Genomic plasticity of the MHC class I A region in rhesus macaques: extensive haplotype diversity at the population level as revealed by microsatellites

Doxiadis, Gaby G. M.; Groot, Nanine de; Otting, Nel; Blokhuis, Jeroen H.; Bontrop, Ronald E.

doi:10.1007/s00251-010-0486-4

Cited by 42 publications

(60 citation statements)

References 66 publications

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“…Selection pressure by pathogens drives the generation of polymorphism in the functional genes (Parham et al 1995). The details of these processes and the outcomes vary greatly between species: humans, for example, have a fixed complement of three classical MHC class I genes (HLA-A, HLA-B and HLA-C); rhesus macaques in contrast have very variable combinations of duplicated Mamu-A and Mamu-B genes, thus demonstrating region configuration polymorphism (Bodmer 1987;Bonhomme et al 2008;Doxiadis et al 2011).…”

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confidence: 98%

Constraints on haplotype structure and variable gene frequencies suggest a functional hierarchy within cattle MHC class I

et al. 2012

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Six major histocompatibility complex (MHC) classical class I genes have been identified in cattle, and up to three of these are expressed in variable combinations on different haplotypes. The origin and functional significance of this genetic complexity is unknown. However, an improved assembly of the cattle genome, an expanded database of full-length cDNA sequences and high-resolution frequency data concerning expressed class I genes in an economically important cattle breed combine to provide a new opportunity to study the significance of cattle MHC class I diversity. Analysis of these new data supports assignment of alleles to six discrete genes and further shows that all these classical genes share a common ancestor with a single non-classical gene, NC1. While haplotype structure is variable, with thirteen gene configurations identified, there are nevertheless clear constraints relating to both the number and combination of genes. Haplotypes expressing two classical genes are most frequently observed, and the classical class I gene 2 is almost invariably present. The frequency data support the dominance of gene 2, showing that close to 100 % of individuals carry at least one copy. This indicates a hierarchy in the functional importance of particular genes and haplotype structures. Haplotype frequency in cattle populations is therefore likely to impact on differential disease susceptibilities. This knowledge will be important for development of informed breeding strategies aimed at increasing the ability of cattle to survive in the face of future unpredictable pathogen exposure.

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Section: Introductionmentioning

confidence: 98%

Constraints on haplotype structure and variable gene frequencies suggest a functional hierarchy within cattle MHC class I

et al. 2012

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“…However, this in itself is not always straightforward due to the fluid, and sometimes rapidly evolving nature of the MHC region. In the case of the rhesus macaque for example, there are variable numbers of 'A' locus genes, due to block duplications and recombination (Doxiadis et al 2011). These have been named A1 to A7 based to an extent on phylogenetic relationships; however, it has been shown that their relative map positions can vary substantially between haplotypes.…”

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confidence: 97%

“…This can be seen at the level of genetic polymorphism, but also in variations in gene number and haplotype complexity (Kelley et al 2005;Doxiadis et al 2011). Livestock species are crucial to global food security; thus, it is important to gain a detailed understanding of these genes and their role in disease resistance in such species.…”

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Cattle MHC nomenclature: is it possible to assign sequences to discrete class I genes?

et al. 2012

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The cattle major histocompatibility complex (MHC) region contains a variable number of classical class I genes encoding polymorphic molecules involved in antigen presentation. Six classical class I genes have been described, but assigning sequences to these genes has proved problematic. We propose a refinement of the existing nomenclature, which currently names the 97 known classical class I sequences in a single series. Phylogenetic analysis of the 3' portion of the coding region allows segregation of these into six groups; thus, we have prefixed existing names with the appropriate number. Although it is clear that some of these groups correspond to discrete genes, it is currently not possible to state definitively that all do. However, the main groupings are consistent, and in conjunction with other evidence, we feel it is now appropriate to rename the sequences accordingly. Segregation of sequences into groups in this way will facilitate ongoing research and future use of the cattle MHC section of the Immuno Polymorphism Database.

