Comparative genomics of the human, macaque and mouse major histocompatibility complex

Summary

The MHC is a highly polymorphic genomic region that encodes the transplantation and immune regulatory molecules. It receives special attention for genetic investigation because of its important role in the regulation of innate and adaptive immune responses and its strong association with numerous infectious and/or autoimmune diseases. The MHC locus was first discovered in the mouse and for the past 50 years it has been studied most intensively in both mice and humans. However, in recent years the macaque species have emerged as some of the more important and advanced experimental animal models for biomedical research into MHC with important human immunodeficiency virus/simian immunodeficiency virus and transplantation studies undertaken in association with precise MHC genotyping and haplotyping methods using Sanger sequencing and next‐generation sequencing. Here, in this special issue on ‘Macaque Immunology’ we provide a short review of the genomic similarities and differences among the human, macaque and mouse MHC class I and class II regions, with an emphasis on the association of the macaque class I region with MHC polymorphism, haplotype structure and function.

Introduction

The genomic locus of the MHC encodes the polymorphic cell‐membrane‐bound glycoproteins known as MHC classical class I and class II molecules (antigens) that regulate the immune response by presenting peptides of fragmented proteins to circulating cytotoxic and helper T lymphocytes, respectively.1, 2, 3 The MHC classical class I antigens are produced by most tissues and they associate non‐covalently with β₂‐microglobulin to present intracellularly processed peptide antigens (8–11 amino acids in length) to T‐cell receptors of specific CD8⁺ T cells in order to induce their activation and/or cytotoxicity.2 The processed peptides may arise from the cell's own proteome or from foreign intracellular pathogens.4 Mature dendritic cells use the MHC class I system to present peptides deriving from antigens captured by endocytosis.5 This process, called cross‐presentation, plays a crucial role in the initiation of responses of specific T CD8⁺ lymphocytes in peripheral lymphoid organs. In addition, the MHC classical class I proteins may act as ligands for killer‐cell immunoglobulin‐like receptors that regulate the cytotoxic activity of cytotoxic T cells and natural killer cell6, 7, 8, 9 and leucocyte immunoglobulin‐like receptors expressed on myelomonocytes and other leucocyte lineages.10 In contrast to the classical class I antigens, the classical class II antigens form heterodimeric structures specialized in the presentation of exogenous peptides (15–25 amino acids in length) on the surface of lymphoid cells to the CD4⁺ helper T lymphocytes of the immune system.2 The class II gene expression is predominantly restricted to the lymphoid cells, such as B cells, monocytes, macrophages, endothelial cells, dendritic cells and activated T cells. Both the classical class I and class II genes are often highly polymorphic, presumably to preserve the inter‐individual variability of the antigen‐presenting ability and help the species to defend against and survive the natural selection pressure from various infectious agents.11, 12 The non‐classical class I and class II antigens, although similar in structure to their classical class I or class II counterparts, are usually far less polymorphic, have variable or limited tissue expression and functions that are often distinctly different to those of the classical class I or class II antigens.13 Moreover, several non‐classical MHC class I genes are located outside the MHC.

The MHC was first discovered in mice more than 60 years ago and because it was a tumour‐resistant locus it soon became known as the histocompatibility locus H2.3 Its equivalent in humans was named the human leucocyte antigen (HLA) complex or human MHC after the pioneering description by Jean Dausset of the first alloantibodies against antigens expressed by human leucocytes of certain, but not all, individuals.14, 15, 16 It was later demonstrated that HLA donor/recipient incompatibility was critically involved in organ transplant rejection and graft‐versus‐host disease.3, 11 The MHC is now known to be a highly complex immune‐response genomic region composed of a large group of linked genes, some not necessarily directly associated with the class I and class II genes, but many of them involved functionally with the adaptive and innate immune response systems in all the jawed vertebrates studied so far.17 The MHC genomic regions have been completely sequenced in various representatives of the mammalian (chimpanzee, rhesus macaque, mouse, rat, pig, dog and opossum) and non‐mammalian (chicken, quail, shark and amphioxus) species and comparatively analysed for a better understanding of the evolutionary process responsible for the genetic diversity of the regions and their role in the immune system.2, 18 Although the human MHC has received considerable attention because of its role in immune regulation, transplantation and autoimmune diseases, experimental animal models have been developed to advance biomedical research on various aspects of the MHC such as gene expression and the mechanisms of peptide presentation in the mouse and rat, and diversity in the dog, pig and macaque.

