Comparative Genetics of MHC Polymorphisms in Different Primate Species: Duplications and Deletions

Comparative Genetics of MHC Polymorphisms in Different Primate Species: Duplications and Deletions Ronald E. Bontrop ABSTRACT: Gene products of the major histocompatibility complex (MHC) play a crucial role in the activation of adaptive (antigen-dependent) immune responses. In this paper similarities and dissimilarities among the MHCs of different primate species and their functional implications are reviewed. The human HLA system represents the most

thoroughly investigated MHC of any contemporary living primate species, and so it will serve as a reference. Human Immunology 67, 388 –397 (2006). © American Society for Histocompatibility and Immunogenetics, 2006. Published by Elsevier Inc.

ABBREVIATIONS MHC major histocompatibility HLA human leukocyte antigen MLC mixed lymphocyte culture

4a, 4b, and the Primordial MHC Since the description of the serologically defined supertypic specificities 4a (Bw4) and 4b (Bw6) in the van Rood laboratory [1] an enormous amount of information has become available on the HLA system. The complex itself, located on chromosome 6, encompasses 4 million basepairs and is traditionally divided into three regions, designated class I, class II, and the central MHC, also named the class III or the ⬙inflammatory” region [2]. Each of these regions encode a large collection of molecules involved in immuneand non-immune-related functions. Comparative genome mapping studies have illustrated that the prototype of the MHC must have been present in the progenitor of jawed vertebrate species that lived approximately 500 million years ago [3]. With the exception of fish, the MHC class I and II regions are tightly linked entities that segregate in most vertebrate species on the same chromosome [4]. The presence of HLA paralogous regions on human chromosomes 1, 9, and 19 illustrates that the original syntenic group experienced several rounds of duplications [5]. These block duplications predate the emergence of jawed vertebrates [3].

From the Department of Comparative Genetics and Refinement, Biomedical Primate Research Centre, Lange Kleiweg 139, P.O. Box 3306, 2280 GH Rijswijk, The Netherlands. Address reprint requests to: Dr. R.E. Bontrop. E-mail: [email protected]. Human Immunology 67, 388 –397 (2006) © American Society for Histocompatibility and Immunogenetics, 2006 Published by Elsevier Inc.

HLA-A, -B, -C, and Their Orthologues in Nonhuman Primates Classical MHC class I genes, also designated class Ia, are usually characterized by the following criteria: They are expressed on virtually all nucleated cells, display high expression levels, and exhibit abundant levels of allelic polymorphism. In the human population, the HLA-A, -B, and -C loci are indeed represented by numerous alleles [6]. A mismatch for HLA class I allotypes during transplantation procedures may result in an accelerated rejection of the graft [7]. With regard to their biological function, HLA class I molecules play a pivotal role in immune defense functions, mainly related to the elimination of intracellular infections. HLA class I heavy chains complex with ␤2 microglobulin, a molecule for which the coding sequences map outside the MHC region; this single-copy gene has been under strong purifying selection throughout primate evolution [8]. MHC class I molecules have a peptide binding site that can accommodate a peptide of approximately 9 amino acid residues in length [9]. MHC class I-bound peptides usually originate from intracellular parasites such as viruses. Most of the contact residues in the MHC class I peptide binding site display polymorphism at the population level, illustrating that allelic variability itself resulted from positive Darwinian selection. In his/her lifetime, every human will be exposed to various pathogens; as a consequence, individuals with different MHC class I allotypes tend to select different 0198-8859/06/$–see front matter doi:10.1016/j.humimm.2006.03.007

