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The Journal of Immunology, 2004, 172: 6152-6157.
Copyright © 2004 by The American Association of Immunologists

Genetic Makeup of the DR Region in Rhesus Macaques: Gene Content, Transcripts, and Pseudogenes1

Nanine de Groot2, Gaby G. Doxiadis, Natasja G. de Groot, Nel Otting, Corrine Heijmans, Annemiek J. M. Rouweler and Ronald E. Bontrop

Department of Comparative Genetics and Refinement, Biomedical Primate Research Centre, Rijswijk, The Netherlands


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
In the human population, five major HLA-DRB haplotypes have been identified, whereas the situation in rhesus macaques (Macaca mulatta) is radically different. At least 30 Mamu-DRB region configurations, displaying polymorphism with regard to number and combination of DRB loci present per haplotype, have been characterized. Until now, Mamu-DRB region genes have been studied mainly by genomic sequencing of polymorphic exon 2 segments. However, relatively little is known about the expression status of these genes. To understand which exon 2 segments may represent functional genes, full-length cDNA analyses of -DRA and -DRB were initiated. In the course of the study, 11 cDRA alleles were identified, representing four distinct gene products. Amino acid replacements are confined to the leader peptide and cytoplasmatic tail, whereas residues of the {alpha}1 domain involved in peptide binding, are conserved between humans, chimpanzees, and rhesus macaques. Furthermore, from the 11 Mamu-DRB region configurations present in this panel, 28 cDRB alleles were isolated, constituting 12 distinct cDRA/cDRB configurations. Evidence is presented that a single configuration expresses maximally up to three -DRB genes. For some exon 2 DRB sequences, the corresponding transcripts could not be detected, rendering such alleles as probable pseudogenes. The full-length cDRA and cDRB sequences are necessary to construct Mhc class II tetramers, as well as transfectant cell lines. As the rhesus macaque is an important animal model in AIDS vaccine studies, the information provided in this communication is essential to define restriction elements and to monitor immune responses in SIV/simian human immunodeficiency virus-infected rhesus macaques.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
The rhesus monkey provides a valuable model in preclinical studies of infectious and chronic diseases as well as for tissue and organ transplantation (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11). The application of macaques in immunological research necessitates an extensive characterization of the MHC region, because the high degree of polymorphism of most of its genes is not only a main characteristic in humans, but also in nonhuman primates (12). Cell surface glycoproteins of the MHC, divided into class I and class II gene products, present peptides to effector T cells, and therefore play an important role in adaptive immunology. As one would expect, several susceptibility or resistance traits have been mapped to particular Mhc alleles in humans and rhesus macaques (13, 14, 15, 16, 17, 18, 19, 20, 21, 22).

The polymorphic MHC class II genes of the rhesus macaque (MhcMamu) map to the DP, DQ, and DR regions. One expects that, as is found in humans, the actual polymorphism is mostly confined to exon 2 of the Mamu-DPB1, -DQA1, -DQB1, and -DRB loci encoding the contact residues of the peptide binding site. As a consequence, Mamu class II sequencing has been mainly focused on the determination of allelic variation at exon 2 segments.

The Mamu-DRA locus encoding the DR {alpha}-chain is thought to be monomorphic and highly conserved through primate evolution, as it shows only limited variation in comparison to HLA-DRA (23). The organization of the Mamu-DRB region is complex and it displays variation at the population level with regard to number and/or combination of loci present per configuration (24, 25, 26, 27, 28). In humans, the number of -DRB loci present per configuration differs from one to four, whereas in the rhesus macaque, one to eight loci can be observed (12, 28). Only five HLA-DRB region configurations are known, and all of them display a high degree of polymorphism, mainly at the -DRB1 locus (29, 30). The situation in rhesus macaques is radically different, as >30 Mamu-DRB region configurations have been described so far (28). Although the total number of apparent Mamu-DRB alleles is comparable to those of the HLA-DRB1 locus, the Mamu-DRB region configurations themselves show only a limited degree of allelic variation (25, 26).

