Single haplotype analysis demonstrates rapid evolution of the killer immunoglobulin-like receptor (KIR) loci in primates - PubMed (original) (raw)

Comparative Study

Single haplotype analysis demonstrates rapid evolution of the killer immunoglobulin-like receptor (KIR) loci in primates

Jennifer G Sambrook et al. Genome Res. 2005 Jan.

Abstract

The human killer immunoglobulin-like receptors (KIR) are encoded within the Leukocyte Receptor Complex (LRC) on chromosome 19q13.4. Here we report the comparative genomic analysis of single KIR haplotypes in two other primates. In the common chimpanzee (Pan troglodytes), seven KIR genes (ptKIRnewI, ptKIRnewII, ptKIR2DL5, ptKIRnewIII, ptKIR3DP1, ptKIR2DL4, ptKIR3DL1/2) have been identified, and five KIR genes (mmKIRnewI, mmKIR1D, mmKIR2DL4, mmKIR3DL10, mmKIR3DL1) are present in the haplotype sequenced for the rhesus macaque (Macaca mulatta). Additional cDNA analysis confirms the genes predicted from the genomic sequence and reveals the presence of a fifth novel KIR gene (mmKIRnewII) in the second haplotype of the rhesus macaque. While all known human haplotypes contain both activating and inhibitory KIR genes, only inhibitory KIR genes (characterized by long cytoplasmic tails) were found by in silico and cDNA analyses in the two primate haplotypes studied here. Comparison of the two human and the two non-human primate haplotypes demonstrates rapid diversification of the KIR gene family members, many of which have diverged in a species-specific manner. An analysis of the intronic regions of the two non-human primates reveals the presence of ancient repeat elements, which are indicative of the duplication events that have taken place since the last common ancestor.

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Figures

Figure 1.

Figure 1.

Comparison of KIR haplotypes in three primates (not to scale): rhesus macaque (1), common chimpanzee (2), human haplotype type A (3), and human haplotype type B (4). KIR lineages have been color-coded. Genes that are found in common between the three species have corresponding gene box borders. Only the extracellular immunoglobulin domains of ptKIRnewI are related to human KIR3DL3. PtKIR3DL1/2 shares common features with both human KIR3DL1 and KIR3DL2. Flanking framework genes surrounding the KIR loci are shown in dark gray.

Figure 2.

Figure 2.

Multiple sequence alignment of the novel ptKIRnewII and ptKIRnewIII genes (shown in bold) in the common chimpanzee. Periods (.) indicate identity with ptKIRnewII and dashes (-) indicate the absence of amino acids. Conserved cysteine residues in the immunoglobulin domains are highlighted. ITIM motifs are shown by asterisks. Although closely related to ptKIR2DL6, which is shown to include the D0 domain encoded by pseudoexon 3, it is not clear whether ptKIRnewII and ptKIRnewIII belong to the KIR2D or KIR3D families. The cDNA sequences for ptKIR2DL6 and ptKIR3DL4-6 have been included, and are available under accession numbers AF258806 (ptKIR2DL6), AY122876 (pseudoexon 3 of ptKIR2DL6), AF258800 (ptKIR3DL4), AF258801 (ptKIR3DL5), and AF258802 (ptKIR3DL6).

Figure 3.

Figure 3.

Multiple sequence alignment of the novel mmKIRnewI gene in the rhesus macaque (shown in bold). Periods (.) indicate identity with mmKIRnewI and dashes (-) indicate the absence of amino acids. Human KIR2DL4 and KIR2DL5 genes have the D0+D2 structure. Conserved cysteine residues in the immunoglobulin domains are highlighted. ITIM motifs are shown by asterisks. The cDNA sequences are available under accession numbers AAK26807 (mmKIR2DL5.1) and AAK26808 (mmKIR2DL5.2).

Figure 4.

Figure 4.

Phylogenetic analysis of the KIR genes carried out on a domain-by-domain basis, including Ig D0 (A), Ig D1 (B), Ig D2 (C), and the combined stem, transmembrane, and cytoplasmic tail (D). The tree has been constructed using the Neighbor Joining (NJ) method. Novel genes identified in the common chimpanzee and rhesus macaque haplotypes analyzed are shown in bold. Sequences have been grouped into five lineages (I, II, III, IV, V) and are enclosed within boxes. The previously identified ptKIR3DL3 cDNA does not correspond to the human KIR3DL3 gene but rather is allelic to ptKIR3DL1/2.

Figure 4.

Figure 4.

Phylogenetic analysis of the KIR genes carried out on a domain-by-domain basis, including Ig D0 (A), Ig D1 (B), Ig D2 (C), and the combined stem, transmembrane, and cytoplasmic tail (D). The tree has been constructed using the Neighbor Joining (NJ) method. Novel genes identified in the common chimpanzee and rhesus macaque haplotypes analyzed are shown in bold. Sequences have been grouped into five lineages (I, II, III, IV, V) and are enclosed within boxes. The previously identified ptKIR3DL3 cDNA does not correspond to the human KIR3DL3 gene but rather is allelic to ptKIR3DL1/2.

Figure 5.

Figure 5.

Repeat analysis of the KIR intronic regions showing the presence of ancient retroelements and Alu repeats (not to scale). Genes have been grouped according to their lineages (I, II, III, IV, V). Distinct domains are labeled as follows: signal peptide, D0, D1, and D2 for the Ig domains, stem, transmembrane domain, and cytoplasmic tail. Lineage I genes have a D0+D2 structure. Although the three Ig domains are shown for ptKIRnewII and ptKIRnewIII, it is likely that they contain a pseudoexon 3, indicated by the striped boxes, and express the 2D structure. Splice variants of mmKIR1D may be missing the D2 or TM domains, as indicated by the open boxes.

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