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The major histocompatibility complex (MHC) plays a key role in immune defense, and the Mhc genes of cynomolgus macaque display a high degree of polymorphism. Based on their geographic distribution, different populations of cynomolgus macaques are recognized. Here we present the characterization of the Mhc class I and II repertoire of a large pedigreed group of cynomolgus macaques originating from the mainland north of the isthmus of Kra (N = 42). Segregation analyses resulted in the definition of 81 unreported Mafa-A/B/DRB/DQ/DP haplotypes, which include 32 previously unknown DRB regions. In addition, we report 13 newly defined Mafa-A/B/DRB/DQ/DP haplotypes in a group of cynomolgus macaques originating from the mainland south of the isthmus of Kra/Maritime Southeast Asia (N = 16). A relatively high level of sharing of Mafa-A (51%) and Mafa-B (40%) lineage groups is observed between the populations native to the north and the south of isthmus of Kra. At the allelic level, however, the Mafa-A/B haplotypes seem to be characteristic of a population. An overall comparison of all currently known data revealed that each geographic population has its own specific combinations of Mhc class I and II haplotypes. This illustrates the dynamic evolution of the cynomolgus macaque Mhc region, which was most likely generated by recombination and maintained by selection due to the differential pathogenic pressures encountered in different geographic areas., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The major histocompatibility complex (MHC) is one of the most gene-dense regions of the mammalian genome. Multiple genes within the human MHC (HLA) show extensive polymorphism, and currently, more than 26,000 alleles divided over 39 different genes are known. Nonhuman primate (NHP) species are grouped into great and lesser apes and Old and New World monkeys, and their MHC is studied mostly because of their important role as animal models in preclinical research or in connection with conservation biology purposes. The evolutionary equivalents of many of the HLA genes are present in NHP species, and these genes may also show abundant levels of polymorphism. This review is intended to provide a comprehensive comparison relating to the organization and polymorphism of human and NHP MHC regions., (© 2020 John Wiley & Sons Ltd.)

The major histocompatibility complex (MHC) is central to the innate and adaptive immune responses of jawed vertebrates. Characteristic of the MHC are high gene density, gene copy number variation, and allelic polymorphism. Because apes and monkeys are the closest living relatives of humans, the MHCs of these non-human primates (NHP) are studied in depth in the context of evolution, biomedicine, and conservation biology. The Immuno Polymorphism Database (IPD)-MHC NHP Database (IPD-MHC NHP), which curates MHC data of great and small apes, as well as Old and New World monkeys, has been upgraded. The curators of the database are responsible for providing official designations for newly discovered alleles. This nomenclature report updates the 2012 report, and summarizes important nomenclature issues and relevant novel features of the IPD-MHC NHP Database.

The IPD-MHC Database is the official repository for non-human MHC sequences, overseen and supported by the Comparative MHC Nomenclature Committee, providing access to curated MHC data and associated analysis tools. To address the increasing amount and complexity of data being submitted, an entirely upgraded version of the IPD-MHC Database was recently released to maintain IPD-MHC as the central platform for the comparison of curated MHC data. As a consequence, a new level of nomenclature standardisation is required between the different species to enable data submission and to allow the unambiguous inter- and intra-species comparison of alleles. However, any changes must retain the flexibility demanded by the unique biology of different taxonomic groups. Here, we describe the rationale for a standardised nomenclature system and summarise the changes that have been driven by the requirements of implementing the IPD-MHC database. This modified nomenclature system is essential to maintain the current functionality of IPD-MHC and provide a scalable future-proof database organisation to fully exploit the bioinformatic tools used for analysis.

Significant progress has been made over the last decade in defining major histocompatibility complex (MHC) diversity at the nucleotide, allele, haplotype, diplotype, and population levels in many non-human species. Much of this progress has been driven by the increased availability and reduced costs associated with nucleotide sequencing technologies. This report provides an update on the activities of the comparative MHC nomenclature committee which is a standing committee of both the International Society for Animal Genetics (ISAG) and the International Union of Immunological Societies (IUIS) where it operates under the umbrella of the Veterinary Immunology Committee (VIC). A previous report from this committee in 2006 defined the role of the committee in providing guidance in the development of a standardized nomenclature for genes and alleles at MHC loci in non-human species. It described the establishment of the Immuno Polymorphism Database, IPD-MHC, which continues to provide public access to high quality MHC sequence data across a range of species. In this report, guidelines for the continued development of a universal MHC nomenclature framework are described, summarizing the continued development of each species section within the IPD-MHC project.