The absence or lack of allelic polymorphism at Mamu-DRB region configurations can be explained in several ways. One interpretation is that these configurations are relatively young and did not have time to accumulate variation. Alternatively, it is conceivable that these configurations experience conservative selection and have been maintained over longer evolutionary time spans. In both cases, rhesus macaques used a radically different strategy than humans to initiate Th cell responses to combat infections. While the human population invested mainly in generating a high degree of allelic variation at the various DRB loci, the rhesus macaque population primarily generated a large number of singular combinations of DRB loci. We published evidence recently that Mamu-DR/DQ configurations appear to be unique for a given population living at distinct geographic locations (31). This implies that Mamu-DR/DQ region configurations originated after the separation of eastern and western rhesus macaque populations, which is thought to have been caused by a glacial ice barrier during the Pleistocene era (32).

Most of the Mamu-DRB alleles belong to lineages or loci that are shared between humans and macaques. In addition, present in the rhesus macaque are loci/lineages for which no human equivalent is known (-DRBW). Some of the Mamu-DRB loci appear to have been duplicated and can be present twice, or even three times, on the same configuration (26).

One needs to realize that many pseudogenes have been identified in the various HLA-DR regions. However, little is known about the expression of the various Mamu-DRB loci, lineages, or alleles. For example, the Mamu-DRB6 locus, although it may be transcribed (33, 34), does not seem to code for a functional class II gene product, because its exon 2 sequences show various characteristics such as inserts, stop codons, and deletions that would render it a pseudogene (24). Only for some alleles of the Mamu-DRB1*03, -DRB1*10, -DRB1*04, -DRB*W3, DRB*W4, and -DRB*W5 lineages, immunoprecipitation studies suggested that these particular alleles code for a class II molecule (12, 35). Restriction element studies revealed that certain alleles of the -DRB1*03 lineage, as well as -DRB1*0406 and -DRB*W201, encode gene products which are able to present peptides to CD4+ Th cells (1, 36, 37). Only for these last two alleles, and one particular -DRB1*03 allele, has the complete cDRB sequence been published (23). Mamu-DRB1*0406, and especially -DRB*W201, seem to be significant restriction elements in cellular response to conserved regions of SIV/simian human immunodeficiency virus (38, 39).

To assign a full-scale analysis of the Mamu-DR region genetic makeup and the transcription of its genes, we analyzed cDRA and cDRB alleles present on the most prominent -DR region configurations in our pedigreed colony of rhesus macaques.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Animals and cells

The rhesus macaques (Macaca mulatta) were serologically typed for their MHC class I (Mamu-A and -B) and class II (Mamu-DR) Ags. In the Biomedical Primate Research Center breeding colony (Rijswijk, The Netherlands), 253 MHC haplotypes have been defined based on the segregation of 13 Mamu-A, 14 Mamu-B, and 9 Mamu-DR serotypes. Peripheral blood lymphocytes or immortalized B cell lines used in this study originate from 14 pedigreed animals in Biomedical Primate Research Center’s self-sustaining colony (Indian origin). Of these rhesus macaques, five were homozygous and derived from consanguineous origin, two were homozygous, and seven were heterozygous for their Mhc regions. This panel covers 11 of the most frequent Mamu-DRB region configurations present in our colony, as well as some examples of DRB region configurations displaying allelic polymorphism (12, 26, 28, 31).

RNA extraction, cDNA synthesis, and amplification

RNA was extracted from immortalized B cell lines of rhesus macaques using the RNeasy mini kit (Qiagen, Hilden, Germany) according to the manufacturer’s recommendations. cDNA was then synthesized from freshly extracted mRNA using the Universal RiboClone cDNA Synthesis System (Promega, Madison, WI) according to the manufacturer’s recommendations. Full-length Mamu-DRA sequences were amplified by PCR from cDNA using primers specific for human DRA 5' and 3' untranslated sequences (1): 5'DRA-SalI, 5'-TCC CGT CGA CCG CCC AAG AAG AAA ATG GCC-3', and 3'DRA-BamHI, 5'-CAT TGG ATC CGA AGT TTC TTC AGT GAT CTT-3'.