Although the mouse still remains the premier animal model for MHC research,18 the macaque species such as the rhesus macaques (Macaca mulatta; Mamu), the cynomolgus macaques (Macaca fascicularis; Mafa) and southern pig‐tailed macaques (Macaca nemestrina; Mane) have emerged more recently as important MHC experimental models because of their relatively close phylogenetic relationship to humans (Fig. 1). In addition, the macaques have considerable immunological similarities with humans as demonstrated by frequent and high interspecies cross‐reactivity of antibodies raised against human antigens.19, 20 Although macaques are phylogenetically closer to humans than rodents, they differ significantly from humans by many blood group systems including their MHC.21 Also, murine anti‐HLA monoclonal antibodies to monomorphic and polymorphic epitopes have been compared for their reactivity in humans and M. nemestrina.22 One of these monoclonal antibodies, P77·1, which detects the human allo‐antigen HLA‐Bw6, was highly conserved and reacted with 87% of the macaque epitopes, a frequency very close to that observed in humans. Since the macaque species have immunological similarities with the human, they are often used for biomedical studies of infectious, neurological and reproductive diseases, transplantation and immunotherapy. Many of these studies would benefit from a better understanding of the MHC genetic background in these animals.

Figure 1.

Phylogenetic relationships between the human and five representative experimental animals. The time of divergence is on the Time Tree website (http://www.timetree.org/).

Here, in this special issue on ‘Macaque Immunology’ we briefly review the genomic similarities and differences among the macaque, human and mouse MHC regions with particular emphasis on the comparative polymorphisms, haplotype structure and function of the class I region of humans and macaques.

Genomic characteristics of the HLA genomic region

The first fully sequenced and gene annotated human genomic MHC was published in 1999.23 This sequence was a ‘virtual MHC’ because it was composed of a mosaic of different human haplotypes rather than representing any one particular haplotype. Subsequently, the genomic sequences of at least eight different human ancestral MHC haplotypes11 were published for a more precise comparative genomic analysis of the similarities and differences.24 Figure 2 shows the current gene map of the HLA genomic region based on Genome Reference Consortium Human Build 38 patch release 2 (GRCh38.p2) in the National Center for Biotechnology Information (NCBI) database (http://www.ncbi.nlm.nih.gov/gene/). The HLA super locus is located on the short arm of chromosome 6, band p21.3, with the class I region located at the telomeric end and the class II region located at the centrometric end, both separated from each other by an extended class III region of 61 protein‐coding genes. Whereas the HLA class I and class II genomic regions encode the highly polymorphic gene complex of the HLA class I and HLA class II genes,25, 26 the class III region consists of many different genes that are involved in stress (HSPA1A, HSPA1B and HSPA1L), the complement cascade (C4A, C4B, C2, CFB), and inflammation (cytokine genes LTB, TNF, LTA and regulatory genes NFKBIL1 and DDX39B).2, 11 The class II region also contains some proteosome‐processing and peptide antigen transportation genes such as PSMB8, PSMB9, TAP1 and TAP2.4 The TAP‐binding protein, TAPBP, is in the extended class II region. The ‘Class I’ region ranges from HLA‐F to MICB, ‘Class III’ ranges from PPIAP9 to BTNL2, and ‘Class II’ ranges from HLA‐DRA to HLA‐DPA3. There are also sub‐regions from the telomeric side of the Class I sub‐regions and the centromeric side of the Class II sub‐regions that are called the ‘Extended class I’ (telomeric side of HCG4P11) and ‘Extended class II’ (centromeric side of COL11A2) sub‐regions, respectively.27 The class I region is additionally divided into three genomic blocks, α, β and κ, that include duplicated HLA genes and two framework gene blocks that include well‐conserved non‐MHC genes in mammalian species.18 HLA‐A, HLA‐G and HLA‐F are in the α block, HLA‐B and HLA‐C are in the β block, and HLA‐E is in the κ block.