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peptides for activation of an immune response. The outcome of infection is at least in part dependent on the inherited immune system. One can imagine that particular MHC allotypes that are protective for a particular disease may exert a negative effect on another. For that reason, MHC polymorphism is thought to minimize the possibility that a given pathogen could exterminate an entire population. Host–pathogen interactions are extremely complex. As selection operates only on an individual, differences in MHC allele frequencies reflect the process of evolution at the population level. Several intracellular parasites have developed strategies to interfere with the MHC class I expression pathway [10, 11]. To minimize the potential risk of this type of immune evasion, natural killer (NK) cells are equipped with specialized receptors that scan for the presence or absence of classical MHC class I molecules [12, 13]. The absence of MHC class I cell surface expression may result in lysis of the cell. Equivalents of the HLA-A, -B, and -C genes are present in great ape species such as the common chimpanzee (Pan troglodytes) and have been designated Patr-A, -B, and -C. These chimpanzee genes also display abundant levels of polymorphism. Phylogenetic analyses allow the grouping of evolutionarily related alleles into lineages [14 –16]. Comparison of human and chimpanzee sequences illustrate that a considerable number of Mhc class I lineages indeed predate speciation, although the total number of Mhc class I lineages in chimpanzees is reduced dramatically due to an ancient selective sweep [17, 18]. The phenomenon that human and chimpanzee class I allotypes share a high degree of similarity is mirrored by the reactivity with the same antisera and monoclonal antibodies and the sharing of, for instance, the Bw4 and Bw6 epitopes [19], which play a crucial role as recognition structures for NK receptors. As expected, the genomic organization of the human and chimpanzee MHC class I region is highly similar, although the gene content itself differs slightly due to insertions and deletions [20]. The Mhc-C gene originated from a duplication of an ancestral Mhc-B-like gene, which took place in an ancestor of humans and great ape species approximately 12 million years ago. The Mhc-A and -B genes are much older, and orthologues have been described in Old World monkey species such as the rhesus macaque (Macaca mulatta). The Mhc class I region in rhesus macaques experienced several duplication rounds [21], resulting in the presence of multiple Mamu-A- and -B-like gene copies [22]. Similar observations on other macaque species have been made [23–26], and an assessment of multiple animals has illustrated that the number of Mamu-A- and -B-like genes differs between haplotypes. Moreover, these genes may display marked differences in

expression levels [27]. A similar situation has been documented in chickens, where it has been shown that both types of molecules may have a profound impact on the immune response to particular pathogens [28]. Whereas in humans and chimpanzees the classical Mhc-A, -B, and -C genes display abundant allelic variation within a given lineage, rhesus macaques display limited levels of allelic polymorphism. Individuals in a rhesus macaque population, however, appear to differ markedly for the number and combination of Mhc class I genes on a given haplotype [27]. Like allelic polymorphism, a defense strategy based on a differential number and combination of genes (diversity) may quarantee that a given pathogen does not sweep through an entire population. Next to allelic polymorphism and diversity (differential gene copy number), the existence of MHC class I majors (characterized by high expression levels) and minors (defined by low expression levels) defines another level of complexity that is operative for the MHC region. Nonclassical MHC Class I Genes in Primates Some HLA class I-like molecules may display differential tissue distribution and low levels of allelic polymorphism. These molecules, designated HLA-E, -F, and -G in humans, are referred to as nonclassicals (class Ib) and exert specialized functions. For example, cell surface expression of HLA-E (on virtually every nucleated cell) depends on the presence and binding of peptides originating from the leader sequences of classical HLA class I molecules and HLA-G [29]. The presence of cell surface expression of HLA-E molecules is scanned for by the highly conserved NKG2/CD94 structures belonging to the lectin-like set of NK cell receptors. The failure of HLA-A, -B, and -C gene expression will result in the absence of HLA-E cell surface expression, subsequently followed by NK cell lysis. The human cytomegalovirus genome encodes several gene products that interfere directly with HLA-A, -B, and -C expression and with a gene product, identical to the HLA-Cwⴱ03 signal peptide, which serves as a ligand for HLA-E and thus prevents NK cell-mediated lysis [30]. Highly conserved orthologous structures of the HLA-E gene have been detected in great ape and Old World monkey species [31, 32], suggesting that the specialized function of this nonclassical gene has been operative for at least 30 million years in primate species and their ancestors. HLA-F is mainly expressed on lymphoid tissues, and although its function is not known, HLA-F is capable of binding to the inhibitory ILT2 and ILT4 receptors that are related to the KIR gene family [33]. The HLA-F gene equivalents are also highly conserved in different nonhuman primate species [34, 35].