Likewise, Mamu-DRB sequences were amplified by PCR using primers specific for human 5'- and 3'-untranslated sequences (1): 5'DRB-SalI, 5'-GCC CGT CGA CCT GTC CTG TTC TCC AGC ATG-3', and 3'DRB-BamHI, 5'-GGC GGG ATC CCT TTT CAT CCT GCA AAG CTG-3'. Primers were synthesized by Invitrogen (Paisley, U.K.). PCR was performed in a 100 µl reaction volume containing 5 U of Taq polymerase (kindly donated by M. Mörl, Max-Planck-Institut, Saarbrücken, Germany) with 0.5 µM of each primer, 1.5 mM MgCl2, 250 µM dNTPs, 1x PCR buffer II (Applied Biosystems, Foster City, CA), and 10 µl of DNA. The cycling parameters were a 2 min at 94°C initial denaturation step, followed by 25 cycles of a 2 min at 94°C denaturation step, a 2 min at 60°C annealing step, and a 2 min at 72°C extension step. A final extension step was performed for 7 min at 72°C.

Cloning and sequencing

PCR products were digested with the restriction enzymes SalI and BamHI (Invitrogen). The 5' SalI and 3' BamHI restriction sites facilitated sticky-ended ligations into the multiple cloning site of the sequencing vector M13mp18 (Qbiogene, Montreal, Canada). The M13mp18 vector includes a M13 sequence before the cloning site, which is used for the sequencing of the product. The purified cDNA was sequenced on the ABI 3100 genetic analyzer (Applied Biosystems, Foster City, CA) using 0.2 µM M13 primer, 1 µl of BigDye Terminator (Applied Biosystems), and 2 µl of 5x dilution buffer (400 mM Tris-HCl, 10 mM MgCl2) in a total of 10 µl. The resulting sequences were analyzed using the Sequence Navigator program (Applied Biosystems). All sequences have been deposited in the databank (cDRA accession numbers: AJ586874–AJ586884, and cDRB accession numbers: AJ601348–AJ601351, AJ601354–AJ601362, and AJ601364–AJ601372) and are also available via the IMGT/MHC database (www.ebi.ac.uk/ipd/mhc/nhp; European Bioinformatics Institute, Cambridge, U.K.).

Phylogenetic analysis

Phylogenetic analysis of the cDRA and cDRB sequences was performed using PAUP, version 4.0b.10 (40). Pairwise distances were calculated using the Kimura-2 parameter, and the neighbor-joining method was used to create a phylogram. Confidence estimates of the groupings were calculated according to the bootstrap method generated from 1000 replicates.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Mamu-cDRA alleles

As in humans, the Mamu-DRA gene encoding the DR {alpha}-chain is thought to be monomorphic. However, only one study on a full-length cDRA sequence has been published (23) and to our knowledge, population analyses have not been conducted. To investigate the existence of Mamu-DRA polymorphism, full-length cDRA alleles of 17 selected B cell lines have been amplified and sequenced. This enterprise resulted in the detection of 11 unpublished cDRA alleles. Based on deduced amino acid sequences, four distinct Mamu-cDRA transcripts could be distinguished in our panel named Mamu-DRA*0102 to -DRA*0105 (Fig. 1, A and B). The existence of the previously reported Mamu-DRA*0101 allele could not be confirmed in our panel of Indian monkeys, but its sequence is nevertheless included in the alignments. Most of the alleles have point mutations with a synonymous character, as is reflected in the names of the alleles: Mamu-DRA*01021 to -DRA*01027 (30). The end of exon 3 of the Mamu-DRA alleles is characterized by the presence of two different motifs (Fig. 1A). Phylogenetic analysis demonstrates that, based on the presence of these motifs, the Mamu-DRA alleles cluster into two distinct lineages (Fig. 2). Based on the generally accepted divergence time of rhesus monkeys and humans of 35 million years, the mean evolutionary rate of HLA-DRA and Mamu-DRA alleles can be calculated to be ~0.31 x 10–9 substitutions per site, per year (41). The divergence time of the two Mamu-DRA lineages is then calculated to be >10 million years. Thus, the Mamu-DRA lineages seem to be relatively old and, as a consequence, they may also be present in other macaque and Old World monkey species. The Mamu-DRA*01041 and -DRA*01042 alleles code for the same protein (Fig. 1B). However, they do group into different lineages (Figs. 1A and 2). This example illustrates that the boxed polymorphic motif probably has been exchanged in a recombination-like event (Fig. 1A). Hence, at this stage we have decided not to implement a nomenclature protocol that discriminates between the two Mamu-DRA lineages.



