Genesis of the ILT/LIR/MIR clusters within the human leukocyte receptor complex

The human leukocyte receptor complex (LPC) contains at least 26 genes which belong to the immunoglobulin superfamily. The genes include two clusters o f immunoglobulin-like transcript (ILT)/leukocyte immunoglobulin-like recept or (LIR)/monocyte-macrophage inhibitory receptor (MIR) loci, a cluster of k iller cell inhibitory receptor (KIR) genes, two leukocyte-associated immuno globulin-ne receptor genes, as well as the Fc receptor for IgA and the natu ral cytotoxicity receptor I loci. It has already been postulated that these genes have evolved by multiple duplications, while the two ILT clusters ar e likely to have been generated by the inverse duplication of an ancient IL T cluster. To shed more light on the possible origin of the loci within the LRC, we have now investigated the presence of KIR and ILT loci in a variet y of vertebrates by hybridizations and compared the genomic sequences of al l ILT genes. Our results lead to the following conclusions: 1) the origin o f KIR genes dates back to about 100 million years, but only primate and hum an KIRs are closely related; 2) in contrast, genes which are detectable wit h human ILT cDNAs are already found in birds, suggesting their presence alr eady about 300 million years ago. Using the sequence data produced by the h uman genome project, we have developed a hypothesis that reconstructs the g enesis of the two human ILT clusters in detail which will help to understan d the function of the LRC.