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HLA-G expression is restricted to the placenta and it binds preferentially to the ILT2 and ILT4 structures [36], which is thought to help the fetus generate a state of immune tolerance, thus preventing rejection by the maternal immune system. A premature stop codon mapping to exon 6 prevents translation of most of the cytoplasmatic domain. The evolutionary history of the Mhc-G gene is peculiar because, although great apes have an orthologue of HLA-G, presumably with a similar function [37], the Old World monkey equivalent has been inactivated [38, 39]. In rhesus macaques the function of the Mamu-G pseudogene has been taken over by Mamu-AG, which resulted from the recruitment of a duplicated Mamu-A gene. This gene also has a premature stop codon and possesses an expression profile similar to that of HLA-G [40]. An equivalent has recently been described for baboons [41], suggesting that this is common to the Old World monkey lineage. Most New World monkeys examined thus far appear to lack the functional equivalents of HLA-A, -B, and -C [42]. In the cotton top tamarin (Saguinus oedipus), the classical MHC class I function is taken over by an ortologue of HLA-G, which is expressed on virtually all nucleated cells. This gene displays limited allelic polymorphism [43], which may explain why cotton top tamarins are highly susceptible to particular viral infections. In owl monkeys (Aotus nancymaae) a similar profile is observed [44]. This set of observations illustrates that MHC class I genes are flexible with regard to their function because the same gene can have a classical MHC class I function in one range of species, whereas it may display nonclassical functions in another. Some nonhuman primate species possess Mhc class Ib genes for which no apparent human equivalents exist. Examples are possibly the chimpanzee Patr-AL locus, displaying differential haplotype distribution [45], and the Mamu-I locus in rhesus macaques [46]. Their functions and potential ligands are not yet known. MIC Genes The HLA class I region contains functional copies of the MICA and B genes, whereas the MICC to MICG genes are characterized by features that render them pseudogenes [47]. The presence of these highly related MIC genes is an evolutionary relic of the fact that during its evolution the HLA system experienced several rounds of duplications. The MIC genes are distant relatives of the MHC class I genes and can be distinguished based on a separate exon–intron organization. The MICA and MICB promotor regions contain heat shock elements, and expression of these genes, predominantly on intestinal mucosal fibroblasts, can be induced in response to stress [48]. MIC molecules do not complex with ␤2 microglobulin and do not bind peptides, but they are broadly

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reactive with ␥␦ T cell receptor-positive cells [49] or with the NKG2D ligand [50]. In the human population, both the MICA and the MICB gene show marked levels of allelic polymorphism [51]. Common chimpanzees, however, have only one functional copy of a MIC gene. This gene, designated MICA/B, is a fusion product of the MICA and B genes and was generated by an in-frame deletion event [20, 52]. This hybrid gene displays low levels of allelic polymorphism, as is consistent with the observation that a selective sweep targeted the chimpanzee MHC region [53]. In rhesus macaques, two distinct haplotypes can be observed; one harbors the orthologues of the human MICA and B genes [54, 55], whereas the other possesses a MICB gene and a hybrid MICA/B gene (unpublished). Nothing is known about the presence or absence of MIC genes in New World monkeys. Central MHC Region The central HLA region is densely packed with genes, some of which play a crucial role in inflammatory immune reactions. A comparative analysis of the human and rhesus macaque genomes suggests that the organization of this region has been highly conserved in primates [21, 56]. The central MHC region in humans contains some of the complement cascade genes such as C2, C4, and factor B [57]. Equivalents of these genes are also present in the MHC regions of various other primate species [58, 59]. In particular the evolutionary history of the primate C4 region has been studied thoroughly. In some human individuals there are two copies of the gene, designated C4A and C4B, which lie approximately 10 kb apart. Each of the C4 genes is flanked at its 3= end by a CYP21 (21 hydroxylase) gene. The gene linked to the C4A gene is inactivated, whereas the partner of the C4B gene is functional. Other individuals, for instance those with the HLA-A1-B8-DR3 haplotypes, have only a single set of C4-CYP21 genes. With regard to copy number, considerable variation can be seen in the human population. Duplicated tandems have been observed in chimpanzees, gorillas, and rhesus macaques, whereas in orangutans three C4-CYP21 tandems can be observed [21, 60]. With reference to gene copy number, the rhesus macaque appears to rival the human population, whereas chimpanzee and gorilla populations appear to exhibit no diversity. In the human population there are short and long C4A genes. The long gene has an insertion of an endogenous retrovirus ERV-K(C4) in intron 9. The same insertion has been observed in C4 genes of orangutans, rhesus macaques, and African green monkeys, illustrating that the insertion of ERV-K(C4) predates radiation of Old World Monkeys, great apes, and humans [61, 62]. As chimpanzees [59, 62] have only short forms of the C4

