Characterization of diversity at the killer immunoglobulin-like receptor (KIR) locus has progressed over the past several years, particularly since the entire sequence of the complex became available. To date, segregation analysis has been used to estimate full KIR haplotypes in four studies, representing a total of 79 families (roughly 316 independent KIR haplotypes). Based on the previously published gene order, we have compiled a listing of 37 unique haplotypes derived from these studies. Although it is possible that one or more of these haplotypes are incorrect, as a number of assumptions had to be made when deducing the haplotypes, it represents an astonishing number of haplotypes given the relatively few independent chromosomes that were studied. In order to define more precisely the extent of haplotypic variability based on gene content among individuals of northern European descent, we have completed typing of 59 Centre d'Etude Polymorphisme Humain (CEPH) families (> 400 independent chromosomes) for presence/absence of all KIR genes. KIR2DL4 has been subtyped by sequence analysis, and minimal subtyping of other KIR genes has been performed. The data will be analyzed by Dr. Richard Single at the University of Vermont. Clearly, expansion and contraction of the haplotypes have occurred (in some cases to an extreme degree), perhaps due to unequal crossing over in the region. The CEPH KIR haplotype data has already been useful in our disease studies and, upon completion, will be an invaluable resource for the interpretation of data derived from studies involving individuals of European descent. KIR haplotypic variability across ethnic groups appears to be extensive, as indicated by KIR gene profiles determined in unrelated individuals in a limited number of populations. These differences in KIR gene/allele frequencies may explain some of the observed variability in disease susceptibility across ethnic groups, particularly in regard to human leukocyte antigens (HLA) class I associations. We have now completed typing of samples from 29 populations for both KIR and HLA class I, and the data are now ready to be analyzed. Given the breadth of the population distributions throughout the world that are represented in this sample, we believe that this study will comprehensively define the extent of inter- and intra-population KIR haplotypic variability, potentially suggesting a role for selection in the generation of diversity across populations. Comparisons of individual KIR gene sequences within and across primate species indicate that the KIR gene family is characterized by historic instability, perhaps evolving rapidly in response to species-specific pathogenic organisms. KIR genes have now been identified in several primate species and KIR-like genes were identified in the cow. In spite of the distinctions, some similarities have persisted over tens of millions of years, including the maintenance of KIR2DL4 in all primate species tested. While these studies have provided useful information regarding the evolution of KIR genes across primate species, comparisons of gene order and complete haplotypic sequence in different primate species would serve as a solid foundation for more accurately reconstructing the evolutionary history of the locus. Furthermore, a complete haplotypic KIR sequence in rhesus monkey, the species that serves as the primary animal model for human HIV disease, would greatly foster functional studies regarding the role of natural killer (NK) cell activity (as regulated by KIR molecules) in AIDS pathogenesis. We have performed comparative genomic analysis of the KIR regions in two primates. We selected bacterial artificial chromosome (BAC) clones containing the KIR genes from the common chimpanzee (Pan troglodytes) and rhesus monkey (Macaca mulatta) genomic libraries. Complete KIR haplotypes from both species were then performed at the Sanger Centre under the direction of Dr. Stephan Beck. The chimpanzee haplotype contained seven KIR genes whereas five KIR genes were present in the rhesus monkey. Three novel genes were present on the haplotypes: two in chimpanzee, and one in macaque. While all known human haplotypes contain both activating and inhibitory KIR genes, only inhibitory KIR genes were found in the two primate haplotypes studied here. To confirm the predicted gene structures, we isolated cDNA from peripheral blood mononuclear cells (PBMCs) of the macaque that was used for the genomic library construction. We cloned all five macaque KIR cDNAs corresponding to the sequenced haplotype. In addition, another five cDNAs were identified in this animal indicating that the second haplotype is quite divergent. Comparison of the two human and the two non-human primate haplotypes demonstrates rapid evolution of the KIR gene family members, many of which have diverged in a species-specific manner. KIR haplotypes generally range in gene content from about 6-12 expressed genes, although rare haplotypes that are very short (<6 genes) or very long (>12 genes) have been observed. The gene content and sequence of some KIR alleles strongly suggests that unequal crossing over in the region may account for much of the expansion and contraction this locus has undergone over time. For example, we have recently identified a hybrid gene of two distinct KIR genes, KIR2DL5A and KIR3DP1 on a haplotype that contains two copies of two different KIR genes. We have proposed a model involving unequal crossing over that could explain this haplotype. We have determined the genomic order of the KIR genes on this haplotype, supporting a mechanism involving unequal crossing over in the derivation of this haplotype. We have also identified other unusual haplotypes and these will be sequenced in collaboration with Dr. John Trowsdale and Dr. Stephan Beck.
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