Human-Specific Evolution and Adaptation Led to Major Qualitative Differences in the Variable Receptors of Human and Chimpanzee Natural Killer Cells

Fred Hutchinson Cancer Research Center, United States of America
PLoS Genetics (Impact Factor: 7.53). 11/2010; 6(11):e1001192. DOI: 10.1371/journal.pgen.1001192
Source: PubMed


Natural killer (NK) cells serve essential functions in immunity and reproduction. Diversifying these functions within individuals and populations are rapidly-evolving interactions between highly polymorphic major histocompatibility complex (MHC) class I ligands and variable NK cell receptors. Specific to simian primates is the family of Killer cell Immunoglobulin-like Receptors (KIR), which recognize MHC class I and associate with a range of human diseases. Because KIR have considerable species-specificity and are lacking from common animal models, we performed extensive comparison of the systems of KIR and MHC class I interaction in humans and chimpanzees. Although of similar complexity, they differ in genomic organization, gene content, and diversification mechanisms, mainly because of human-specific specialization in the KIR that recognizes the C1 and C2 epitopes of MHC-B and -C. Humans uniquely focused KIR recognition on MHC-C, while losing C1-bearing MHC-B. Reversing this trend, C1-bearing HLA-B46 was recently driven to unprecedented high frequency in Southeast Asia. Chimpanzees have a variety of ancient, avid, and predominantly inhibitory receptors, whereas human receptors are fewer, recently evolved, and combine avid inhibitory receptors with attenuated activating receptors. These differences accompany human-specific evolution of the A and B haplotypes that are under balancing selection and differentially function in defense and reproduction. Our study shows how the qualitative differences that distinguish the human and chimpanzee systems of KIR and MHC class I predominantly derive from adaptations on the human line in response to selective pressures placed on human NK cells by the competing needs of defense and reproduction.

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    • "One possibility is that the advantage conferred by these allotypes was their function as C1-bearing ligands for KIR2DL2/3. Whereas human C1+ HLA-B allotypes are rare, C1+ allotypes of Patr-B, the chimpanzee ortholog of HLA-B, are common (Abi-Rached et al., 2010). This contrast suggests there was much loss of C1+ HLA-B allotypes during human evolution, caused either by selection or genetic drift. "
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    • "For example, orthology established by both concepts was confirmed between human and chimp KIR3DL3 (cf. Abi-Rached et al. 2010). "
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    • "Originating in simian primates, the KIR is relatively a new gene family that evolves rapidly to keep up with species-specific evolution and adaptation [12]. Because KIRs have considerable species-specificity and are lacking in rodents, it is critical to study humans to understand the impact of KIR on health and disease. "
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