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gene, they must have lost the long equivalents during evolution. HLA Class II Region The HLA-D region was originally defined by the observation that cells derived from HLA-A-, -B-, and -Cidentical serotyped individuals could provoke stimulation in the mixed lymphocyte culture (MLC) test. The discovery that some sera were able to inhibit the proliferative capacity of certain cell combinations in the MLC test led to the definition of the HLA-DR allelic series [63]. In additionn, the HLA-DQ region products were first defined by antisera, whereas HLA-DP molecules were discovered by the primed lymphocyte test [64]. MHC class II molecules consist of two transmembrane glycoproteins, and the alpha and beta chain gene subunits map within the MHC region. At the genomic level, each of the three isotype regions (HLA-DR, -DQ, and -DP) possess multiple genes that display variable degrees of polymorphism [6]. Like MHC class I molecules, MHC class II heterodimers are peptide receptors that can present processed peptides—in this case usually derived from extracellular pathogens—to T helper cells. The HLA class II antigens display differential tissue distribution and are normally expressed on cells of the white blood cell lineage; they play a crucial role in the regulation of immune responses. This can be either by regulating antibody production or by providing help (cytokine production) to cytotoxic T cells. While the peptide binding site of MHC class I molecules is closed at both ends, the equivalent structure of the MHC class II molecules is open. Hence, MHC class II bound peptides tend to be generally longer than their MHC class I equivalents and may extend to 20 amino acid residues. Again most of the polymorphic codons in Mhc class II genes encode contact residues mapping to the peptide binding site. Evolutionary Stability of the Mhc-DP Region in Primates Humans, chimpanzees, rhesus macaques, and cotton top tamarins share a similar and remarkably stable Mhc-DP region organizationn [21, 65, 66]. In all primate species tested, only the Mhc-DPA1 and -DPB1 genes encode a potentially functional gene product, whereas the other set of genes in the region are inactive. With regard to expression, the situation in New World monkeys may be more complex. Owl monkeys and cotton top tamarins seem to have functional Mhc-DPB1 genes displaying limited levels of allelic variation [67]. In contrast, however, common marmosets (Callithrix jacchus) may have lost or inactivated the Mhc-DP region genes because all attempts to identify Caja-DPB sequences have failed [68].

TABLE 1 Allelic variability at Mhc-DP region loci in primates Species

Mhc-DPA1

Mhc-DPB1

Human Chimpanzee Rhesus macaque Cotton top tamarin Common marmoset Squirrel monkey

23 3 1 ND ⫹ 3

120 29 16 1 — ND

Data were extracted from the IMGT/NHPMHC data base [74]. Sequences were (⫹) detected, (⫺) absent, or (ND) not determined.

