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Evidence for balancing selection acting on KIR2DL4 genotypes in rhesus macaques of Indian origin

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Abstract

The interaction of killer-cell immunoglobulin-like receptors (KIR) and their respective major histocompatibility complex (MHC) ligands can alter the activation state of the natural killer (NK) cell. In both humans and rhesus macaques, particular types of non-classical MHC class I molecules are predominantly expressed on the trophoblast. In humans, human leukocyte antigen G has been demonstrated to act as a ligand for KIR2DL4, present on all NK cells, whereas Mamu-AG may execute a similar function in rhesus macaques. During primate evolution, orthologues of KIR2DL4 appear to have been highly conserved, suggesting strong purifying selection. A cohort of 112 related and unrelated rhesus macaques of mostly Indian origin were selected to study their KIR2DL4 genes for the occurrence of polymorphism. Comparison of the proximal region provided evidence for strong conservative selection acting on the exons encoding the Ig domains. As is found in humans, in the Indian rhesus macaque population, two different KIR2DL4 entities are encountered, which differ for their intra-cellular signalling motifs. One genotype contains a complex mutation in the distal region of exon 9, which negates a serine/threonine kinase site. Furthermore, both allelic entities are present in a distribution, which suggests that balancing selection is operating on these two distinct forms of KIR2DL4.

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Acknowledgements

The authors wish to thank Donna Devine for editing the manuscript, Natasja de Groot for critical reading, and Henk van Westbroek for preparing the figures.

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  1. Department of Comparative Genetics and Refinement, Biomedical Primate Research Centre, Lange Kleiweg 139, Rijswijk, 2288 GJ, The Netherlands

    Jeroen H. Blokhuis, Marit K. van der Wiel, Gaby G. M. Doxiadis & Ronald E. Bontrop

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  1. Jeroen H. Blokhuis
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  2. Marit K. van der Wiel
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  3. Gaby G. M. Doxiadis
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  4. Ronald E. Bontrop
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Correspondence to Jeroen H. Blokhuis.

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Supplemental Fig. 1

Microscopy of HEK293 cells 2 days after transfection (magnification ×400). From left to right: bright-field picture, 4′,6-diamidino-2-phenylindole-stained fluorescent nucleus, YFP-fusion protein, merge of previous pictures. Cells were transfected with pcDNA6.2/C-YFP-GW/TOPO containing as an insert a Mamu-KIR2DL4*001 (2DL4.1), b Mamu-KIR2DL4*01501 (2DL4.2) and c control chloramphenicol acetyl transferase. Since transfection efficiencies differ, some cells do not show YFP fluoresence because they were not transfected (JPEG 1709 kb)

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Blokhuis, J.H., van der Wiel, M.K., Doxiadis, G.G.M. et al. Evidence for balancing selection acting on KIR2DL4 genotypes in rhesus macaques of Indian origin. Immunogenetics 61, 503–512 (2009). https://doi.org/10.1007/s00251-009-0379-6

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