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Genome Res. 14:1501-1515, 2004 ©2004 by Cold Spring Harbor Laboratory Press; ISSN 1088-9051/04 $5.00 Letter Genetic Divergence of the Rhesus Macaque Major Histocompatibility Complex1 The Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA 2 Institute for Systems Biology, Seattle, Washington 98103, USA
The major histocompatibility complex (MHC) is comprised of the class I, class II, and class III regions, including the MHC class I and class II genes that play a primary role in the immune response and serve as an important model in studies of primate evolution. Although nonhuman primates contribute significantly to comparative human studies, relatively little is known about the genetic diversity and genomics underlying nonhuman primate immunity. To address this issue, we sequenced a complete rhesus macaque MHC spanning over 5.3 Mb, and obtained an additional 2.3 Mb from a second haplotype, including class II and portions of class I and class III. A major expansion of from six class I genes in humans to as many as 22 active MHC class I genes in rhesus and levels of sequence divergence some 10-fold higher than a similar human comparison were found, averaging from 2% to 6% throughout extended portions of class I and class II. These data pose new interpretations of the evolutionary constraints operating between MHC diversity and T-cell selection by contrasting with models predicting an optimal number of antigen presenting genes. For the clinical model, these data and derivative genetic tools can be implemented in ongoing genetic and disease studies that involve the rhesus macaque.
Genetic and evolutionary studies of the immune response have often centered on the major histocompatibilty complex (MHC), comprised of the class I, class II, and class III regions, and including the MHC class I and class II genes involved in immune recognition (Parham 1999
Among the first immune loci to be carefully studied in the rhesus macaque (macaca mulatta or mamu) were the class I and class II loci (Watkins 1994
Beyond the preliminary characterization of class I and class II cDNAs and genomic clones, little information is available about the larger-scale genetic structure of the macaque MHC and about the diversity of MHC genes other than class I and class II. Because more than a third of MHC resident genes may be involved in the immune response (MHC Consortium 1999 These considerations provided motivation to better understand the genetic diversity and genomics of the immune response in rhesus macaques both to aid clinical studies, as well as to advance our understanding of the evolutionary history of primates through comparative genomic analysis. Toward these ends, we have obtained finished high-quality sequence data spanning the complete mamu MHC. Among the differences between rhesus and human observed, were a major expansion from six class I genes per haplotype in humans to as many as 22 potentially active MHC class I genes on a single haplotype in rhesus. In addition, high levels of genetic polymorphism were found over most of the region, including within many other MHC resident genes.
Isolation and Sequencing of the Rhesus MHC To isolate the rhesus MHC region, we utilized PCR amplicons derived from the finished human MHC sequence (MHC Consortium 1999  ) to generate macaque probes for screening the BAC resource (Geraghty et al. 2002). Using this strategy, it was possible to map clones for sequencing and to assign each BAC to one of the two haplotypes represented in the library. Subsequent clone isolations required the use of sequence data from the ends of BACs bordering gaps to generate new PCR probes for additional library screening. A contiguous sequence assembly derived from 54 BACs and five short gaps spanning the mamu MHC is presented in
Figure 1.
The sequence extends from the telomeric end near mamu-F to the centromeric end following mamu-DP over a distance of 5,291,973 bp. The telomeric class I sequence extending into the approximate middle of the mamu-B region, is derived from a single haplotype excepting  29 kb derived from BAC 337E2. The sequence including the entire B region extending to the end of mamu class II was obtained from a second haplotype without gaps. An additional 2,131,545 bp have been derived from overlapping sequence from the alternate chromosome. All of the sequences were high-quality finished data, essential to distinguish functional genes from nonfunctional genes, especially in the mamu-A and mamu-B regions, where single nucleotide substitutions were responsible for inactivating some of the class I genes.
The Rhesus MHC Compared With the Human The first striking observation apparent between the rhesus and human was the relatively large increase in size of the rhesus MHC. Where the human sequence extends over 3.7 Mb, the rhesus spans about 5.3 Mb, given the same start and end positions. Virtually all of this size difference is the result of significant internal expansions within the mamu class I A and class I B gene regions (Fig. 1). In other regions, the overall gene content of rhesus largely parallels that of human. In total, 10 genes or pseudogenes are distinct between human and rhesus, four found in human, but not rhesus, and six in rhesus, but not human, and an additional eight that are common to both MHCs, but which are altered relative to one another by changes in the protein-coding start or stop positions (color coded in Fig. 1). The remainder of the gene content of some 140 genes appears unaltered, with expected coding-sequence divergence. All comparisons with the human MHC are largely paralleled with any of the chimpanzee, as a recent analysis confirmed the existence of a high degree of sequence similarity between the human and chimpanzee class I regions (Anzai et al. 2003).