Very little is currently known about the major histocompatibility complex (MHC) region of cynomolgus macaques (Macaca fascicularis; Mafa) from Chinese breeding centers. We performed comprehensive MHC class I haplotype analysis of 100 cynomolgus macaques from two different centers, with animals from different reported original geographic origins (Vietnamese, Cambodian, and Cambodian/Indonesian mixed-origin). Many of the samples were of known relation to each other (sire, dam, and progeny sets), making it possible to characterize lineage-level haplotypes in these animals. We identified 52 Mafa-A and 74 Mafa-B haplotypes in this cohort, many of which were restricted to specific sample origins. We also characterized full-length MHC class I transcripts using Pacific Biosciences (PacBio) RS II single-molecule real-time (SMRT) sequencing. This technology allows for complete read-through of unfragmented MHC class I transcripts (~1100 bp in length), so no assembly is required to unambiguously resolve novel full-length sequences. Overall, we identified 311 total full-length transcripts in a subset of 72 cynomolgus macaques from these Chinese breeding facilities; 130 of these sequences were novel and an additional 115 extended existing short database sequences to span the complete open reading frame. This significantly expands the number of Mafa-A, Mafa-B, and Mafa-I full-length alleles in the official cynomolgus macaque MHC class I database. The PacBio technique described here represents a general method for full-length allele discovery and genotyping that can be extended to other complex immune loci such as MHC class II, killer immunoglobulin-like receptors, and Fc gamma receptors.

The IPD-MHC Database project (http://www.ebi.ac.uk/ipd/mhc/) collects and expertly curates sequences of the major histocompatibility complex from non-human species and provides the infrastructure and tools to enable accurate analysis. Since the first release of the database in 2003, IPD-MHC has grown and currently hosts a number of specific sections, with more than 7000 alleles from 70 species, including non-human primates, canines, felines, equids, ovids, suids, bovins, salmonids and murids. These sequences are expertly curated and made publicly available through an open access website. The IPD-MHC Database is a key resource in its field, and this has led to an average of 1500 unique visitors and more than 5000 viewed pages per month. As the database has grown in size and complexity, it has created a number of challenges in maintaining and organizing information, particularly the need to standardize nomenclature and taxonomic classification, while incorporating new allele submissions. Here, we describe the latest database release, the IPD-MHC 2.0 and discuss planned developments. This release incorporates sequence updates and new tools that enhance database queries and improve the submission procedure by utilizing common tools that are able to handle the varied requirements of each MHC-group., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The Mamu-A, Mamu-B, and Mamu-DRB genes of the rhesus macaque show several levels of complexity such as allelic heterogeneity (polymorphism), copy number variation, differential segregation of genes/alleles present on a haplotype (diversity) and transcription level differences. A combination of techniques was implemented to screen a large panel of pedigreed Indian rhesus macaques (1,384 individuals representing the offspring of 137 founding animals) for haplotype diversity in an efficient and inexpensive manner. This approach allowed the definition of 140 haplotypes that display a relatively low degree of region variation as reflected by the presence of only 17 A, 18 B and 22 DRB types, respectively, exhibiting a global linkage disequilibrium comparable to that in humans. This finding contrasts with the situation observed in rhesus macaques from other geographic origins and in cynomolgus monkeys from Indonesia. In these latter populations, nearly every haplotype appears to be characterised by a unique A, B and DRB region. In the Indian population, however, a reshuffling of existing segments generated "new" haplotypes. Since the recombination frequency within the core MHC of the Indian rhesus macaques is relatively low, the various haplotypes were most probably produced by recombination events that accumulated over a long evolutionary time span. This idea is in accord with the notion that Indian rhesus macaques experienced a severe reduction in population during the Pleistocene due to a bottleneck caused by geographic changes. Thus, recombination-like processes appear to be a way to expand a diminished genetic repertoire in an isolated and relatively small founder population.

The major histocompatibility complex (MHC) plays a central role in the adaptive immune response. The MHC region is characterised by a high gene density, and most of these genes display considerable polymorphism. Next to humans, non-human primates (NHP) are well studied for their MHC. The present nomenclature report provides the scientific community with the latest nomenclature guidelines/rules and current implemented nomenclature revisions for Great Ape, Old and New World monkey species. All the currently published MHC data for the different Great Ape, Old and New World monkey species are archived at the Immuno Polymorphism Database (IPD)-MHC NHP database. The curators of the IPD-MHC NHP database are, in addition, responsible for providing official designations for newly detected polymorphisms.

Genetic factors such as the MHC influence the immunocompetence of an individual. MHC genes are the most polymorphic genes in primates, which is often interpreted as an adaptation to establish good T cell responses to a wide range of (evolving) pathogens. Chimpanzee MHC (Patr) genes are less polymorphic than human MHC (HLA) genes, which is surprising because chimpanzee is the older species of the two and is therefore expected to display more variation. To quantify the effect of the reduced polymorphism, we compared the peptide binding repertoire of human and chimpanzee MHC molecules. Using a peptide-MHC binding predictor and proteomes of >900 mammalian viruses, we show that, at the population level, the total peptide binding repertoire of Patr-A molecules is ~36% lower than that of their human counterparts, whereas the reduction of the peptide binding repertoire of the Patr-B locus is only 15%. In line with these results, different Patr-A molecules turn out to have largely overlapping peptide binding repertoires, whereas the Patr-B molecules are more distinct from each other. This difference is somewhat less apparent at the individual level, where we found that only 25% of the viruses are significantly better presented by "simulated" humans with heterozygous HLA-A and -B loci. Taken together, our results indicate that the Patr-B molecules recovered more after the selective sweep, whereas the Patr-A locus shows the most signs of the selective sweep with regard to its peptide binding repertoire.