Figure 2.

Gene map of the HLA genomic region. The MHC gene map corresponds to the genomic coordinates of 29 602 228 (GABBR1) to 33 410 226 (KIFC1) in the human genome GRCh38.p2 primary assembly of the NCBI map viewer. The regions separated by arrows show the HLA sub‐regions such as extended class I, class I, class III, classical class II and extended class II regions from telomere (left and top side) to centromere (right and bottom side). Blue and pink boxes show the spans of α, β and κ blocks and framework gene blocks, respectively. White, grey, dotted and black boxes show protein‐coding genes, non‐coding RNAs (ncRNAs), small nucleolar RNAs (snoRNAs) and pseudogenes, respectively. Red and blue letters indicate HLA class I / MIC and class II genes, respectively. The location of the α, β and κ blocks containing the cluster of duplicated HLA class I genes and framework gene blocks between them in the class I region are indicated by blue and pink arrows, respectively.

A total of 283 loci have now been identified and/or reclassified in the 3·78‐Mb HLA genomic region of the PGF haplotype28 from GABBR1 located on the Extended class I region to KIFC1 located on the Extended class II region (Fig. 2 and Table 1). When all the loci of the HLA genomic region are grouped into four categories of gene types, then 144 loci are classified as a protein‐coding gene, 53 loci are non‐coding RNA (ncRNA), five loci are small nucleolar RNA (snoRNA) and 81 loci are pseudogenes (Table 1, and see Supplementary material, Table S1). Of the 283 loci, 15·5% (44 loci) are occupied by HLA and HLA‐like genes (HLA class I, HLA class II and MHC class I polypeptide‐related sequence; MIC genes).

Table 1.

Gene numbers in the HLA genomic region

Gene status	Protein coding	ncRNA	snoRNA	Pseudo	Total
Extended Class I (GABBR1–HCG4P11)	3	0	0	3	6
Class I	47	30	0	55	132
Class III	61	12	5	8	86
Class II	18	4	0	10	32
Extended Class I (COL11A2–KIFC1)	15	7	0	5	27
Total for all regions	144	53	5	81	283

Of the HLA and HLA‐like genes, 18 HLA class I genes (six protein‐coding genes and 12 pseudogenes) and seven MIC genes (two protein‐coding genes and five pseudogenes) are located in the HLA class I region, and 18 HLA class II genes (13 protein‐coding genes and five pseudogenes) are located in the HLA class II region (Fig. 2 and Table 2). Interestingly, one HLA class I pseudogene (HLA‐Z) is located close to the HLA‐DMB gene in the HLA class II region. In addition, the classical HLA class I genes, HLA‐A, HLA‐B and HLA‐C, and the classical HLA class II genes, HLA‐DR, HLA‐DQ and HLA‐DP, are distinguished by their extraordinary polymorphisms, whereas the non‐classical HLA class I genes, HLA‐E, HLA‐F and HLA‐G, are distinguished by their tissue‐specific expression and limited polymorphism.25, 26

Table 2.