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“…In humans, the classical HLA-A, -B, and -C genes are restricted to a single locus, and are characterized by extensive polymorphism [14]. In the rhesus macaque, the homologs of HLA-A and -B, designated Mamu-A and -B respectively, are present, while the ortholog of HLA-C is absent [15].Contrary to HLA, the Mamu-A and -B genes show a lesser degree of polymorphism but are expanded in their copy number, leading to many haplotypes with variable gene content, referred to as region configurations [16,17]. In both species, the MHC has evolved in its own manner; functionally, however, these molecules behave in the same way.…”

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confidence: 99%

“…Contrary to HLA, the Mamu-A and -B genes show a lesser degree of polymorphism but are expanded in their copy number, leading to many haplotypes with variable gene content, referred to as region configurations [16,17]. In both species, the MHC has evolved in its own manner; functionally, however, these molecules behave in the same way.…”

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The extreme plasticity of killer cell Ig‐like receptor (KIR) haplotypes differentiates rhesus macaques from humans

et al. 2011

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NK cells are essential in shaping immune responses and play an important role during pregnancy and in controlling infections. Killer cell immunoglobulin-like receptors (KIRs) educate the NK cell and determine its state of activation. Our goal was to determine how the KIR repertoire of the rhesus macaque (Macaca mulatta) has been shaped during evolution. The presence or absence of 22 KIR gene groups was determined in 378 animals. Some unexpected observations were made in an outbred colony comprising animals of different origins. For instance, the KIR region appears to be highly plastic, and an unprecedented number of genotypes and haplotypes was observed. In contrast to humans, there is no distinction between group A and B haplotypes in the rhesus macaque, suggesting that different selective forces may be operative. Moreover, specific genes appear to be either present or absent in animals of different geographic origins. This extreme plasticity may have been propelled by co-evolution with the rhesus macaque MHC class I region, which shows signatures of expansion. The mosaic-like complexity of KIR genotypes as observed at the population level may represent an effective strategy for surviving epidemic infections. [3] but they are also involved with the vascularisation process during placentation, and thus contribute to reproductive success [4]. The education and activation state of the NK-cell is determined by the interactions of its receptors with their cognate ligands [5]. It is the shift in equilibrium of inhibitory and activating receptor signaling that ultimately leads to NK-cell activation in the form of cytokine production, cytotoxicity, or priming of the adaptive immune system [6].Killer cell immunoglobulin-like receptors (KIRs) may influence this balance through interactions with their ligands, the MHC molecules, which are called human leukocyte antigens 2719(HLA) in humans. Since both the HLA system and the KIR gene complex are characterized by variation in locus content, and segregate independent of each other, the potential array of interactions can vary considerably between individuals. Understanding the evolution and complexity of these receptor systems has broad medical relevance, since particular combinations of KIR and HLA alleles are associated with the outcome of viral infection, relapse of leukemia after transplantation, susceptibility to autoimmune disease, and successful pregnancy [7][8][9][10]. Because of its close evolutionary relationship to humans, and evidenced by similar immunological responses, the rhesus macaque (Macaca mulatta) is an important animal model to study the onset, progression, and outcome of infectious diseases, experimentally induced autoimmunity, and transplantation [11][12][13]. Moreover, certain human pathogens or their simiantrophic family members have adapted to primates as their natural host, and may show a host-specific pathology. Since in an experimental setting the onset of disease or the actual challenge with a pathogen can be controlled, it is possible to stu...

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Genomic plasticity of the MHC class I A region in rhesus macaques: extensive haplotype diversity at the population level as revealed by microsatellites

Cited by 42 publications

References 66 publications

Constraints on haplotype structure and variable gene frequencies suggest a functional hierarchy within cattle MHC class I

Constraints on haplotype structure and variable gene frequencies suggest a functional hierarchy within cattle MHC class I

Cattle MHC nomenclature: is it possible to assign sequences to discrete class I genes?

The extreme plasticity of killer cell Ig‐like receptor (KIR) haplotypes differentiates rhesus macaques from humans

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