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.

To improve the results gained by serotyping rhesus macaque major histocompatibility complex (MHC) antigens, molecular typing techniques have been established for class I and II genes. Like the rhesus macaque Mamu-DRB loci, the Mamu-A and -B are not only polymorphic but also polygenic. As a consequence, sequence-based typing of these genes is time-consuming. Therefore, eight MHC-linked microsatellites, or short tandem repeats (STRs), were evaluated for their use in haplotype characterization. Polymorphism analyses in rhesus macaques of Indian and Chinese origin showed high STR allelic diversity in both populations but different patterns of allele frequency distribution between the groups. Pedigree data for class I and II loci and the eight STRs allowed us to determine extended MHC haplotypes in rhesus macaque breeding groups. STR sequencing and comparisons with the complete rhesus macaque MHC genomic map allowed the exact positioning of the markers. Strong linkage disequilibria were observed between Mamu-DR and -DQ loci and adjacent STRs. Microsatellite typing provides an efficient, robust, and quick method of genotyping and deriving MHC haplotypes for rhesus macaques regardless of their geographical origin. The incorporation of MHC-linked STRs into routine genetic tests will contribute to efforts to improve the genetic characterization of the rhesus macaque for biomedical research and can provide comparative information about the evolution of the MHC region.

One of the main host factors controlling resistance to disease appears to be the MHC. The recent poor results in HIV-1/AIDS Phase 3 vaccine field trials underline the importance of non-human primate models for AIDS. These models have been, and will continue to be, important for the definition of protective immune responses relevant to successful vaccine design because they supply essential information on the basic biology of lentivirus infections, mechanisms of resistance, escape and vaccine development.

Background: Many species are threatened with extinction as their population sizes decrease with changing environments or face novel pathogenic threats. A reduction of genetic diversity at major histocompatibility complex (MHC) genes may have dramatic effects on populations' survival, as these genes play a key role in adaptive immunity. This might be the case for chimpanzees, the MHC genes of which reveal signatures of an ancient selective sweep likely due to a viral epidemic that reduced their population size a few million years ago. To better assess how this past event affected MHC variation in chimpanzees compared to humans, we analysed several indexes of genetic diversity and linkage disequilibrium across seven MHC genes on four cohorts of chimpanzees and we compared them to those estimated at orthologous HLA genes in a large set of human populations. Results: Interestingly, the analyses uncovered similar patterns of both molecular diversity and linkage disequilibrium across the seven MHC genes in chimpanzees and humans. Indeed, in both species the greatest allelic richness and heterozygosity were found at loci A, B, C and DRB1, the greatest nucleotide diversity at loci DRB1, DQA1 and DQB1, and both significant global linkage disequilibrium and the greatest proportions of haplotypes in linkage disequilibrium were observed at pairs DQA1 ~ DQB1, DQA1 ~ DRB1, DQB1 ~ DRB1 and B ~ C. Our results also showed that, despite some differences among loci, the levels of genetic diversity and linkage disequilibrium observed in contemporary chimpanzees were globally similar to those estimated in small isolated human populations, in contrast to significant differences compared to large populations. Conclusions: We conclude, first, that highly conserved mechanisms shaped the diversity of orthologous MHC genes in chimpanzees and humans. Furthermore, our findings support the hypothesis that an ancient demographic decline affecting the chimpanzee populations – like that ascribed to a viral epidemic – exerted a substantial effect on the molecular diversity of their MHC genes, albeit not more pronounced than that experienced by HLA genes in human populations that underwent rapid genetic drift during humans' peopling history. We thus propose a model where chimpanzees' MHC genes regenerated molecular variation through recombination/gene conversion and/or balancing selection after the selective sweep. [ABSTRACT FROM AUTHOR]

Chimpanzees have been used for some time as an animal model in research on immune-related diseases in humans. The major histocompatibility complex (MHC) region of the chimpanzee has also been the subject of studies in which the attention was mainly on the class I genes. Although full-length sequence information is available on the DRB region genes, such detailed information is lacking for the other class II genes and, if present, is based mainly on exon 2 sequences. In the present study, full-length sequencing was performed on DQ, DP, and DRA genes in a cohort of 67 pedigreed animals, thereby allowing a thorough analysis of the MHC class II repertoire. The results demonstrate that the number of MHC class II lineages and alleles is relatively low, whereas haplotype diversity (combination of genes/alleles on a chromosome) seems to have been maximised by crossing-over processes. [ABSTRACT FROM AUTHOR]

Thirty newly identified full‐length MHC class II alleles in three New World monkey species. [ABSTRACT FROM AUTHOR]

MHC class I and II molecules play an important role in the adaptive immune response. The genes encoding the MHC molecules are highly polymorphic, thus enabling each molecule to bind a unique repertoire of peptides, which are then presented to T cells, and may induce an immune reaction. MHC class I and II alleles of non-human primates (NHP) have been shown to influence the susceptibility or resistance to various diseases: for example, autoimmune diseases like rheumatoid arthritis and multiple sclerosis. Thus, knowledge of the susceptibility and/or resistance markers is of value for studying these diseases in experimental settings. Furthermore, in AIDS research, HLA class I molecules of human elite controllers have been shown to share a similar peptide binding motif, like the rhesus macaque class I molecules that are linked to elite control. This finding suggests that immunodominant epitopes of MHC molecules associated with SIV control may also be significant in human HIV control. Thus, macaques have been proven to be an excellent model for HIV/SIV research. [ABSTRACT FROM AUTHOR]