Numbers of HLA and MIC genes in the HLA genomic region

	Protein coding	Pseudo	Total
HLA class I genes	6	13	19
HLA class II genes	13	5	18
MIC genes	2	5	7
Total for HLA‐like genes	21	23	44

Genomic comparison among human, rhesus macaque and mouse

MHC regions

The MHC genomic regions of the mouse13, 18 and macaque29, 30 were still only partially sequenced 3–5 years after the human MHC genomic sequence was first published in 1999.23 Figure 3 shows a schematic, comparative MHC genomic map, considering the nucleotide length of each of the MHC class I, class II and class III regions in human, rhesus macaque and mouse. The entire Mamu region from the start of class I to the end of class II is 4·72 Mb in length based on the genomic map data29, 30 compared with the 3·41 Mb of the HLA (GRCh38.p2) and 2·91 Mb of the mouse MHC (H2) class I to class II regions [Genome Reference Consortium Mouse Build 38 patch release 3 (GRCm38.p3]. In comparing the length of each region, the HLA and Mamu class II regions have similar lengths (0·69–0·70 Mb), whereas the H2 orthologous region is much shorter at only 0·26 Mb. On the other hand, the length of the HLA, Mamu and H2 class I regions are 1·79 Mb, 3·07 Mb and 1·72 Mb, respectively, with significant differences observed in the lengths of the α, β and κ blocks where the MHC class I gene duplications are located. Namely, the α block of the Mamu is 690 kb in length in comparison to 286 kb in the HLA region and 15 kb in the H2 region. The κ block of the H2 is 791 kb in length, compared with 235 kb in the HLA region and 200 kb in the Mamu region. The β block of the Mamu is the longest at 1140 kb, in comparison to 242 kb in the HLA region and 203 kb in the H2 region (Fig. 3). These differences in the length of the blocks with the class I region of the three species were generated by segmental duplications and insertions and deletions involving the MHC class I genes and repeat sequences.11, 31 In contrast, the class III region is essentially the same length in the three species showing a high level of orthologous gene density.

Figure 3.

Comparison of genomic structures of the HLA, Mamu‐MHC and H2 regions. Genomic information of the HLA and H2 region was based on the current genome database at the NCBI site, and genomic information of the Mamu‐MHC region was referred from a previous report.25

MHC genes

Figure 4 shows a schematic, comparative gene map of the protein coding MHC class I and class II genes in the three species. The Mamu has 33 MHC (22 class I and 11 class II genes) and two MIC genes in the Mamu region compared with 19 HLA genes (six class I and 13 class II genes) and two MIC genes in the HLA region, and 39 H2 genes (30 class I and nine class II genes) in the H2 region. These numbers are increased by including the pseudogenes, 73 MHC (56 class I and 17 class II genes) and 11 MIC genes are located on the Mamu region compared with 44 (19 class I, 18 class II and seven MIC genes) and 47 (36 class I and 11 class II genes) in the HLA and H2 regions, respectively (see Supplementary material, Tables S2 and S3). Therefore, the overall structure of the Mamu class I region is more complex than the HLA and the H2 class I regions.

Figure 4.

Comparative genomic map of the protein coding MHC loci among the HLA, Mamu and H2 regions. Orange and blue boxes indicate MHC class I and class II genes, respectively. The classification for protein‐coding genes and pseudogenes is shown in the Supplementary material (Table S3).

The rhesus macaque counterparts of the classical HLA‐A and HLA‐B genes and the non‐classical HLA‐E, HLA‐F and HLA‐G genes were identified in the α, β or κ block and designated Mamu‐A, Mamu‐B, Mamu‐E, Mamu‐F and Mamu‐G, respectively. Mamu‐G appears to be a pseudogene and its function may have been taken over by Mamu‐AG, which is expressed on the rhesus monkey placenta and shares unique features with HLA‐G.32, 33 There are two Mamu‐A and four Mamu‐AG in the α block, one Mamu‐E in the κ block and 14 Mamu‐B genes in the β block based on the Mamu genomic sequence used in Fig. 4. The orthologues of the HLA‐C gene have not been identified so far in rhesus macaques and in any other species of Old World monkeys, although some Mamu‐B genes (Mamu‐B5, ‐B9, ‐B18, ‐B6, ‐B2, ‐B8, ‐B1, ‐B7, ‐B3 and ‐B13) showed closer relationships with HLA‐C than with HLA‐B (Fig. 5). Also, there is a Mamu‐Z pseudogene l similar to the HLA‐Z pseudogene located in the class II orthologous region.

