In mammals many natural killer (NK) cell receptors, encoded by the leukocyte receptor complex (LRC), regulate the cytotoxic activity of NK cells and provide protection against virus-infected and tumor cells. To investigate the origin of the Ig-like domains encoded by the LRC genes, a subset of C2-type Ig-like domain sequences was compiled from mammals, birds, amphibians, and fish. Phylogenetic analysis of these sequences generated seven monophyletic groups in mammals (MI, MII, and FcI, FcIIa, FcIIb, FcIII, FcIV), two in chicken (CI, CII), four in frog (FI-FIV), and five in zebrafish (ZI-ZV). The analysis of the major groups supported the following order of divergence: ZI [or a common ancestor of ZI and F (a cluster composed of the FcIII and FIII groups)], F, CII (or a common ancestor of CII and MII), MII, and MI-CI. The relationships of the remaining groups were unclear, since the phylogenetic positions of these groups were not supported by high bootstrap values. Two main conclusions can be drawn from this analysis. First, the two groups of mammalian LRC sequences must diverged before the separation of the avian and mammalian lineages. Second, the mammalian LRC sequences are most closely related to the Fc receptor sequences and these two groups diverged before the separation of birds and mammals.
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