The Mamu-A and Mamu-B Regions
Segmental duplication has also occurred in the mamu-B region in one of the most remarkable findings of this work. In humans, the two HLA-B and HLA-C genes lie within a 100-kb segment, whereas the largely equivalent region containing the mamu-B genes has swelled to about 1.3 Mb. This increase has resulted from a complex series of segmental duplications and a single transposition of some 43 kb of sequences from the mamu-A region (including mamu-75a3). In the complete haplotype 1 sequence presented in Figure 3, 19 mamu-B-like genes were found arrayed in a tandem arrangement. Similar to the mamu-A region, the mamu-B region can be grossly subdivided into two segments. The telomeric portion extending from mamu-B1, interrupted by the mamu-A transposed segment, and continuing to mamu-B10 has arisen in part from six tandem duplications of a segment some 60 kb in length, whereas the centromeric portion from mamu-B11 to mamu-B19 has arisen in part from a single larger tandem duplication of about 150 kb (Fig. 3B). Such a historical relationship between mamu-B1 through mamu-B10 and the mamu-B11 to mamu-B19 genes is reflected in the evolutionary distances among them (Fig. 3C).
Although this finding is fascinating evolutionarily, another important issue raised is whether the expansion in gene number could significantly alter the progress or development of an acquired or innate immune response of the rhesus macaque relative to human. To answer this first question requires knowledge of which of these genes are transcribed and translated into functional class I products. Of the 19 B-like genes on haplotype 1, seven have identical matches to cDNAs (derived from macaque peripheral blood), and seven have typical class I protein-encoding capacity, including apparently functional exons and highly similar promoter regions. Of the remaining five genes, four have stop codons within exons 2–4, presumably inactivating the gene, and a single gene encodes a protein without a leader peptide (Table 2).
One unique and relevant feature of mamu-B genes may be the structure of exon 1 and the placement of the ATG start codon. There are three arrangements found; the first is typical of MHC class I in having two ATG start codons with the downstream ATG following in frame at amino acid position 4 (ATGC GGGTCATG). A second arrangement contains only the downstream ATG yielding a signal peptide with 21 amino acids. A third coding sequence has the first ATG encountered out of frame with the remainder of the protein-coding sequence (AT GCGG-TCATG, typified by mamu-B*17), suggesting that the second ATG is used as the start codon (Table 2). All three types are transcribed as examples of representative cDNAs that have been found for each. In addition, peptide-binding motifs and SIV cytotoxic T-lymphocyte epitopes have been deciphered for each type (Evans et al. 2000 ; Mothe et al. 2002), suggesting that they may all function as antigen-presenting molecules. Thus, there may be as many as 28 functional mamu-B antigen-presenting molecules expressed in an individual macaque. Our initial attempts to unravel the mamu-B region encountered difficulty because it was not possible to assign a BAC to one haplotype unambiguously, due to the underlying complex repetitive structure of the mamu-B sequences. Further, the complex arrangement of genes heightened interest in a comparison of the sequence from both haplotypes. Therefore, we combined the sequence from haplotype 1 with data from over half of haplotype 2, the latter including nine additional mamu-B genes. Of these, three had identical matches to cDNA sequences and five genes were structurally intact with a typical class I coding capacity (Table 2). One gene appeared to be an allele of mamu-B19, but contained several in frame stop codons not found in the allelic sequence. It was possible to align the two haplotypes at the 5' and 3' ends of the regions using the single occurrence of the HCGIX sequence at the 5' end and MIC1 at the 3' end. Missing at the 5' end of haplotype 2 was the transposed mamu-A region sequences and mamu-B1 (Fig. 4). However, despite having anchors at the ends, it was apparent that any notion of alleles between mamu-B genes at corresponding positions between the two sequences was ambiguous. Thus, mamu-h2B5 was more closely related to mamu-B6, whereas mamu-h2B6 and mamu-h2B7 aligned most significantly with mamu-B3 and mamu-B4, respectively. Further, mamu-h2B17 and mamu-h2B18 both appeared to be allelic to mamu-B18 and only distantly related to mamu-B17 (Fig. 4B,C).