Figure 5.

Nucleotide sequence‐based phylogenetic tree of MHC class I and class II genes. Multiple sequence alignment was created using the clustalW Sequence Alignment program of the Molecular Evolution Genetics Analysis software 5 (MEGA5: http://www.megasoftware.net/)107 Phylogenetic trees of the MHC genes were constructed by the neighbour‐joining method (MEGA5)108 with a Maximum Composite Likelihood model using exon 4 and exon 3 of the MHC class I and class II genes, respectively. Parentheses and bold letters indicate GenBank/EMBL/DDBJ accession numbers and human MHC genes, respectively.

In contrast to human and macaque, the mouse MHC genomic sequence determined for the C57BL/6J strain has classical class Ia genes, H2‐D1 and H2‐K1 in the β block and the extended class II region between RING1 and VPS52, respectively. Contrary to the mouse b haplotype, the mouse strain C57BL/6J and bc haplotype have an additional classical class Ia gene, H2‐L, located between the H2‐D1and H2‐Q cluster.34, 35 Of the protein coding non‐classical class Ib genes, 12 H2‐M genes are included in the extended class I region, and the α and κ blocks, and nine H2‐T, one H2‐BI and six H2‐Q genes are included in the κ and β blocks, respectively (Fig. 4). Interestingly, whereas the κ block of the Mamu and HLA each has only one MHC class I gene, Mamu‐E and HLA‐E, respectively, the mouse κ block has at least 19 MHC class I genes, with 10 H2‐T like genes and nine H2‐M like genes on either side of the TRIM39 and RPP21 orthologous framework genes. The reason for the large number of duplicated MHC class I genes in the κ block of the mouse H2 is not known, but many of them are considered to have non‐classical, non‐immune functions and are expressed differentially compared with the ubiquitous expression of the classical class Ia genes.13, 35, 36, 37, 38 For example, the H2‐M1 and H2‐M10 families of the class Ib genes interact specifically with the V2R class of pheromone receptors presented on the cell surfaces of the vomeronasal organ.18 The transcripts of some other H2‐M and H2‐T genes are expressed widely, including in the brains of adult and embryonic mice.13 Many reports are published concerning the gene function of the non‐classical MHC class Ib genes.13, 36, 37, 38, 39, 40, 41, 42, 43, 44

The protein‐coding MICA and MICB genes and MIC1 and MIC2 are identified in the β block of the HLA and Mamu class I regions, respectively. Two combinations of MIC1 and MIC2, and MIC3 and MIC2 are identified in the Mamu haplotypes of the β block. The MIC1 and MIC2 genes are the orthologues of the human MICA and MICB genes, respectively. The MIC3 gene is a hybrid of MICA and MICB generated by a crossing over event with one breakpoint in intron 3, and MIC3 is named as MICA/B.45 However, the MIC orthologous gene is not observed in the H2 region.

The MHC class II genes (MHC‐DRA, ‐DQA1, ‐DQB1, ‐DOB, ‐DMB, ‐DMA, ‐DOA, ‐DPA1 and ‐DPB1) are well conserved between the HLA and Mamu regions, excluding the MHC‐DRB, MHC‐DQA2 and MHC‐DQB2 genes that were generated by different evolutionary processes.46 The gene order within the HLA and Mamu class II orthologous gene regions is essentially the same (Fig. 4). In contrast, H2‐Ea, which is thought to be the HLA‐DRA orthologue, has not been observed in some H2 haplotypes including the C57BL/6J strain, and the MHC‐DPA1 and DPB1 genes are missing from all H2 haplotypes.

