(A) Pairwise analysis of the cattle complex and flanking regions using dotter with a 250-bp sliding windows (55). inactivated by point mutation. Selective inactivation of and activating receptor genes leaves a functional cohort of one inhibitory KIR3DL, one activating KIR3DX, and six inhibitory KIR3DX. Functional KIR diversity developed from in cattle and from in simian primates. Although independently evolved, cattle and human gene families share important function-related properties, indicating that cattle KIR are NK cell receptors for cattle MHC class I. Combinations of and are the major genetic factors associated with human disease and merit investigation in cattle. Introduction Genes of the immune and reproductive systems exhibit the most variance between mammalian genomes (1, 2). This variability displays the strong selection pressures imposed by the vital functions of immunity and reproduction. NK cells are a diverse and unique populace of lymphocytes that contribute to both immunity and reproduction. In the defense against infection, particularly viral infections, NK cells are the principal lymphocytes of the innate NK314 immune response (3). They kill virus-infected cells NK314 and secrete cytokines that recruit other leukocytes to the infected tissue. NK cells also help initiate the adaptive immune response and make prominent contributions to the control and removal of malignancy (4, 5). In reproduction, NK cells cooperate with extravillous trophoblast cells in formation of the placenta, the organ that provides the growing fetus with nourishment throughout pregnancy (6). Unlike B and T lymphocytes, NK cells do not express variable Rabbit polyclonal to ZKSCAN4 Ag receptors made from rearranging genes. Instead, NK cells express different combinations of a variety of different cell-surface receptors, many of which are encoded by genes in either the leukocyte receptor complex (receptors have extracellular Ig-like domains that form NK314 the ligand-binding sites, whereas the extracellular domains of receptors resemble the ligand-binding domains of C-type lectins. The ligands for many of these receptors are MHC class I molecules or molecules that in their structure and development are related to MHC class I molecules (7). Initial studies of mice and humans showed that both species have a system of variable NK cell receptors that identify polymorphic determinants of classical MHC class I molecules. Even though mouse Ly49 and human killer cell IgClike receptor (KIR) systems are functionally comparable, they are structurally unrelated. Ly49 receptors have extracellular lectin-like domains and are encoded; KIR have extracellular Ig-like domains and are encoded (8). That such structurally and genetically unrelated receptors perform analogous functions in two mammalian species is a striking example of convergent development and points to the dynamic selection pressures imposed on the immune and reproductive functions of NK cells. The disparity of the variable NK cell receptors in humans and mice stimulated studies to determine what other placental mammals resemble humans in using KIR as variable NK receptors for MHC class I. In other simian primates, the contains a family of genes that corresponds to the human gene family, but which also exhibits considerable species-specific character. For example, of 15 chimpanzee genes, only three have strict orthologs among the 15 human genes (9). In contrast with simian primates, the of prosimian primates contains a single gene and it is not functional (10). Either the prosimian primates have lost their families of genes or they never had them, and the systems we observed emerged and developed specifically in the simian primates. Study of nonprimate mammals shows that the usually contains one gene or has no genes (11C15). A possible exception to this generalization emerged from studies of cDNA, which uncovered a diversity of expressed in domestic cattle (16, 17). Phylogenetic comparison showed the cattle created two clades (18). One clade, represented by a single is usually most closely related to the divergent, nonfunctional human gene that is physically separated from your other genes NK314 but still in the locus around the centromeric side (19). These data are consistent with a model where duplication in the of an ancestral and child genes. Subsequently, successive duplication of the gene produced the family of variable NK cell receptors of humans and other simian primates, whereas successive duplications of the gene produced the diversity of functional KIR in cattle (18). NK314 Because nothing was known of cattle genes, their genomic business, and the cattle haplotype and the partial sequence of.