Research Areas:

Comparative Genetics & Refinement

The immune system is orchestrated by many different genes. These genes can differ from individual to individual. This genetic variation within a population is called polymorphism. Polymorphisms explain why some people are susceptible for a certain disease while others do not develop the disease. Hence, the diversity generated by these polymorphisms prevents the elimination of an entire population by one single pathogen.

The Major Histocompatibility Complex (MHC) and killer cell immunoglobulin-like receptor (KIR) system are examples of polymorphic gene systems. A successful immune response is multifactorial, and depends on the cooperation between the KIR and MHC system. In general, the MHC system is involved in discriminating between self and non-self and thus the recognition of invading pathogens while the KIR system may be seen as fine tuning and serves as a correction mechanism for the MHC system. KIR genes are involved in the immune defense to viruses and cancer cells.

Monkeys are genetically similar to people. Understanding genetic polymorphisms in monkeys, and their role in the immune system, teaches us much about the functional immune defense in humans. This is particularly important in the development of a whole new generation of medicines, the so-called personalized medicines.

In the Comparative Genetics and Refinement department, we investigate MHC and KIR genes from different monkey and ape species. For this, we use DNA-sequencing and other techniques, like fragment analyses on short tandem repeats (STR). We not only study the DNA from animals from our own breeding colonies but also DNA samples from other institutions and zoos.

West-African chimpanzees show limited MHC class II gene variation

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Genetic diversity is detrimental for the survival of a species. When a ‘new’ pathogen invades the population genetic diversity increases the chance that some of the individuals survive and prevent the species from extinction. If all the individuals within a population have the same genetic background and these genes are not capable of generating an immune response against the pathogen, all individuals will die and the species will become extinct. Genetic diversity can prevent this and the survivors can reproduce to generate a new population. In evolutionary terms this is called a selective sweep. In ancient history chimpanzees went through a selective sweep. As a result they have a reduced variation in their MHC class I genes . BPRC has a collection of blood cell samples from western chimpanzees. Recently, we used these samples to investigate five genes that belong to the MHC class II region. We observed that the repertoire of variants of these class II genes was limited. However, the number of different combinations of the five genes (haplotypes) was high. These results indicate that -after the selective sweep- variation within the class II gene-region was generated by crossing-over processes. Our results underline the plasticity of the primate’s immune system to remain genetically diverse. This mechanism can decrease the vulnerability of the species and therefore increase the chance of survival of the species in case of another new pathogen invades the population.

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Does the MHC confer protection against malaria in bonobos?

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Malaria parasites are widespread among wild chimpanzees and gorillas. Yet, malaria is rare in the smaller cousin of the common chimpanzee, the bonobo. Immunological factors explaining the near absence of malaria parasites in bonobos are not yet understood. In humans the class I variants HLA-B*53 and B*78 are associated with protection from malaria. In 2018, we observed functionally similar MHC class I molecules in bonobos. Our data suggest that the MHC class I repertoire in bonobo was positively selected to control malaria infection.

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MHC class I variation in olive baboons

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The olive baboon (Papio anubis, Paan) belongs to the Old-World monkeys, and is used as a model species in various fields of biomedical research, like neuroscience and transplantation. Little is known about the olive baboon MHC class I genes. We combined two fast and accurate molecular typing methods to unravel this complex gene system and found a high number of baboon MHC class I A (Paan-A) and B (Paan-B) alleles. Similar to other old-world monkey species, such as the rhesus macaque, the alleles show different transcription levels, and the combination and number of genes (haplotypes) vary. Moreover, we showed that particular olive baboon MHC class I alleles share a specific part (epitope) with human and rhesus macaque MHC class I alleles, that could be recognized by KIRs expressed on Natural Killer cells. Future binding experiments between MHC and KIR molecules in baboons or other old-world monkey species are needed to elucidate if their molecular interactions are similar as observed for the HLA-KIR interaction in humans.

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Killer cell immunoglobulin-like receptor (KIR) polymorphism, a comparison between humans and rhesus macaques

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Natural Killer cells express a diverse repertoire of killer cell immunoglobulin-like receptors (KIRs) on their cell surface. KIRs can either activate or inhibit NK cell function and are thereby important regulators of an immune responses. The KIR genes display abundant copy number variation as well as high levels of polymorphism, and as a result, it is challenging to characterize this structurally dynamic region. We used a Pacific Bioscience’s Sequel platform to sequence the KIR transcriptome of both human and rhesus macaque families. This approach allowed the identification of human and rhesus macaque KIR haplotypes, of which the latter contained several novel Mamu-KIR alleles. In addition, this method identified hybrid genes that are the result of chromosomal recombination. Using the same approach, extensive alternative splicing has been demonstrated for the human and rhesus macaque KIR transcripts, which diversifies the KIR repertoire even more. Overall, these results illustrate the plasticity of the KIR gene system in primates, and provides a better understanding and interpretation of KIR associated diseases, as well as the immune reactivity in transplantation and reproductive biology.

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