Abstract
The fast evolving human KIR gene family encodes variable lymphocyte receptors specific for polymorphic HLA class I determinants. Nucleotide sequences for 24 representative human KIR haplotypes were determined. With three previously defined haplotypes, this gave a set of 12 group A and 15 group B haplotypes for assessment of KIR variation. The seven gene-content haplotypes are all combinations of four centromeric and two telomeric motifs. 2DL5, 2DS5 and 2DS3 can be present in centromeric and telomeric locations. With one exception, haplotypes having identical gene content differed in their combinations of KIR alleles. Sequence diversity varied between haplotype groups and between centromeric and telomeric halves of the KIR locus. The most variable A haplotype genes are in the telomeric half, whereas the most variable genes characterizing B haplotypes are in the centromeric half. Of the highly polymorphic genes, only the 3DL3 framework gene exhibits a similar diversity when carried by A and B haplotypes. Phylogenetic analysis and divergence time estimates, point to the centromeric gene-content motifs that distinguish A and B haplotypes having emerged ∼6 million years ago, contemporaneously with the separation of human and chimpanzee ancestors. In contrast, the telomeric motifs that distinguish A and B haplotypes emerged more recently, ∼1.7 million years ago, before the emergence of Homo sapiens. Thus the centromeric and telomeric motifs that typify A and B haplotypes have likely been present throughout human evolution. The results suggest the common ancestor of A and B haplotypes combined a B-like centromeric region with an A-like telomeric region.
Highlights
Humans, apes and monkeys have expanded families of genes encoding killer cell immunoglobulin-like receptors (KIR)
Based upon KIR gene content, cell lines derived from 12 individuals were chosen for complete sequence analysis of KIR haplotypes
The distinctive organization of the human KIR locus drives the generation of gene-content diversity
Summary
Apes and monkeys have expanded families of genes encoding killer cell immunoglobulin-like receptors (KIR) (reviewed in [1]). Genetics and variegated expression, primate KIR are very similar to rodent Ly49, these common properties are the result of convergent evolution [4] Because both receptor and ligand are highly polymorphic, the interactions between KIR and HLA class I that regulate NK cell function are extraordinarily diverse. They include susceptibility to infection [7,8] and autoimmunity [9,10,11,12,13,14,15], the outcome of hematopoietic cell transplantation [16,17] and the success of placental reproduction [18]
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