The authors regret that an error was present in the Fig. 5 of the above article; some digits in the DRB allele-designations in Fig. 5 have been lost, and are incorrectly presented by only two digits. The correct allele-designations should have been four (or six) digits. The correct Figure is now presented correctly. [ABSTRACT FROM AUTHOR]

In the absence of treatment, most HIV-1-infected humans develop AIDS. However, a minority are long-term nonprogressors, and resistance is associated with the presence of particular HLA-B*27/ B*57 molecules. In contrast, most HIV-1-infected chimpanzees do not contract AIDS. In comparison with humans, chimpanzees experienced an ancient selective sweep affecting the MHC class I repertoire. We have determined the peptide-binding properties of frequent chimpanzee MHC class I molecules, and show that, like HLA-B*27IB*57, they target similar conserved areas of HIV1/SlVcpz. In addition, many animals appear to possess multiple molecules targeting various conserved areas of the HlV-1/SlVcpz Gag protein, a quantitative aspect of the immune response that may further minimize the chance of viral escape. The functional characteristics of the contemporary chimpanzee MHC repertoire suggest that the selective sweep was caused by a lentiviral pandemic. [ABSTRACT FROM AUTHOR]

The major histocompatibility complex (MHC) class I B gene/allelic repertoire was investigated in a pedigreed population of cynomolgus macaques of mixed Indonesian/Malaysian origin. The Mafa-B alleles detected in this cohort are mostly specific for a given geographic area, and only a small number of alleles appears to be shared with other populations. This suggests the fast evolution of Mafa-B alleles due to adaptation to new environments. In contrast to humans, the B locus in Old World monkeys displays extensive copy number variation. The Mafa-B and previously defined -A gene combinations segregate in families and thus allowed the definition of extended haplotypes. In many cases it was possible to assign a particular Mafa-I allele to one of these Mafa-A/B haplotypes as well. The presence of a large number of stable haplotypes in this cohort of animals, which was pedigreed for up to eight generations, looks promising for developing discriminative MHC typing tools that are less cumbersome. Furthermore, the discovery of 53 unreported Mafa-B sequences expands the lexicon of alleles significantly, and may help in understanding the complex organisation of the macaque B region. [ABSTRACT FROM AUTHOR]

The interaction of killer-cell immunoglobulin-like receptors (KIR) and their respective major histocompatibility complex (MHC) ligands can alter the activation state of the natural killer (NK) cell. In both humans and rhesus macaques, particular types of non-classical MHC class I molecules are predominantly expressed on the trophoblast. In humans, human leukocyte antigen G has been demonstrated to act as a ligand for KIR2DL4, present on all NK cells, whereas Mamu-AG may execute a similar function in rhesus macaques. During primate evolution, orthologues of KIR2DL4 appear to have been highly conserved, suggesting strong purifying selection. A cohort of 112 related and unrelated rhesus macaques of mostly Indian origin were selected to study their KIR2DL4 genes for the occurrence of polymorphism. Comparison of the proximal region provided evidence for strong conservative selection acting on the exons encoding the Ig domains. As is found in humans, in the Indian rhesus macaque population, two different KIR2DL4 entities are encountered, which differ for their intra-cellular signalling motifs. One genotype contains a complex mutation in the distal region of exon 9, which negates a serine/threonine kinase site. Furthermore, both allelic entities are present in a distribution, which suggests that balancing selection is operating on these two distinct forms of KIR2DL4. [ABSTRACT FROM AUTHOR]

In humans, the single polymorphic B locus of the major histocompatibility complex is linked to the microsatellite MIB. In rhesus macaques, however, haplotypes are characterized by the presence of unique combinations of multiple B genes, which may display different levels of polymorphism. The aim of the study was to shed light on the evolutionary history of this highly complex region. First, the robustness of the microsatellite MIB-linked to almost half of the B genes in rhesus macaques (Mamu-B)-for accurate B haplotyping was studied. Based on the physical map of an established haplotype comprising 7 MIB loci, each located next to a certain Mamu-B gene, two MIB loci, MIB1 and MIB6, were investigated in a panel of MHC homozygous monkeys. MIB1 revealed a complex genotyping pattern, whereas MIB6 analysis resulted in the detection of one or no amplicon. Both patterns are specific for a given B haplotype, show Mendelian segregation, and even allow a more precise haplotype definition than do traditional typing methods. Second, a search was performed for retroelements that may have played a role in duplication processes as observed in the macaque B region. This resulted in the description of two types of duplicons. One basic unit comprises an expressed Mamu-B gene, adjacent to an HERV16 copy closely linked to MIB. The second type of duplicon comprises a Mamu-B (pseudo)gene, linked to a truncated HERV16 structure lacking its MIB segment. Such truncation seems to coincide with the loss of B gene transcription. Subsequent to the duplication processes, recombination between MIB and Mamu-B loci appears to have occurred, resulting in a hyperplastic B region. Thus, analysis of MIB in addition to B loci allows deciphering of the compound evolutionary history of the class I B region in Old World monkeys. [ABSTRACT FROM AUTHOR]