Non‐MHC genes

The 123 protein‐coding non‐MHC genes were identified in the HLA genomic framework gene region, the class III region and the extended class I and class II regions (Fig. 2 and Table 1). Of the 120 genes excluding three genes (C4A, C4B and CYP21A2) that have CYP21A‐C4 haplotype structure, 94·2% (113 genes) are commonly observed among the macaque MHC, HLA and H2 regions (see Supplementary material, Table S4). In contrast, two genes (LOC105375108 and PSORS1C1), four genes (MUC21, MCCD1, NCR3 and C6orf48) and one gene (BTNL2) are observed in only HLA, HLA and macaque species, and HLA and H2, respectively.

The paralogy and diversity of the MHC class I genes

To summarize the comparative data analysis, the basic organizational structure of the MHC regions is largely conserved among the mice, macaques and humans with the exception that the class I genes within the α, β and κ blocks are constantly remodelled between the species by ‘birth and death’ evolution in response to environmental pathogens.47 Although the framework genes within the MHC class I region essentially have remained conserved and orthologous, the number of MHC classical and non‐classical class I genes vary enormously between the three species. This suggests that despite the possibility of some trans‐species inheritance the majority of the reorganization of the MHC class genes has occurred during and/or after speciation. Human MHC gene sequences are closer to those of the macaque than the mouse and similar to the phylogenetic relationships shown in Fig. 1, but the MHC class I genes are also paralogous within each of the three species. In contrast, the MHC class II genes are essentially orthologous between the three species (Fig. 5). This paralogy within the MHC class I region highlights its uniqueness within these three mammalian genomes and easily distinguishes it from the other two major regions, class II and class III, within the MHC supra loci. Most of these paralogous genes have arisen from monogenic and multigenic duplication events involving retro‐elements, especially ancient endogenous retroviruses, as part of the duplication or inversion mechanisms during speciation.11, 13, 31, 48

MHC polymorphism and haplotype structure

The MHC class I and class II gene regions are among the most polymorphic nucleotide stretches within the genome of mammals.4, 11, 12 These polymorphisms include single nucleotide polymorphisms, deletions, substitutions, insertions and repeat elements including short tandem repeats or microsatellites. The reasons for this extensive and extreme polymorphism is not always readily clear, although the hypervariable exonic sites of the MHC class I and class II genes are generally interpreted as necessary for allowing the transport of a greater diversity of peptide sequences for MHC presentation to circulating immune cells. Another possibility is that many of the polymorphisms have evolved rapidly within and between species as a result of duplication events, indel activity, sequence mutations and associated hitchhiking diversity in response to adaptation of the MHC to the constantly evolving microbial antigenic attack.12

Of the total of 14 232 HLA allele sequences reported by the IMGT/HLA database release 3·23 in January 2016, 10 574 were in the class I region and 3658 were in the class II gene regions. In contrast to the HLA, a total of only 1704 Mafa, 1407 Mamu and 721 Mane MHC alleles were released by IPD‐MHC database on 2 April, 2016 (available from: http://www.ebi.ac.uk/ipd/mhc/; Table 3, and see Supplementary material, Table S5). Most of the macaque allele sequences were determined by RT‐PCR‐based Sanger sequencing and next generation sequencing and were probably free of contaminated PCR products originating from pseudogenes. Of the macaque MHC‐B alleles, 101 alleles were perfectly matched with at least two species (Fig. 1). These trans‐species polymorphisms were probably already generated before speciation of the macaques 2·4–4·2 million years ago.49 In addition, MICA, MICB and MICA/B genes in macaque species are polymorphic like the human MICA and MICB genes.45, 50

Table 3.

Allele numbers of MHC alleles in three macaque species

	Locus	Mafa	Mamu	Mane
Class I	MHC‐F	8	6	0
	MHC‐G	10	4	0
	MHC‐AG	35	9	1
	MHC‐A a	380	336	150
	MHC‐E	5	22	8
	MHC‐B b	501	462	285
	MHC‐I	42	43	44
Class II	MHC‐DRA	50	28	16
	MHC‐DRB c	283	261	113
	MHC‐DQA1	82	46	30
	MHC‐DQB1	95	79	40
	MHC‐DOA	15	0	0
	MHC‐DOB	16	0	0
	MHC‐DMA	11	0	0
	MHC‐DMB	7	0	0
	MHC‐DPA1	80	50	18
	MHC‐DPB1	84	61	16
	Total	1704	1407	721

^aTotal allele numbers of A1‐A8 loci.