In humans, and probably also in great apes, allelic variation at the Mhc-DPB1 locus is generated by the frequent exchange of polymorphic sequence motifs, promoting speedy evolution of -DPB1 lineages [69 –71], whereas Old World monkey-DPB1 lineages appear to be more stable [72]. In rhesus macaques only one MamuDPA1 allele has been identified [73], whereas this locus displays polymorphism in humans and chimpanzees (Table 1). In contrast to humans, Mamu-DP allotypes appear to experience a strong type of purifying selection, possibly due to an as yet unknown functional constraint. The presence of a likely recombination hotspot, in the vicinity of the Mamu-DP region ensures that different Mamu-DPB1 alleles can be and are readily distributed over different haplotypes [75, 76]. At this stage, little is known about the functional characteristics of Mamu class II molecules, although the Mamu-DPB1ⴱ01 restriction element has been linked to susceptibility to develop experimentally induced autoimmune encephalomyelitis [77]. Primate Mhc-DQ Region The DQ region in humans contains two highly related sets of genes that are designated HLA-DQB1-DQA1 and HLA-DQB2-DQA2 [6]. The first set of genes is expressed, and both genes display polymorphism. The other tandem is not expressed and is considered to represent pseudogenes. Restriction fragment length polymorphism and subsequent sequencing studies have illustrated that similar organization and expression profiles exist in great ape and New World monkey species, whereas the Mhc-DQB2-DQA2 tandem was deleted somewhere along the path of Old World monkey radiation [78, 79]. As prosimians have only one set of Mhc-DQA2- DQB2-like genes, the initial duplication resulting in two sets of Mhc-DQ gene pairs took place at least 55 million years ago. Both the MhcDQA1-DQB1 genes display plentiful allelic polymorphism in humans, great apes, and Old World monkeys, whereas in most New World monkey species low levels of allelic polymorphism are observed (Table 2). An

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TABLE 2 Distribution of Mhc-DQA1/B1 alleles/lineages among different primate species Lineage DQA1ⴱ01 DQA1ⴱ02 DQA1ⴱ03 DQA1ⴱ04 DQA1ⴱ05 DQA1ⴱ06 DQA1ⴱ20 DQA1ⴱ23 DQA1ⴱ24 DQA1ⴱ26 DQA1ⴱ27 DQB1ⴱ02 DQB1ⴱ03 DQB1ⴱ04 DQB1ⴱ05 DQB1ⴱ06 DQB1ⴱ15 DQB1ⴱ16 DQB1ⴱ17 DQB1ⴱ18 DQB1ⴱ21 DQB1ⴱ22 DQB1ⴱ23 DQB1ⴱ24

HLA

Patr

Mamu

Saoe

Caja

11 1 3 5 9 3 — — — — — 5 22 2 7 32 — — — — — — — —

1 — — — 3 — 3 — — — — — 5 — — 6 3 — — — 1 — — —

7 — — — 4 — — 2 4 4 — — — — — 12 3 3 10 13 — — — 1

— — — — — — — — — — 3 — — — — — — — — — — 2 1 —

1 — — — — — — — — — 1 — — — — — — — — — — 2 2 —

Data were extracted from the IMGT/NHPMHC data base [74].

exception to this rule is provided by one of the owl monkey species that displays abundant polymorphism at the Aona-DQB1 locus [80]. As compared to humans, chimpanzees seem to have lost some lineages and appear to have a reduced repertoire [81]. Some lineages are remarkably stable: for instance, the Mhc-DQA1ⴱ01 and -DQB1ⴱ06 lineages are at least 35 million years old (Table 2). In contrast to the Mhc-DP gene, which evolves mainly due to recombination (exchange of polymorphic sequence cassettes), the evolution of both Mhc-DQ genes is mainly caused by accumulation of point mutations. HLA antigens are expressed in a codominant fashion. As both DQ allotypes are polymorphic, the molecular repertoire of dimers that can be formed can be increased due to transcomplementation. In humans, the gene product of a particular HLA-DQA1 allele can pair with different HLA-DQB1 allotypes (and vice versa). A recombination hotspot mapping between the two genes facilitated the generation of many potential pairs segregating in a cis-encoded configuration. No such observation has been made with regard to rhesus and cynomolgus macaques, suggesting that Mhc-DQA1-DQB1 pairs turn out to be fixed entities in Old World monkeys [75, 76, 82, 83].