To begin to unravel the complex relationships between the two mamu-B haplotypes, we took advantage of the presence within the repeat units of large numbers of retroposed elements (Alus, LINEs, etc.), which produced unique repeat patterns. The simplest reconstruction of the events that might have occurred to generate these divergent haplotype structures is depicted in Figure 4D. The pivotal event in this reconstruction is the duplication of 230 kb of ancestral sequence, including genes B4, B5, and B6. Haplotype 1 evolved from the ancestral, unduplicated sequence by a series of deletions, one of which erased the allele of h2B2. Haplotype 2 evolved, after the 230-kb duplication, by deleting the alleles of B4 and B5, and by a further duplication that generated h2B17 and h2B18. Thirteen additional mamu-B genes are predicted to be located in the yet-unsequenced regions of this haplotype, but some may have also been lost by deletions.
Mamu-DR, Mamu-DQ, and Mamu-DP Loci
The first obvious difference between human and rhesus DQ genes is that both monkey chromosomes have only one copy of the DQA and DQB genes, whereas the human locus has two DQA loci and two copies of DQB and one DQB pseudogene (MHC Consortium 1999
Sequence Divergence Spanning the Mamu MHC
We compared 470 kb of contiguous sequences from the mamu class II region from each of the two haplotypes (Fig. 5) to highlight sequence divergence in class II between mamu chromosomes and human. For comparison with the orthologous region in human, we used contiguous sequence data from two human chromosomes sequenced by the Sanger Institute MHC haplotype project (http://www.sanger.ac.uk/HGP/Chr6/MHC/). Sequences were aligned as described in the Methods section, and the numbers of insertions, deletions, and substitutions were plotted versus position for the rhesus versus rhesus, rhesus versus human, and human versus human comparisons (Fig. 5). From this simple comparison, it was evident that the rhesus haplotypes have diverged significantly more than in the human. In immune-related genes other than MHC class I or class II, the divergence found was about 10-fold higher than human (e.g., the transporter associated with antigen processing subunits, TAP1 and TAP2, and DMB) and near class II genes, the divergence between rhesus chromosomes was as high or higher than that found between the orthologous rhesus and human chromosomes (e.g., near DPA1). Some regions with high %GC and containing closely packed genes correlated with lower levels of divergence, implying conservation of coding sequences. This extent of divergence constitutes a second major distinguishing feature of the mamu MHC that may relate directly to the immune response. Of the
Immunological Divergence Between Rhesus and Human It is reasonable to suppose that selective pressures have been responsible for the enormous expansion of the number of mamu-B genes in the rhesus. The ability of the rhesus MHC to expand is illustrated not only by an increase in the number of mamu-A and mamu-B-loci, but also by the transposition of sequences, such as the mamu-A segment transposed into the B region in haplotype 1 and by the inversion of the DQB gene on haplotype 2. These structures reflect events that are ongoing in the rhesus population, as they are haplotype specific and may reflect evolutionary mechanisms that have not been observed in human populations to date. Among a plethora of distinguishing details, our studies have revealed two fundamental differences in MHC structure between rhesus macaques and humans that relate directly to the immune response. The expansion in the number of class I-B, and to a lesser extent, the class I-A and class II-DRB genes may be an important issue when attempting to dissect a T cell-mediated immune response, as it may not be clear how many of these loci are involved in a specific response. The high polymorphism found throughout the mamu MHC introduces a second major consideration. Polymorphisms in MHC loci with immune-related function, other than the class I and class II genes, can have a direct effect on antigen presentation (e.g., TAP, or the proteasome subunits, LMP-2 and LMP-7), on cytokine levels and efficacy, and on interactions with other components of both the innate and acquired immune response.
An essential step in resolving some of these issues is clearly to determine which of the mamu-B genes are functional. Of the 14 intact genes in haplotype 1, all are predicted to produce functional proteins on the basis of cDNA and transfection analysis (Evans et al. 2000
TCR Diversity and MHC Polymorphism
It is clear that the rhesus has found a way around this limitation, especially in the case of the class I loci. The number of functional class I loci, as assessed by the existence of identical cDNA sequences, is at least nine per haplotype (two A loci and seven B loci), and may be as many as 16, judging by the number of loci that appear structurally intact (two A loci and 14 B loci). Whereas the functionality of some of these genes remains to be established, all appear intact and functional as judged by the prior demonstration of structurally similar B-like loci that bind peptide and present antigen to cytotoxic T cells (Dzuris et al. 2000 Thus, the rhesus may provide a remarkable example of a unique reaction to pathogens along the divergent evolutionary road that separates these animals from humans. Perhaps this quantitative expansion in antigen-presenting capacity had consequences that enabled rhesus to modify its immune response by expanding the ability within individuals to detect foreign antigen. However, it is also possible that such an increase in gene number could alter qualitatively other aspects of the rhesus immune response, such as the interaction with the NK inhibitory and activatory network. The latter possibility would be important to understand in light of the extensive use of these animals as models for comprehending and evaluating human disease and vaccination.