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  		FIGURE 1. Polymorphic sites of the full-length coding Mamu-DRA nucleotide sequences (A) and deduced amino acid sequences (B) in comparison to HLA-DRA and Patr-DRA. Only polymorphic sites are shown using small and capital letters, which indicates synonymous and nonsynonymous mutations, respectively. Identity to the consensus is illustrated by a dash. The Mamu-DRA*0101 sequence published earlier is boxed (23 ). The two shadowed boxes represent two distinct lineages. 4 Patr, Pan troglodytes; 5 LP, leader peptide; 6 TD, transmembrane domain; 7 CD, cytoplasmatic domain.

 


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  		FIGURE 2. Phylogenetic tree of HLA-, Patr-, and Mamu-cDRA alleles. As in Fig. 1, the shadowed boxes represent two distinct lineages. The tree is rooted with Patr-DRA as the outgroup. 4 Patr, Pan troglodytes.

 
Whereas the synonymous mutations are randomly distributed over the entire cDRA sequence, the nonsynonymous mutations observed in the rhesus macaque panel result in amino acid replacements restricted to the leader peptide or the cytoplasmic domain (Fig. 1, A and B). If one takes the HLA-DR {alpha}-chain as a reference, the chimpanzee orthologue displays only two polymorphic residues, whereas in total, 16 aa replacements have been observed in the Mamu-DR {alpha}-chains (Fig. 1B). Humans, chimpanzees, and rhesus macaques shared a common ancestor >35 million years ago. Because all the anchor residues of the {alpha}1 domain have been conserved in all three primate species studied (Fig. 1B), this observation underlines the importance of these specific amino acids for peptide binding. The question left to answer is why do rhesus macaques display polymorphism at the Mamu-DRA gene, and is a similar phenomenon apparently not the case for HLA-DRA gene in the human population? One argument could be that not many human subjects have been studied for HLA-DRA polymorphism. A more plausible explanation takes the differential divergence times of both species into account, which is thought to be 250,000 years for modern humans and ~700,000 years for rhesus monkeys (32, 42, 43). In brief, the time period needed to accumulate point mutations was approximately three times longer for rhesus macaques. On top of that, and as will be discussed later in detail, the Mamu-DRA alleles appear to be more or less Mamu-DR configuration-specific. This suggests that some of these DR configurations may have been stable entities over a relatively long evolutionary time span.

Mamu-cDRB alleles

To date, 134 Mamu-DRB exon 2 sequences have been identified (30). Most of these alleles belong to loci/lineages that are shared between humans and rhesus macaques, whereas for the DRB*W alleles, no human equivalents have been described. Little is known about the gene products (35) and only a meager number of full-length cDRB sequences have been published so far (23, 37). To learn more about the peptide-binding profiles of rhesus macaque class II molecules it is, in the first place, essential to know if the class II genes are actually expressed. An example is provided by the Mamu-DRB*W201 molecule, which plays an important role in the peptide binding of conserved epitopes of the simian human immunodeficiency virus (39, 44).

