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The natural killer (NK) receptor gene complex (NKC) encodes a large number of C-type lectin-like receptors, which are expressed on NK and other immune-related cells. These receptors play an important role in regulating NK-cell cytolytic activity, protecting cells against virus infection and tumorigenesis. To understand the evolutionary history of the NKC, we characterized the C-type lectin-like NKC genes and their organization from four major orders of placental mammals, primates (human), rodents (mouse and rat), carnivores (dog), and artiodactyls (cattle) and then conducted phylogenetic analysis of these genes. The results indicate that the NKC of placental mammals is highly heterogeneous in terms of the gene content and rates of birth and death of different gene lineages, but the NKC is also remarkably conserved in its gene organization and persistence of orthologous gene lineages. Among the 28 identified NKC gene lineages, 4, KLRA1, KLRB1, CLEC2D, and CLEC4A/B/C, have expanded rapidly in rodents only. The high birth and death rate of these 4 gene families might be due to functional differentiation driven by positive selection. Identification of putative NKC sequences in opossum and chicken genomes implies that the expansion of the NKC gene families might have occurred before the radiation of placental mammals but after the divergence of birds from mammals.

Heterogeneous but conserved natural killer receptor gene complexes in four major orders of mammals