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

Abstract

The Mamu-A genes of the rhesus macaque show different degrees of polymorphism, transcription level variation, and differential haplotype distribution. Per haplotype, usually one "major" transcribed gene is present, A1 (A7), in various combinations with "minor" genes, A2 to A6. In silico analysis of the physical map of a heterozygous animal revealed the presence of similar Mamu-A regions consisting of four duplication units, but with dissimilar positions of the A1 genes on both haplotypes, and in combination with different minor genes. Two microsatellites, D6S2854 and D6S2859, have been selected as potential tools to characterize this complex region. Subsequent analysis of a large breeding colony resulted in the description of highly discriminative patterns, displaying copy number variation in concert with microsatellite repeat length differences. Sequencing and segregation analyses revealed that these patterns are unique for each Mamu-A haplotype. In animals of Indian, Burmese, and Chinese origin, 19, 15, or 9 haplotypes, respectively, could be defined, illustrating the occurrence of differential block duplications and subsequent rearrangements by recombination. The haplotypes can be assigned to 12 unique combinations of genes (region configurations). Although most configurations harbor two transcribed A genes, one or three genes per haplotype are also present. Additionally, haplotypes lacking an A1 gene or with an A1 duplication appear to exist. The presence of different transcribed A genes/alleles in monkeys from various origins may have an impact on differential disease susceptibilities. The high-throughput microsatellite technique will be a valuable tool in animal selection for diverse biomedical research projects.

Fig. 1

Schematic representation of Mamu-A region configurations observed in Indian, Chinese, and Burmese rhesus macaques. Only transcribed Mamu-A loci are represented and color-coded. The order and distances of all loci, including those of region configuration 1 and 5 of the physical map, are schematically drawn. * Region configuration 3 has not been detected in this study

Fig. 2

Detailed physical map of the Mamu-A region of a heterozygous rhesus macaque. Location of Mamu-A genes/pseudogenes, microsatellite D6S2854 and D6S2959, L1, and HERV16/HERVP71A loci are indicated in scale. Haplotype 1 is based on the pysical map of Shiina and coworkers and haplotype 2 on data of Daza-Vamenta and colleagues (Daza-Vamenta et al. ; Shiina et al. 2006)