To obtain more fundamental insight into the genetics of the Mamu-DR region and the expression status of the various genes, cDRB genes were analyzed in a panel of 15 animals with thoroughly defined DRB configurations. From these animals, 28 cDRB alleles could be isolated, and the deduced amino acid sequences have been determined (Fig. 3). Moderate heterogeneity is observed within the {beta}2 domain, whereas relatively little variation is noticed in the leader peptide, connecting peptide, transmembrane domain, and cytoplasmatic domain. As expected, the {beta}1 domain encoded by exon 2 represents the most polymorphic part of the -DRB gene. Most of the residues that are known from the HLA-DRB1 molecule to contribute to the peptide binding are variable in the rhesus macaque (45). Phylogenetic analysis shows that alleles of the same lineage within one species, for example, members of the Mamu-DRB*W6 lineage, cluster tightly together. A similar observation can be made for rhesus macaque, chimpanzee, and human -DRB5 lineage (Fig. 4). If sequences fall apart in the phylogenetic analysis, an identical or similar motif constituted by aa 9–13, has been the decisive factor for lineage designation. (Figs. 3 and 4).



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  		FIGURE 3. Deduced amino acid sequences of full-length Mamu-cDRB alleles. The HLA-DRB1*0101 sequence is chosen as reference. Identity to the consensus is illustrated by dashes. The three Mamu-DRB alleles published earlier are boxed (23 ). The underlined and shadowed amino acid sequences of the {beta}1 domain, represent the motifs differentiating the lineages. CP, Connecting peptide; TD, transmembrane domain; CD, cytoplasmatic domain.

 


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  		FIGURE 4. Phylogenetic tree of HLA-, Patr-, and Mamu-cDRB alleles. Some selected HLA-DRB and Patr- alleles, representing different lineages, have been added to the phylogenetic analysis. The tree was rooted with the -DRB orthologue, Sanguinus oedipus -DRB*02, of the cotton-top tamarin as the outgroup. 9 Saoe, Sanguinus oedipus.

 
Mamu-DR configurations

Although Mamu-DRB sequences show a high degree of variability, the main feature is its unprecedented -DRB region configuration polymorphism, which is defined by a variable number and content of -DRB genes per haplotype (28). Animals selected for this study possess the 11 most prominent Indian DRB region configurations in our colony and each configuration harbors 2–4 -DRB genes (28, 31). In addition, nearly every Mamu-DRB configuration contains 1–3 DRB6 genes, most of them characterized by a 62 bp deletion (24, 26). The choice of animals, which are mainly homozygous for their MHC, allowed us to define the DRA/DRB gene combinations segregating on one haplotype (Fig. 5). As can be seen, the 11 Mamu-DRB region configurations analyzed previously could be divided into 12 different DRA/DRB combinations. Only one -DRB region configuration displayed limited allelic variation at the DRB loci (Fig. 5; 1a, 1b, 2a, and 2b), which can be separated into two DRA/DRB configurations according to different accompanying -DRA alleles. The DRB combinations 1a/1b and 2a/2b differ only for one nucleotide in their DRB1*03 or DRB1*10 lineage alleles, respectively. This is most likely an example of a polymorphism that was generated after the DRB region configurations themselves were established. We have postulated that the differential numbers of Mamu-DR genes and their order is due to rearrangements by unequal crossing-over events (12, 26). In this light, the following observation is highly indicative. In one rhesus macaque of Burmese origin, three different -DRA alleles have been detected, and the presence of two -DRA alleles on one haplotype was proven by segregation analysis (data not shown). This unique configuration is probably caused by an unequal crossing-over event, once again illustrating the great plasticity of the Mamu-DR region. Future plans to initiate the sequencing of the whole genome of the rhesus macaque will elucidate the order of the genes and shed light on the recombination hotspots and physical distances between the different loci. On average, one can conclude, however, that most of the DRB configurations segregate in combination with a unique Mamu-DRA allele (Fig. 5).



