Genomic plasticity of the immune-related Mhc class I B region in macaque species

Abstract

Background: In sharp contrast to humans and great apes, the expanded Mhc-B region of rhesus and cynomolgus macaques is characterized by the presence of differential numbers and unique combinations of polymorphic class I B genes per haplotype. The MIB microsatellite is closely linked to the single class I B gene in human and in some great apes studied. The physical map of the Mhc of a heterozygous rhesus monkey provides unique material to analyze MIB and Mamu-B copy number variation and then allows one to decipher the compound evolutionary history of this region in primate species.

Results: In silico research pinpointed 12 MIB copies (duplicons), most of which are associated with expressed B-genes that cluster in a separate clade in the phylogenetic tree. Generic primers tested on homozygous rhesus and pedigreed cynomolgus macaques allowed the identification of eight to eleven MIB copies per individual. The number of MIB copies present per haplotype varies from a minimum of three to six in cynomolgus macaques and from five to eight copies in rhesus macaques. Phylogenetic analyses highlight a strong transpecific sharing of MIB duplicons. Using the physical map, we observed that, similar to MIB duplicons, highly divergent Mamu-B genes can be present on the same haplotype. Haplotype variation as reflected by the copy number variation of class I B loci is best explained by recombination events, which are found to occur between MIBs and Mamu-B.

Conclusion: The data suggest the existence of highly divergent MIB and Mamu-B lineages on a given haplotype, as well as variable MIB and B copy numbers and configurations, at least in rhesus macaque. Recombination seems to occur between MIB and Mamu-B loci, and the resulting haplotypic plasticity at the individual level may be a strategy to better cope with pathogens. Therefore, evolutionary inferences based on the multiplicated MIB loci but also other markers close to B-genes appear to be promising for the study of B-region organization and evolution in primates.

Figure 1

Location of MIB copies and B genes on the physical map of rhesus macaque Mhc. Blank and filled arrows indicate MIB and Mamu-B gene copies, respectively. BAC clones, from which MIBs and Mamu-B genes were retrieved, are positioned at the top of the figure. The names of the Mamu-B01 to -B19 genes – labelled as such by Daza-Vamenta and colleagues [11] and also annotated differently by Shiina and colleagues [42] – have been replaced by the latest Mamu-B loci/lineage names (B*) whenever possible; these represent "major'' or "minor'' expressed Mamu-B loci [15,16]. Green arrow indicates transcription direction.

Figure 2

Bayesian phylogenetic tree of flanking sequences of MIB copies in human, great apes, M. mulatta, and M. fascicularis. Numbers at nodes are posterior probability values for node support. Braces identify strictly identical sequences differing only by the microsatellite repeat number, indicating an orthologous relationship between species, as well as allelic (microsatellite) polymorphism within a species and sometimes within the same individual. Brackets identify the shared indels. Stars pinpoint eight different well supported lineages. M. mulatta sequences are represented in green (light = individual 2B, semi-dark = 3C, dark = GenBank individual), M. fascicularis sequences are orange (individual K), pink (individual G) and purple (individual B). Hsa, Ptr, and Gor represent human, chimpanzee, and gorilla MIB sequences, respectively. Note that the two MIB5(8) copies show identical flanking sequences but a slightly different microsatellite repeat length.

Figure 3

Bayesian phylogenetic tree of Mamu-B gene (exons and introns) in human and M. mulatta. Numbers at nodes are posterior probability values for node support. Blue and red circles indicate Mamu-B loci present on haplotype 1 and 2, respectively, of the published material [11]. Green rectangles indicate pseudogenes or low expressed genes. Mamu-B loci with a "B*" name are expressed genes. Next to Mamu-B loci are shown associated MIBs. Mamu-B loci with the same colour indicate phylogenetic relatedness, the same annotation was made for MIB loci. The figure do shows that only the locus I presents close linkage to MIB. The asterisk indicates the sub-clade (PPV = 0.95) within clade 1, which B-genes are associated with MIBs.