Plasticity of the DR Region in Primates In humans, five distinct HLA-DR region configurations differing in number and combination of distinct types of HLA-DRB genes have been defined [6, 74]. Each of these configurations displays abundant allelic variation at the HLA-DRB1 locus, which is known to control a high number of lineages. In contrast, the HLA-DRB3 and -DRB5 genes, and particularly the functional copy of the HLA-DRB4 gene, display markedly lower levels of polymorphism [6]. These configurations may also harbor the highly related HLA-DRB2, -DRB4, and -DRB6 pseudogenes, which share the insertion of a long terminal repeat originating from a mammary tumor virus [84, 85]. Other pseudogenes are HLA-DRB7 and the truncated -DRB8 gene, whereas the -DRB9 represents an isolated exon 2 [86]. Essentially, orthologues of all these Mhc-DRB genes are present in other primate species, but the copy number and the arrangement of these genes appear to differ dramatically between primate species (Figure 1). For example, in a relatively small population of common chimpanzees at least eight different DR region configurations that display moderate allelic variation at the Patr-DRB1 locus have been defined [74, 79]. In chimpanzees, only one configuration that is most likely identical to its human equivalent in HLA-DR7 positive individuals has been identified [79]. In rhesus macaques, at least 24 different Mamu-DR region configurations that display, however, low levels of allelic polymorphism within a given configuration have been defined [75, 90, 91], Although some of the regions may carry a high number of Mamu-DRB genes, subsequent cDNA analyses have illustrated that rhesus macaques probably express a number of DR molecules, similar to that of humans [92]. On top of that, the Mamu-DRA gene appears to be polymorphic, whereas the HLA-DRA gene is considered to be essentially monomorphic. Mhc-DRB genes have also been defined in several New World monkey species [93–95]. Common marmosets, for insstancce, have only one region configuration, with three different Caja-DRB genes [68]. One of these genes, CajaDRBⴱW1201 appears to be monomorphic, as is consistent with the observation that all common marmosets are susceptible to developing EAE [96, 97]. The two other genes also exhibit low levels of polymorphism, thus providing one explanation as to why common marmosets are particularly sensitive to bacterial infections [68]. The evolution of Mhc-DRB genes is a concerted action involving point mutations and recombination processes. Some lineages appear to be particularly stable, and an example is provided by the Mhc-DRB1ⴱ03 lineage. Antigen presentation studies have demonstrated that the

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FIGURE 1 Schematic organization of various Mhc-DR regions in different primate species. The gene order of the HLA-DR region configurations has been determined based on genomic analyses. The chimpanzee configurations have been defined based on segregation studies, with the exception of configuration VIII, which was mapped by genomic sstudies [87]. This situation is also applicable to the common marmoset and the rhesus macaque configurations, except for configuration XVI [21]. Gene name and/or lineage assignments are based on generally accepted nomenclature proposals [88, 89].

high degree of similarity of evolutionary HLA-DR3-like molecules is also reflected by shared antigen presentation capacities [98, 99]. HLA-DR3-like sequences are also present in New World monkeys due to convergent evolution [68]. Most of the Mhc-DRB1 alleles are species unique. An unexpected exception to this rule is provided by the rhesus and cynomolgus macaques; they share many identical exon 2 sequences at the DRB locus, whereas their Mhc class I alleles are different [100]. This suggests that both species experienced a conservative type of selection on at least part of the Mhc class II region genes.

ACKNOWLEDGMENTS The author thanks Ms. Donna Devine for editing the manuscript and Henk van Westbroek for preparing the figures. Gaby Doxiadis and Natasja de Groot contributed with critical discussions. This study was supported in part by the National Institutes of Health, project 1-R24-RR16038-01 (Catalog of Federal Domestic Assistance 93.306), and by NIH/NCRR project U24-RR18144-01.

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