primate MHC-E molecules and the IFN- and
-ß genes. Molecular studies of mammalian type I
IFN have demonstrated that IFN- and
IFN-ß genes have been subject to purifying selection,
particularly within the putative receptor binding domains. Strong
functional constraints associated with IFN receptor binding, and hence
powerful selective pressure to eliminate nonsynonymous mutations in
regions involved in receptor binding, have dramatically shaped the
evolution of the IFN- and -ß genes in
mammals. Contrastingly, the pattern of nonsynonymous nucleotide
substitutions observed within the IFN-
genes suggests
that positive Darwinian selection has acted to diversify mammalian
IFN- (39). The pattern of diversification, common among
IFN- genes in mammals and among classical MHC class I
genes in primates, is virtually absent in mammalian IFN-
and -ß genes and in primate MHC-E genes, where
strong purifying selective pressures have conserved the critical
receptor and peptide binding regions.
Although the precise function of HLA-E molecules remains undescribed, the extraordinary conservation of the codons encoding the PBR of this locus throughout anthropoid primate evolution suggests that the products of the MHC-E locus play an important role in the primate immune response. Moreover, the remarkable similarities between HLA-E and the murine nonclassical MHC class Ib gene, Qa-1, offer clues to the function of the products of the HLA-E locus. Both Qa-1 and HLA-E loci exhibit reduced polymorphism, shared residues in highly invariant positions within the PBR (5), similar patterns of gene expression (5, 6), and the ability to bind signal sequence-derived peptides (5, 8). In the case of Qa-1, the molecules are known to present leader peptides from murine H-2D class I proteins to alloreactive T cells (7). Importantly, MHC-E transcripts have also been found in placental tissue in humans (50, 51) and macaques (24). Taken together, these findings suggest that further insight into the function of HLA-E genes may come from studies of primate placental and extraplacental membranes.
It appears that evolutionary selective pressures have conserved amino acids within the PBR of primate MHC-E molecules. Despite the seemingly numerous recombinations, inactivations, and duplications that have occurred at adjacent MHC class I loci throughout primate evolution, primate MHC-E genes have remained remarkably preserved over approximately 55 million yr (52). Our MHC-E sequence data from New World monkeys and comparisons with other primate MHC genes suggest that the MHC-E locus is the most well conserved of all known primate histocompatibility genes, and the remarkable evolutionary history of the codons encoding the PBR suggests an important immunologic role for HLA-E.
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Acknowledgments |
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Footnotes |
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2 The sequences reported in this manuscript have been deposited with GenBank under accession numbers AF004918 to AF004925.
3 Address correspondence and reprint requests to Dr. Leslie A. Knapp, Dept. Biological Anthropology, University of Cambridge, Downing Street, Cambridge, CB2 3DZ, U.K.
4 Abbreviations used in this paper: PBR, peptide binding region; DGGE, denaturing gradient gel electrophoresis.
Received for publication June 9, 1997. Accepted for publication September 15, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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J. A. Urvater, N. Otting, J. H. Loehrke, R. Rudersdorf, I. I. Slukvin, M. S. Piekarczyk, T. G. Golos, A. L. Hughes, R. E. Bontrop, and D. I. Watkins Mamu-I: A Novel Primate MHC Class I B-Related Locus with Unusually Low Variability J. Immunol., February 1, 2000; 164(3): 1386 - 1398. [Abstract] [Full Text] [PDF]
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A. Kubota, S. Kubota, S. Lohwasser, D. L. Mager, and F. Takei Diversity of NK Cell Receptor Repertoire in Adult and Neonatal Mice J. Immunol., July 1, 1999; 163(1): 212 - 216. [Abstract] [Full Text] [PDF]
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D. T. Evans, L. A. Knapp, P. Jing, M. S. Piekarczyk, V. S. Hinshaw, and D. I. Watkins Three Different MHC Class I Molecules Bind the Same CTL Epitope of the Influenza Virus in a Primate Species with Limited MHC Class I Diversity J. Immunol., April 1, 1999; 162(7): 3970 - 3977. [Abstract] [Full Text] [PDF]
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