Background: The major histocompatibility complex (MHC) is a key model of genetic polymorphism. Selection pressure by pathogens or other microevolutionary forces may result in a high rate of non-synonymous substitutions at the codons specifying the contact residues of the antigen binding sites (ABS), and the maintenance of extreme MHC allelic variation at the population/species level. Therefore, selection forces favouring MHC variability for any reason should cause a correlated evolution between substitution rates and allelic polymorphism. To investigate this prediction, we characterised nucleotide substitution rates and allelic polymorphism (i.e. the number of alleles detected in relation to the number of animals screened) of several Mhc class II DRB lineages in 46 primate species, and tested for a correlation between them. Results: First, we demonstrate that species-specific and lineage-specific evolutionary constraints favour species- and lineage-dependent substitution rate at the codons specifying the ABS contact residues (i.e. certain species and lineages can be characterised by high substitution rate, while others have low rate). Second, we show that although the degree of the non-synonymous substitution rate at the ABS contact residues was systematically higher than the degree of the synonymous substitution rate, these estimates were strongly correlated when we controlled for species-specific and lineage-specific effects, and also for the fact that different studies relied on different sample size. Such relationships between substitution rates of different types could even be extended to the non-contact residues of the molecule. Third, we provide statistical evidence that increased substitution rate along a MHC gene may lead to allelic variation, as a high substitution rate can be observed in those lineages in which many alleles are maintained. Fourth, we show that the detected patterns were independent of phylogenetic constraints. When we used phylogenetic models that control for similarity between species, due to common descent, and focused on variations within a single lineage (DRB1*03), the positive relationship between different substitution rates and allelic polymorphisms was still robust. Finally, we found the same effects to emerge in the analyses that eliminated within-species variation in MHC traits by using strictly single population-level studies. However, in a set of contrasting analyses, in which we focused on the non-functional DRB6 locus, the correlation between substitution rates and allelic variation was not prevalent. Conclusion: Our results indicate that positive selection for the generation of allelic polymorphism acting on the functional part of the protein has consequences for the nucleotide substitution rate along the whole exon 2 sequence of the Mhc-DRB gene. Additionally, we proved that an increased substitution rate can promote allelic variation within lineages. Consequently, the evolution of different characteristics of genetic polymorphism is not independent. [ABSTRACT FROM AUTHOR]

Chimpanzees experienced a reduction of the allelic repertoire at the major histocompatibility complex (MHC) class I A and B loci, which may have been caused by a retrovirus belonging to the simian immunodeficiency virus (SIV) family. Extended MHC haplotypes were defined in a pedigreed chimpanzee colony. Comparison of genetic variation at microsatellite markers mapping inside and outside the Mhc region was carried out in humans and chimpanzees to investigate the genomic extent of the repertoire reduction. Multilocus demographic analyses underscored that chimpanzees indeed experienced a selective sweep that mainly targeted the chromosomal segment carrying the Mhc class I region. Probably due to genetic linkage, the sweep also affected other polymorphic loci, mapping in the close vicinity of the Mhc class I region genes. Nevertheless, although the allelic repertoire at particular Mhc class I and II loci appears to be limited, naturally occurring recombination events allowed the establishment of haplotype diversity after the sweep. However, recombination did not have sufficient time to erase the signal of the selective sweep. [ABSTRACT FROM AUTHOR]

The original version of this article contained a spelling error in the Acknowledgments regarding the name of the funding organisation supporting GM and JAH. UKRI-BBSCR should have been UKRI-BBSRC, as is now indicated correctly below. [ABSTRACT FROM AUTHOR]

In contrast to rhesus monkeys, substantial knowledge on cynomolgus monkey major histocompatibility complex (MHC) class II haplotypes is lacking. Therefore, 17 animals, including one pedigreed family, were thoroughly characterized for polymorphic Mhc class II region genes as well as their mitochondrial DNA (mtDNA) sequences. Different cynomolgus macaque populations appear to exhibit unique mtDNA profiles reflecting their geographic origin. Within the present panel, 10 Mafa-DPB1, 14 Mafa-DQA1, 12 Mafa-DQB1, and 35 Mafa-DRB exon 2 sequences were identified. All of these alleles cluster into lineages that were previously described for rhesus macaques. Moreover, about half of the Mafa-DPB1, Mafa-DQA1, and Mafa-DQB1 alleles and one third of the Mafa-DRB exon 2 sequences are identical to rhesus macaque orthologues. Such a high level of Mhc class II allele sharing has not been reported for primate species. Pedigree analysis allowed the characterization of nine distinct Mafa class II haplotypes, and seven additional ones could be deduced. Two of these haplotypes harbor a duplication of the Mafa-DQB1 locus. Despite extensive allele sharing, rhesus and cynomolgus monkeys do not appear to possess identical Mhc class II haplotypes, thus illustrating that new haplotypes were generated after speciation by recombination-like processes. [ABSTRACT FROM AUTHOR]