Conclusions
These data emphasize the need for genomic sequence data from other immune complexes within the rhesus macaque genome and from other nonhuman primates used in clinical research. At present, more than 30 species of nonhuman primates are targets for biomedical research (Austad 1997
Rhesus Macaque Sequence-Ready BAC Contig We had previously identified 580 human MHC-amplicons, designed as both unique sequence probes and unique PCR assays (Geraghty et al. 2002 ), and used this resource to test rhesus macaque DNA for cross reactivity. Of these, 384 were positive on rhesus genomic DNA in PCR-sequencing assays, showing from 80% to 99% sequence identity to the respective human sequence. These data were then used to outline a preliminary mapping strategy for the isolation of the rhesus macaque MHC. The CHORI-250 Rhesus macaque BAC library constructed at the Children's Hospital Oakland Research Institute, BACPAC Resources was purchased, and with high-density hybridization filters, were screened according to the manufacturer's protocol using combinations of MHC-amplicon probes spread over 500-kb segments. Positive BACs were organized as directed by the MHC PCR assays assuming colinearity of rhesus MHC with human. The rhesus blood donor used to create the library is of Indian origin and was born at the California Regional Primate Research Center (CRPRC). Blood and a cell line from this animal were generously provided to us by Marta L. Marthas (mlmarthas{at}ucdavis.edu) at the (CRPRC). Covering about 70% of the MHC, PCR assays and finger-prints of overlapping BACs yielded confirmation of accurate representation of the rhesus genomic sequence. In regions where a low density of clones were isolated or where ambiguous PCR-sequencing results were obtained, additional probes from those regions were used in a second library screening. This approach succeeded in obtaining correct representation of the rhesus MHC with the exception of the class I A-like and class I B-like regions. At this point, shotgun sequencing of BACs was initiated and sequence data from BACs was used to design new probes for library screening and clone characterization. Considerable overlap between BACs in the class I-A and class I-B regions was needed to distinguish the haplotypes and to confirm the fidelity of clone coverage. This was due to the high similarity of duplicated segments in these regions (e.g., in the A-like region only eight nucleotide differences extending over two 80-kb segments). After two successive rounds of sequencing and probe design, the complete set of BACs spanning the rhesus MHC was obtained. At this point, it was also possible to assign unambiguously each BAC to one of the two haplotypes by PCR-sequence analysis. Five small gaps remained before contiguous sequence could be achieved, and these were filled by either PCR sequencing from BACs or by partial accumulation of whole BAC shotgun sequence. All of the haplotype assignments were confirmed by MHC–PCR analysis of the donor genomic DNA used to create the library.
DNA Sequencing
Sequencing of all BACs proceeded through three phases of analysis as follows: (1) shotgun sequencing, where
Sequence Data Analysis
Annotation of the MHC started with the previous annotation to the human MHC (MHC Consortium 1999
Ruihan Wang provided outstanding informatics support for all phases of the project. Simon Fortelny provided important analysis support and sequence data curation. Quyen Vu, Luke Williams, Bethany Richards, Jana Stonehocker, and Barrett Nelson at the FHCRC and Brian Birditt, Scott Bloom, and Ericka Johnson at the ISB provided valuable help with sequencing at various stages of the project. The generous help of David O'Connor and David Watkins who provided unpublished mamu cDNA sequences for analysis, and Ronald Bontrop who provided genomic DNA from unrelated animals was essential for analysis. We thank Lee Hood for reading the manuscript. This work was supported by a grant from the NIH National Center for Research Resources (R24 RR17186) to D.E.G. The publication costs of this article were defrayed in part by payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.
Article and publication are at http://www.genome.org/cgi/doi/10.1101/gr.2134504.
3 Corresponding author. [Supplemental material is available online at www.genome.org and www.fhcrc.org/labs/geraghty. The sequence data from this study have been submitted to GenBank under accession nos. AC148659–AC148717. The following individuals kindly provided reagents, samples, or unpublished information as indicated in the paper: D. Watkins, D. O'Connor, R. Bontrop, and M.L. Marthas.]
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ABSTRACT
RESULTS