^bTotal allele numbers of B, B11L, B12, B16, B17, B20 and B21 loci.

^cTotal allele numbers of DRB*W, DRB1, DRB3, DRB4, DRB5 and DRB6 loci. Detailed allele numbers are shown in the Supplementary material (Table S5).

It was observed in humans that HLA haplotypes are often ancestral in that they have been inherited largely intact over many generations because the polymorphisms within the Class I and Class II blocks have been frozen due to a suppression of meiotic recombination within and between these polymorphic regions.11, 24 Ancestral‐like MHC haplotypes also appear to exist in mice18 and macaques.45, 51, 52, 53, 54, 55 The macaque MHC class I, class II and/or entire MHC haplotypes were estimated using the MHC allele and/or pedigree information in each species such as Mafa,51, 52, 53, 54, 55, 56, 57, 58, 59, 60 Mamu 61, 62, 63 and Mane.64, 65 Copy number variations of the MHC‐A, MHC‐E, MHC‐B, MHC‐I and MHC‐DRB loci were observed in the different macaque species, similar to the HLA‐DR haplotype.66 For example, two MHC‐A, two MHC‐E, three MHC‐B, one MHC‐I and three MHC‐DRB loci were identified in the most frequent Mafa haplotype (tentatively named ‘HT1’) in the Filipino macaque population (Fig. 6).51 Hence, the HLA system has accumulated a large amount of allelic variation at only a few limited HLA loci, whereas the macaque MHC system has many regional configurations generated by birth and death evolution with little allelic variation at many different loci.9

Figure 6.

Gene organization of the most frequent Filipino Mafa‐MHC haplotype. Orange and blue boxes indicate MHC class I and MHC class II genes, respectively.

MHC class I gene functions and disease

Although the MHC was originally considered to be an important chromosomal region with a cluster of genes specifically involved in graft rejection,1, 3, 67 the modern view of the MHC is seen as a large, haplotypic genomic region of more than 250 genes with approximately 40% of them expressed in the immune system.23 It is beyond the scope of this review to elaborate on all the possible functions of these genes, suffice to say that many of them may have some ancillary role in regulating the innate and adaptive immune response. In this regard, we limit our attention here to a brief consideration of the class I genes, which are different to the class II genes, even though they both function to present peptides to T‐cell receptors. However, many MHC class I genes do not necessarily have the classical class I function of peptide presentation to T‐cell receptors. For example, in mice, some of the MHC class Ib molecules expressed by non‐classical class I genes such as H2‐M and H2‐T family members associate with V2R pheromone receptors and have vomeronasal sensory rather than immune functions.36, 39, 40 Hence, the number, type and function of classical and non‐classical class I genes in the MHC is often dependent on the species under investigation.

In humans, the MHC classical class I genes are involved critically in organ transplant rejection and graft‐versus‐host disease following haematopoietic stem cell transplants.1, 67 Various associations have been evidenced between HLA class I molecules and the numerous autoimmune diseases,68, 69, 70, 71 as well as infectious diseases72 and drug adverse reactions.73, 74 Apart from their essential role in the elaboration of adaptive immune responses, the role of MHC class I genes was demonstrated in various steps of reproduction such as pregnancy maintenance, mate selection and kin recognition.75 The MHC has also been considered to be a system primarily for sexual selection and avoidance of inbreeding with histocompatibility fulfilling a secondary role.76 The MHC class I gene products also have impact on central nervous system development and plasticity,13, 77, 78, 79, 80 neurological cell interactions,81, 82 synaptic function and behaviour,83, 84 cerebral hemispheric specialization,85 and neurological and psychiatric disorders.86, 87, 88 Hence, the human MHC class I region is one of the most biomedically diverse and important genomic regions that warrant special attention for genetic investigation.