A thoroughly characterized breeding colony of 172 pedigreed rhesus macaques was used to analyze exon 2 of the polymorphic Mamu-DPB1, -DQA1, -DQB1, and -DRB loci. Most of the monkeys or their ancestors originated in India, though the panel also included animals from Burma and China, as well as some of unknown origin and mixed breeds. In these animals, mtDNA appears to correlate with the aforementioned geographic origin, and a large number of Mamu class II alleles were observed. The different Mamu-DPB1 alleles were largely shared between monkeys of different origin, whereas in humans particular alleles appear to be unique for ethnic populations. In contrast to Mamu-DPB1, the highly polymorphic -DQA1/DQB1 alleles form tightly linked pairs that appear to be about two-thirds population specific. For most of the DQA1/DQB1 pairs, Mamu-DRB region configurations present on the same chromosome have been ascertained, resulting in 41 different -DQ/DRB haplotypes. These distinct DQ/DRB haplotypes seem to be specific for monkeys of a determined origin. Thus, in evolutionary terms, the Mamu-DP, -DQ, and -DR regions show increasing instability with regard to allelic polymorphism, such as for -DP/DQ, or gene content and allelic polymorphism, such as for -DR, resulting in population-specific class II haplotypes. Furthermore, novel haplotypes are generated by recombination-like events. The results imply that mtDNA analysis in combination with Mhc typing is a helpful tool for selecting animals for biomedical experiments. [ABSTRACT FROM AUTHOR]

MHC class I molecules play an essential role in the immune defense against intracellular infections. The hallmark of the MHC is its extensive degree of polymorphism at the population level. However, the present comparison of MHC class I gene intron variation revealed that chimpanzees have experienced a severe repertoire reduction at the orthologues of the HLA-A,-B, and -C loci. The loss of variability predates the (sub)speciation of chimpanzees and did not effect other known gene systems. Therefore the selective sweep in the MHC class I gene may have resulted from a widespread viral infection. Based on the present results and the fact that chimpanzees have a natural resistance to the development of AIDS, we hypothesize that the selective sweep was caused by the chimpanzee-derived simian immunodeficiency virus (SIVcpz), the closest relative of HIV-1, or a closely related retrovirus. Hence, the contemporary chimpanzee populations represent the offspring of AIDS-resistant animals, the survivors of a HIV-like pandemic that took place in the distant past. [ABSTRACT FROM AUTHOR]

Non-human primates are often used in biomedical research, and the application of these animals as a model in immune-related diseases necessitates the characterisation of their MHC system. In particular, the MHC class II regions of the chimpanzee (Pan troglodytes), the rhesus macaque (Macaca mulatta) and the common marmoset (Callithrix jacchus) have been subject of molecular biological studies in recent years. In this study the emphasis was on MHC class II genes of another macaque species, Macaca fascicularis (crab eating macaque or cynomolgous monkey). The exon 2 of the Mhc-DQB gene (Mafa-DQB) was sequenced in each of a random panel of 60 non-pedigreed cynomolgous monkeys. This resulted in the detection of 23 Mafa-DQB1 alleles that had not previously been published. In addition, unreported alleles were found in chimpanzees, rhesus macaques, orang-utans (Pongo pygmaeus) and stump-tailed macaques (Macaca arctoides), of which a few individuals were included in this study. Phylogenetic analyses confirm the trans-species model of evolution of the MHC-DQB lineages, in which a group of major alleles is passed on in the phylogeny, and has led to the sharing of allelic lineages by different species of non-human primates. The sharing of alleles is observed only for closely related macaque species. Furthermore, this manuscript provides an overview of all published, and whenever necessary corrected, non-human primate Mhc-DQB exon 2 alleles. [ABSTRACT FROM AUTHOR]

The rhesus macaque is an important preclinical model in transplantation research and in investigations of chronic and infectious diseases that need a well-characterised major histocompatibility complex (MHC-Mamu). In a large population of pedigreed rhesus macaques, 70 Mamu-DRB, 18-DQA1, 24-DQBl, and 14-DPB1 alleles were detected. In humans, five HLA-DRB region configurations are present, displaying diversity with regard to number and combinations of loci. The HLA-DRB1 gene of each of these configurations is highly polymorphic. For rhesus monkeys, at least 31 Mamu-DRB region configurations have been determined. In contrast to humans, most Mamu-DRB region configurations display no or only limited allelic polymorphism. Segregation analyses revealed 28 Mamu-DQA1/DQB1 pairs, each pair linked to a limited number of Mamu-DRB region configurations and vice-versa. In comparison with humans, the degree of freedom of recombination between Mamu-DQA1 and -DQB1 is extremely low and equivalents of HLA-DQA2/DQB2 are absent. The Mamu-DPA1 gene is invariant and -DPB1 manifests only moderate allelic variation, whereas the HLA-DPA1 gene is oligomorphic and HLA-DPB1 highly polymorphic. Thus, both species used different evolutionary strategies to create polymorphism and diversity at the MHC class II loci in order to cope with pathogens. [ABSTRACT FROM AUTHOR]

