The mosaic of KIR haplotypes in rhesus macaques

To further refine and improve biomedical research in rhesus macaques, it is necessary to increase our knowledge concerning both the degree of allelic variation (polymorphism) and diversity (gene copy number variation) in the killer cell immunoglobulin-like receptor (KIR) gene cluster. Pedigreed animals in particular should be studied, as segregation data will provide clues to the linkage of particular KIR genes/alleles segregating on a haplotype and to its gene content as well. A dual strategy allowed us to screen the presence and absence of genes and the corresponding transcripts, as well as to track differences in transcription levels. On the basis of this approach, 14 diverse KIR haplotypes have been described. These haplotypes consist of multiple inhibitory and activating Mamu-KIR genes, and any gene present on one haplotype may be absent on another. This suggests that the cost of accelerated evolution by recombination may be the loss of certain framework genes on a haplotype

Unparalleled Rapid Evolution of KIR Genes in Rhesus and Cynomolgus Macaque Populations

The killer cell Ig-like receptors (KIR) modulate immune responses through interactions with MHC class I molecules. The KIR region in large cohorts of rhesus and cynomolgus macaque populations were characterized, and the experimental design enabled the definition of a considerable number of alleles (n = 576) and haplotypes, which are highly variable with regard to architecture. Although high levels of polymorphism were recorded, only a few alleles are shared between species and populations. The rapid evolution of allelic polymorphism, accumulated by point mutations, was further confirmed by the emergence of a novel KIR allele in a rhesus macaque family. In addition to allelic variation, abundant orthologous and species-specific KIR genes were identified, the latter of which are frequently generated by fusion events. The concerted action of both genetic mechanisms, in combination with differential selective pressures at the population level, resulted in the unparalleled rapid evolution of the KIR gene region in two closely related macaque species. The variation of the KIR gene repertoire at the species and population level might have an impact on the outcome of preclinical studies with macaque models

Unparalleled Rapid Evolution of KIR Genes in Rhesus and Cynomolgus Macaque Populations

The killer cell Ig-like receptors (KIR) modulate immune responses through interactions with MHC class I molecules. The KIR region in large cohorts of rhesus and cynomolgus macaque populations were characterized, and the experimental design enabled the definition of a considerable number of alleles (n = 576) and haplotypes, which are highly variable with regard to architecture. Although high levels of polymorphism were recorded, only a few alleles are shared between species and populations. The rapid evolution of allelic polymorphism, accumulated by point mutations, was further confirmed by the emergence of a novel KIR allele in a rhesus macaque family. In addition to allelic variation, abundant orthologous and species-specific KIR genes were identified, the latter of which are frequently generated by fusion events. The concerted action of both genetic mechanisms, in combination with differential selective pressures at the population level, resulted in the unparalleled rapid evolution of the KIR gene region in two closely related macaque species. The variation of the KIR gene repertoire at the species and population level might have an impact on the outcome of preclinical studies with macaque models

The orthologs of HLA-DQ and -DP genes display abundant levels of variability in macaque species

The human major histocompatibility complex (MHC) region encodes three types of class II molecules designated HLA-DR, -DQ, and -DP. Both the HLA-DQ and -DP gene region comprise a duplicated tandem of A and B genes, whereas in macaques, only one set of genes is present per region. A substantial sequencing project on the DQ and DP genes in various macaque populations resulted in the detection of previously 304 unreported full-length alleles. Phylogenetic studies showed that humans and macaques share trans-species lineages for the DQA1 and DQB1 genes, whereas the DPA1 and DPB1 lineages in macaques appear to be species-specific. Amino acid variability plot analyses revealed that each of the four genes displays more allelic variation in macaques than is encountered in humans. Moreover, the numbers of different amino acids at certain positions in the encoded proteins are higher than in humans. This phenomenon is remarkably prominent at the contact positions of the peptide-binding sites of the deduced macaque DPβ-chains. These differences in the MHC class II DP regions of macaques and humans suggest separate evolutionary mechanisms in the generation of diversity

Complex MHC Class I Gene Transcription Profiles and Their Functional Impact in Orangutans

MHC haplotypes of humans and the African great ape species have one copy of the MHC-A, -B, and -C genes. In contrast, MHC haplotypes of orangutans, the Asian great ape species, exhibit variation in the number of gene copies. An in-depth analysis of the MHC class I gene repertoire in the two orangutan species, Pongo abelii and Pongo pygmaeus, is presented in this article. This analysis involved Sanger and next-generation sequencing methodologies, revealing diverse and complicated transcription profiles for orangutan MHC-A, -B, and -C. Thirty-five previously unreported MHC class I alleles are described. The data demonstrate that each orangutan MHC haplotype has one copy of the MHC-A gene, and that the MHC-B region has been subject to duplication, giving rise to at least three MHC-B genes. The MHC-B*03 and -B*08 lineages of alleles each account for a separate MHC-B gene. All MHC-B*08 allotypes have the C1-epitope motif recognized by killer cell Ig-like receptor. At least one other MHC-B gene is present, pointing to MHC-B alleles that are not B*03 or B*08. The MHC-C gene is present only on some haplotypes, and each MHC-C allotype has the C1-epitope. The transcription profiles demonstrate that MHC-A alleles are highly transcribed, whereas MHC-C alleles, when present, are transcribed at very low levels. The MHC-B alleles are transcribed to a variable extent and over a wide range. For those orangutan MHC class I allotypes that are detected by human monoclonal anti-HLA class I Abs, the level of cell-surface expression of proteins correlates with the level of transcription of the allele