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  		FIGURE 5. Overview of the gene content of Mamu-DRA/DRB configurations. The different configurations are numbered arbitrarily in Arabic numerals; same configurations with allelic variations are indicated by A and B, respectively. Expressed loci/alleles are depicted in black, whereas pseudogenes are boxed. aOnly DRB6 alleles without the 62-bp deletion are listed. bMHC homozygous animals from consanguineous matings. cMHC homozygous animals. dDRA allele belonging to this confirmation was detected by sequencing analysis of genomic DNA. eThe serological Mamu-DR nomenclature is described by Bontrop et al. (46 ).

 
DR region: transcripts and pseudogenes

Some of the -DRB exon 2 sequences detected by amplifying genomic DNA could not be recovered at the transcript level. In the case of the configuration n 4, the Mamu-DRB6*0101 and -DRB1*0309 genes are not transcribed in such a way that they result in a functional {beta}-chain (Fig. 5). This result was confirmed by the analysis of cDRB of a Burmese-origin rhesus macaque family, in which exon 2 of the DRB1*0309 allele can also be detected on the genomic, but not on the cDNA level. These results have been validated by dot-blot experiments (results not shown). In the case of the Mamu-DRB6 gene, this observation is not surprising because this gene is a pseudogene in humans and chimpanzees (33). Because the separation of eastern (Burmese and Chinese) and western (Pakistan and Indian) macaque populations is speculated to be due to a glacial barrier during the Pleistocene era, the probable inactivation of a formerly active gene took place before that time point (32). In the case of the MHC, it has been shown that pseudogenes are maintained over long evolutionary time spans. This may be due to a "piggy back" effect (one gene is linked to another that is experiencing strong conservative or positive selection). It has also been hypothesized that pseudogenes are a reservoir for gene segments that can be exchanged between related genes by recombination-like processes. In contrast, some pseudogenes contain premature stop codons and may be partially translated into proteins. In such a case, a pseudogene may encode peptides that are important for thymic education/selection.

In five other -DRA/DRB conformations (Fig. 5; n = 3, 6, 9, 11, and 12), there is one -DRB allele of which the exon 2 sequence of genomic DNA was sequenced, but a transcript has not been detected. The results have been confirmed by analysis of a second animal with the same region configuration and whenever necessary, they have been repeated (data not shown). These untranscribed alleles belong to various loci/lineages that have most likely been inactivated and now can be considered as pseudogenes. This phenomenon is known from the human situation where DRB6 as well as other DRB loci, for example DRB2, are rendered as pseudogenes.

However, in rhesus macaques, a certain -DRB locus or even a lineage may harbor transcribed, as well as untranscribed, alleles (pseudogenes); examples are given for -DRB1*03, -DRB3, and Mamu-DRB*W6 (Fig. 5; n = 3, 4, 6, 9, and 11). In relation to HLA, the Mamu-DRB5 locus appears to be coding, whereas none of the -DRB6 alleles was completely transcribed, which is an indication that this locus is a pseudogene in the rhesus macaque as well. The number of Mamu-DRB genes that are transcribed into RNA can vary from 1 to 3 per haplotype.

The results of this study provide a detailed answer to the question of which -DRB alleles are transcribed, and they unravel the complexity caused by the large number of Mamu-DRB region configurations. In conclusion, the data presented here will be invaluable in preclinical studies in which a detailed knowledge of the rhesus macaque DR region makeup is essential.


   Acknowledgments
 
We thank Donna Devine for assistance in editing the manuscript, and Henk van Westbroek for preparing the figures.


   Footnotes
 
1 This study was supported in part by the European Union Project IMGT-QLG2-CT 2000-01287 and the National Institutes of Health Project 1-R24-RR16038-01 (Catalog of Federal Domestic Assistance 93.306). Back

2 Address correspondence and reprint requests to Dr. Nanine de Groot, Biomedical Primate Research Centre, Lange Kleiweg 139, 2288 GJ Rijswijk, The Netherlands. E-mail address: nanine.de.groot{at}bprc.nl Back

Received for publication November 14, 2003. Accepted for publication February 27, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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