The different macaque species have strong immunological similarities with the human and mouse,22 and therefore, they are often used for investigating the role of MHC class I genes in infectious diseases including human immunodeficiency virus/simian immunodeficiency virus,6 influenza,89 tuberculosis90, 91 and severe acute respiratory syndrome,92 neurological diseases including Alzheimer's disease93 and Parkinson's disease,94 reproduction,95 regenerative medicine using induced pluripotent stem cells and/or embryonic stem cells96, transplantation98, 99 and immunotherapy.100 In this regard, it has been important to know the MHC genetic background to understand how the MHC polymorphisms in the various populations affect the results of these various studies.

Recently, it was reported that one of the Mamu‐B genes, Mamu‐B*98, is capable of binding N‐myristoylated 5‐mer peptides and presenting them to specific cytotoxic T lymphocytes101 but an orthologue for this gene has not been identified in the human and mouse. The Mamu‐I gene was reported to be an oligomorphic MHC‐B‐like gene with classical and non‐classical characteristics.102 In addition, although the HLA‐E has very limited polymorphism and serves as the ligand for the inhibitory NKG2A receptor expressed by natural killer cells,103 recent studies have shown that the MHC‐E genes in macaque species are polymorphic.104 Because Mafa‐E and Mamu‐E have increased polymorphism and haplotype diversity, they may have a different function to HLA‐E gene. On the other hand, the Mafa‐F alleles are well conserved and limited in number like those of HLA‐F, which was recently identified to be one of the ligands for natural killer cell immunoglobulin‐like receptors (KIRs).105

Conclusion

Here, we have provided a short review of the genomic similarities and differences between the macaque, human and mouse MHC regions with a particular emphasis on the comparative polymorphisms, haplotype structure and function of the class I region of humans and macaques. As described above, the macaque species have had many more MHC class I genes generated by gene duplication events than those in humans, whereas the organization of MHC class II genes is well conserved between the two species. The MHC class I genes in macaque species have been divided into major expressed genes and minor expressed genes,106 but how most of these genes are regulated and what their functions are remain unknown. The gene clusters, polymorphisms and haplotypes of the KIR genomic region generally have been analysed independently of the MHC genomic region in the macaque species.6, 7, 8 However, the KIR gene cluster has a complex haplotype structure similar to the class I and class II gene clusters in the MHC genomic region, which suggests that the MHC and KIR gene polymorphisms and haplotypes might have co‐evolved in macaques by duplication, deletion and mutation to generate copy number variation.9 Much more genetic diversity and transcriptome data of MHC and KIR genes in macaque species will be necessary for biomedical studies, such as human immunodeficiency virus/simian immunodeficiency virus and transplantation studies, to progress towards a better understanding of the interrelated roles of the MHC and KIR. Hence, the detailed genomic comparison between three distinct mammalian species provided in this review suggests that more comprehensive genotyping and functional studies of the MHC, NK receptor and also MHC accessory genes relating to MHC expression are still required for the macaque species to provide a better insight into the roles of their MHC genes in immunity, neurology, transplantation and infectious diseases.

Disclosures

The authors declare that they have no conflict of interest.

Supporting information

Figure S1. Venn diagram of the number of Mamu, Mafa and Mane MHC‐B alleles shared among three macaque species.

Table S1. Locus information in the HLA genomic region (20 November 2015 to present).

Table S2. Genomic diversity of the MHC genes in the MHC region among the human, rhesus macaque and mouse (20 September 2015 to present).

Table S3. Summary for classification of MHC genes for each sub‐region.

Table S4. Conservation of non‐MHC loci in the MHC genomic region among human, macaque species and mouse (20 NJovember 2015 to present).

Table S5. Details of allele numbers of MHC alleles in representable macaque species.