Long terminal repeats (LTRs) are common retrovirus-related sequences spread throughout the human genome. We previously reported the human-specific integration of one LTR (DQLTR3) located 15 kb upstream of HLA DQB1. To elucidate the contribution of retroviral sequences to the variability and phylogenetic background of HLA DQB1 we investigated another LTR (DQLTR13), located 1.3 kb upstream of HLA DQB1, in German families, great apes, and Old World monkeys. Within German families, DQLTR13 presence was strongly linked to HLA DQB1*0302, *0303, and *0402 haplotypes. All other haplotypes had a low frequency or were devoid of DQLTR13. Phylogenetic analysis of DQLTR13 and adjacent nucleotide sequences in humans and nonhuman primates revealed a high degree of similarity and recent origin of HLA DQB1*0302, *0303, and *0402. Nevertheless, two lineages leading to DQB1*0301 and *0302 were generated by an ancient split of a DQB1*0301, *0302 progenitor. A third lineage consisting of DQB1*05/*06-related sequences may have evolved from the DQB1*0302 lineage, and a DQB1*0201-related sequence shared common ancestry with DQB1*0301. Among the human haplotypes, HLA DQB1*0201 and *0301 are linked to two different DQA1 alleles. Based on the small genetic distance of DQLTR13 as well as the adjacent sequences on these haplotypes, we suggest that a recent recombination is responsible for these associations. In the analysis of nonhuman primate species, we detected DQLTR13 in two lowland gorillas, dating the integration at at least 8 million years ago. We therefore conclude that noncoding sequences up to 1.3 kb upstream of DQB1 provide novel insight into the generation of MHC gene diversity. [ABSTRACT FROM AUTHOR]

In the past decade, the major histocompatibility complex (MHC) class II region of several primate species has been investigated extensively. Here we will discuss the similarities and differences found in the MHC class II repertoires of primate species including humans, chimpanzees, rhesus macaques, cotton-top tamarins and common marmosets. Such types of comparisons shed light on the evolutionary stability of MHC class II alleles, lineages and loci as well as on the evolutionary origin and biological significance of haplotype configurations. [ABSTRACT FROM AUTHOR]

The major histocompatibility complex (MHC) class I region of humans, chimpanzees (Pan troglodytes), and bonobos (Pan paniscus) is highly similar, and orthologues of HLA-A, -B, and -C are present in both Pan species. Based on functional characteristics, the different HLA-A allotypes are classified into different supertypes. One of them, the HLA A03 supertype, is widely distributed among different human populations. All contemporary known chimpanzee and bonobo MHC class I A allotypes cluster genetically into one of the six HLA A families, HLA-A1/A3/A11/A30. We report here that the peptide-binding motif of the Patr-A*05:01 allotype, which is commonly present in a cohort of Western-African chimpanzees, has a strong preference for binding peptides with basic amino acids at the carboxyl terminus. This phenomenon is shared with the family members of the HLA A03 supertype. Based on the chemical similarities in the peptide-binding pocket, we inferred that the preference for binding peptides with basic amino acids at the carboxyl terminus is widely present among the human, chimpanzee, and bonobo MHC-A allotypes. Subsequent in silico peptide-binding predictions illustrated that these allotypes have the capacity to target conserved parts of the HIV-1/SIVcpz proteome. [ABSTRACT FROM AUTHOR]

The IPD-MHC Database was released in 2003 to provide a curated database of MHC sequences from a number of non-human species. The system was modeled on the IPD-IMGT/HLA database but expanded to cover multiple species and nomenclature systems. The initial release contained data on non-human primates, felines and canines. Since this time further data on horse, sheep, swine, cattle, fish and rats has been added. Since its release, the database has grown rapidly and now contains nearly 7000 alleles covering over 70 non-human species. The site averages ∼ 1500 unique visitors a month viewing ∼ 5,000 pages. This growth has led to a number of challenges in maintaining and developing the site. The bioinformatics challenges of running a locus specific database across multiple nomenclature systems and locations have impacted on the performance and sustainability of the current IPD-MHC model. In 2015 a BBSRC Bioinformatics and Biological Resources (BBR) grant (UK) was awarded to fund both essential upgrades and future expansion of IPD-MHC. Work is currently focused on the underlying database, the public website and the submission procedures. The key aims of this first phase are development of a universal cross species data submission and display tool and streamlining and standardising the work of the nomenclature committees in curating the data. This will allow for simpler and more frequent species updates. Future developments aim to incorporate cross-species alignment, primer design tools and the incorporation of NGS data. Ultimately this will create an improved system capable of coping with large number of sequence variants, genes and species within the dataset. The project is overseen by a steering committee representing key stakeholders and non-human MHC nomenclature committees. This group is also helping to develop new MHC nomenclature standards and guidelines. IPD-MHC: https://www.ebi.ac.uk/ipd/mhc/ . [ABSTRACT FROM AUTHOR]

