Nel Otting

Major histocompatibility complex class II polymorphisms in primates

Summary: 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.

Evidence for an ancient selective sweep in the MHC class I gene repertoire of chimpanzees

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.

Microsatellite typing of the rhesus macaque MHC region

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.

MHC class I A region diversity and polymorphism in macaque species

The HLA-A locus represents a single copy gene that displays abundant allelic polymorphism in the human population, whereas, in contrast, a nonhuman primate species such as the rhesus macaque (Macaca mulatta) possesses multiple HLA-A-like (Mamu-A) genes, which parade varying degrees of polymorphism. The number and combination of transcribed Mamu-A genes present per chromosome display diversity in a population of Indian animals. At present, it is not clearly understood whether these different A region configurations are evolutionarily stable entities. To shed light on this issue, rhesus macaques from a Chinese population and a panel of cynomolgus monkeys (Macaca fascicularis) were screened for various A region-linked variations. Comparisons demonstrated that most A region configurations are old entities predating macaque speciation, whereas most allelic variation (>95%) is of more recent origin. The latter situation contrasts the observations of the major histocompatibility complex class II genes in rhesus and cynomolgus macaques, which share a high number of identical alleles (>30%) as defined by exon 2 sequencing.

Unprecedented Polymorphism of Mhc-DRB Region Configurations in Rhesus Macaques

The rhesus macaque is an important model in preclinical transplantation research and for the study of chronic and infectious diseases, and so extensive knowledge of its MHC (MhcMamu) is needed. Nucleotide sequencing of exon 2 allowed the detection of 68 Mamu-DRB alleles. Although most alleles belong to loci/lineages that have human equivalents, identical Mhc-DRB alleles are not shared between humans and rhesus macaques. The number of -DRB genes present per haplotype can vary from two to seven in the rhesus macaque, whereas it ranges from one to four in humans. Within a panel of 210 rhesus macaques, 24 Mamu-DRB region configurations can be distinguished differing in the number and composition of loci. None of the Mamu-DRB region configurations has been described for any other species, and only one of them displays major allelic variation giving rise to a total of 33 Mamu-DRB haplotypes. In the human population, only five HLA-DRB region configurations were defined, which in contrast to the rhesus macaque exhibit extensive allelic polymorphism. In comparison with humans, the unprecedented polymorphism of the Mamu-DRB region configurations may reflect an alternative strategy of this primate species to cope with pathogens. Because of the Mamu-DRB diversity, nonhuman primate colonies used for immunological research should be thoroughly typed to facilitate proper interpretation of results. This approach will minimize as well the number of animals necessary to conduct experiments.

Genome-wide analysis of miRNA expression reveals a potential role for miR-144 in brain aging and spinocerebellar ataxia pathogenesis

Neurodegenerative pathologies associated with aging exhibit clinical and morphological features that are relatively specific to humans. To gain insights into the evolution of the regulatory mechanisms of the aged brain, we compared age-related differences in microRNA (miRNA) expression levels in the cortex and cerebellum of humans, chimpanzees and rhesus macaques on a genome-wide scale. In contrast to global miRNA downregulation, a small subset of miRNAs was found to be selectively upregulated in the aging brain of all 3 species. Notably, miR-144 that is highly conserved appeared to be associated with the aging progression. Moreover, miR-144 plays a central role in regulating the expression of ataxin 1 (ATXN1), the disease-causing gene for the development spinocerebellar ataxia type 1 (SCA1). miRNA activity, including miR-144, -101 and -130 processing, was increased in the cerebellum and cortex of SCA1 and Alzheimer patients relative to healthy aged brains. Importantly, miR-144 and -101 inhibition increased ATXN1 levels in human cells. Thus, the activation of miRNA expression in the aging brain may serve to reduce the cytotoxic effect of polyglutamine expanded ATXN1 and the deregulation of miRNA expression may be a risk factor for disease development.

Mhc-DRB diversity of the chimpanzee (Pan troglodytes)

Fifty-four chimpanzee Patr-DRB and five human HLA-DRB second exons were cloned and sequenced from thirty-five chimpanzees and four B-cell lines and compared with known Mhc-DRB sequences of these two species. Equivalents of the HLA-DRB1*02,-DRB1*03, -DRB1*07 allelic lineages and the HLA-DRB3,-DRB4, -DRB5, -DRB6, and -DRB7 loci were all found in the chimpanzee. In addition, two chimpanzee Patr-DRB lineages (Patr-DRBX and -DRBY) were found for which no human counterparts have been described. None of the Patr-DRB sequences is identical to known HLA-DRB sequences. The Patr-DRB1*0702 and HLA-DRB1*0701 alleles are the most similar sequences in a comparison between the two species and differ by only two nucleotides out of 246 sequences. Equivalents of the HLA-DRB1*01,-DRB1*04, and -DRB1*09 alleles were not found in our sample of chimpanzees. A per locus comparison of the number of Patr-DRB alleles with the HLA-DRB alleles shows that the Patr-DRB3, -DRB4, -DRB5, and -DRB6 locus are, thus far, more polymorphic than ther human homologs. The polymorphism of the Patr-DRB1 locus seems to be less extensive than that reported for the HLA-DRB1 locus. Nevertheless, the Patr-DRB1 locus seems to be the most polymorphic of the Patr-DRB loci. Phylogenetic analyses indicate that the HLA-DRB1*09 allele may have originated from a recombination between a Mhc-DRB5 allele and the DRB1 allele of a Mhc-DR7 haplotype. Although recombination seems to increase the diversity of the Patr-DRB alleles, its contribution to the generation of Patr-DRB variation is probably low. Hence, most Patr-DRB diversity presumably accumulated via recurrent point mutations. Finally, two distinct PAtr-DRB haplotypes are deduced, one of which (the chimpanzee equivalent of the HLA-Dr7 haplotype) is probably older than 6–8 million years.

Evolutionary stability of transspecies major histocompatibility complex class II DRB lineages in humans and rhesus monkeys

Sequence analysis of rhesus monkey (Macaca mulatta) polymorphic second exon of major histocompatibility complex class II DRB subregion genes demonstrates the existence of at least 34 alleles. Some of these rhesus monkey alleles are very similar (or nearly identical) to HLA-DRB alleles. These data demonstrate that members of the lineages for Mhc-DRB1*03, -DRB1*04, -DRB1*10, and the loci of Mhc-DRB3, -DRB4, -DRB5, and -DRB6 predate speciation of man and rhesus monkey and were already present 25 million years ago. Calculation of evolutionary rates suggests that the various allele lineages have differential stabilities. Furthermore, the data indicate that distinct species may not have inherited or lost transspecies Mhc-DRB lineages in evolution, because several allele lineages in rhesus monkeys appear to be absent in humans and vice versa.

Nomenclature report on the major histocompatibility complex genes and alleles of Great Ape, Old and New World monkey species

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.

Differential evolutionary MHC class II strategies in humans and rhesus macaques: relevance for biomedical studies

Summary: 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 ‐DQB1, 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.