The major histocompatibility complex (MHC) represents a multigene family that is known to display allelic and gene copy number variations. Primate species such as humans, chimpanzees (Pan troglodytes), and rhesus macaques (Macaca mulatta) show DRB region configuration polymorphism at the population level, meaning that the number and content of DRB loci may vary per haplotype. Introns of primate DRB alleles differ significantly in length due to insertions of transposable elements as long endogenous retrovirus (ERV) and human ERV (HERV) sequences in the DRB2, DRB6, and DRB7 pseudogenes. Although the integration of intronic HERVs resulted sooner or later in the inactivation of the targeted genes, the fixation of these endogenous retroviral segments over long time spans seems to have provided evolutionary advantage. Intronic HERVs may have integrated in a sense or an antisense manner. On the one hand, antisense-oriented retroelements such as HERV-K14I, observed in intron 2 of the DRB7 genes in humans and chimpanzees, seem to promote stability, as configurations/alleles containing these hits have experienced strong conservative selection during primate evolution. On the other hand, the HERVK3I present in intron 1 of all DRB2 and/or DRB6 alleles tested so far integrated in a sense orientation. The data suggest that multigenic regions in particular may benefit from sense introgressions by HERVs, as these elements seem to promote and maintain the generation of diversity, whereas these types of integrations may be lethal in monogenic systems, since they are known to influence transcript regulation negatively. [ABSTRACT FROM AUTHOR]

In the absence of treatment, most HIV-1-infected humans develop AIDS. However, a minority are long-term nonprogressors, and resistance is associated with the presence of particular HLA-B*27/ B*57 molecules. In contrast, most HIV-1-infected chimpanzees do not contract AIDS. In comparison with humans, chimpanzees experienced an ancient selective sweep affecting the MHC class I repertoire. We have determined the peptide-binding properties of frequent chimpanzee MHC class I molecules, and show that, like HLA-B*27IB*57, they target similar conserved areas of HIV1/SlVcpz. In addition, many animals appear to possess multiple molecules targeting various conserved areas of the HlV-1/SlVcpz Gag protein, a quantitative aspect of the immune response that may further minimize the chance of viral escape. The functional characteristics of the contemporary chimpanzee MHC repertoire suggest that the selective sweep was caused by a lentiviral pandemic. [ABSTRACT FROM AUTHOR]

Abstract: In most primate species, the class II region of the Major Histocompatibility Complex (MHC) displays diversity with regard to gene copy number and combination of DRB genes present per region configuration. Some of these loci exhibit extremely high levels of allelic variability, whereas others display only moderate levels of polymorphism. To understand the evolutionary history of the various HLA-DR region genes, a large number of full-length sequences of rhesus macaques, chimpanzees and humans were determined. The exon–intron organisation of the DRA gene, displaying only low levels of polymorphism, appears to have been highly conserved during primate evolution. The physical length of various DRB genes/alleles, however, fluctuates significantly in primates due to the presence of indels (insertions/deletions), mainly mapping to intron 1. Phylogenetic evidence supports the notion that the generation of new DRB genes is a dynamic and steadily ongoing process. Indeed, most of the primate DRB alleles investigated represent relatively young entities, possessing species-unique sequences. This seems to contradict the current view that the highly similar peptide binding motifs of many HLA-, Patr- and Mamu-DR molecules, encoded by exon 2 of the DRB gene, represent old entities, which predate primate speciation. As no evidence was found for convergent evolution, the combination of these two observations indicates that ancient peptide binding motifs are frequently reshuffled among duplicated members of the HLA-DRB multigene family. [Copyright &y& Elsevier]

Aim: Humans and orangutans shared a common ancestor about 12-16 million years ago. Two orangutan species are officially recognized; one inhabiting Borneo (Pongo pygmaeus) and the other Sumatra (Pongo abelii). Orangutans possess A, B, and C genes that are homologous to their HLA equivalents. Unlike humans where each of these is found as a single copy gene on a haplotype, orangutan haplotypes may possess a duplicated B gene whereas others lack C. In theory, orangutans may express from 3 to 8 different classical MHC class I allotypes. Conventional sequencing of cDNA derived from six different orangutan samples, using 4 different primer sets, suggested that certain alleles, in particular MHC-C, are less well transcribed. Therefor we aimed to investigate the transcription/expression profile of the orangutan MHC class I genes. Methods: cDNA, derived from five different orangutan EBV transformed B-cell-lines (two Popy and three Poab), was used as starting material. Generic primers were designed, and relevant amplicons were sequenced in both directions using massively parallel sequencing. Results: The analyses showed that the A locus is most abundantly transcribed. The B locus exhibits differential transcription patterns that seem to be dependent on the B allotype present in an animal. The present analyses show an almost negligible transcription of the B∗03-locus/lineage. In addition, the C locus, if present, appears to be minutely transcribed. Moreover, the cell-surface expression of several MHC allotypes was assessed using various monoclonal antibodies. Conclusions: The present data suggest a minor immunological role for B∗03-lineage and C-locus molecules in orangutangs as they appear to be virtually absent on peripheral blood derived cells. Besides, all animals investigated transcribe at least one variant of the B∗08-lineage that encodes the C1-epitope, the ligand for particular killer cell Ig-like receptor, and most likely compensate for the partial loss of the C-locus in orangutans. [Copyright &y& Elsevier]