Comparative genomics of natural killer cell receptor gene clusters

Abstract

Many receptors on natural killer (NK) cells recognize major histocompatibility complex class I molecules in order to monitor unhealthy tissues, such as cells infected with viruses, and some tumors. Genes encoding families of NK receptors and related sequences are organized into two main clusters in humans: the natural killer complex on Chromosome 12p13.1, which encodes C-type lectin molecules, and the leukocyte receptor complex on Chromosome 19q13.4, which encodes immunoglobulin superfamily molecules. The composition of these gene clusters differs markedly between closely related species, providing evidence for rapid, lineage-specific expansions or contractions of sets of loci. The choice of NK receptor genes is polarized in the two species most studied, mouse and human. In mouse, the C-type lectin-related Ly49 gene family predominates. Conversely, the single Ly49 sequence is a pseudogene in humans, and the immunoglobulin superfamily KIR gene family is extensive. These different gene sets encode proteins that are comparable in function and genetic diversity, even though they have undergone species-specific expansions. Understanding the biological significance of this curious situation may be aided by studying which NK receptor genes are used in other vertebrates, especially in relation to species-specific differences in genes for major histocompatibility complex class I molecules.

Figure 1. Examples of Inhibitory and Activating NK Cell Receptors and the Consequences of Their Binding

This figure shows the association of NK receptors with MHC class I molecules and portions of the resulting signaling pathway, as described in the text. “Src Kinase” represents various kinases capable of participating in this interaction, such as Syk and ZAP70. SHP2 (PTPN11) is used in place of SHP1 (PTPN6) in some circumstances, such as associating with KIR2DL4. Symbols show the continuation of the pathway where arrows are not drawn. −, negatively charged residue; +, positively charged residue; AKT1, v-akt murine thymoma viral oncogene homolog 1 (also called RAC); DAG1, dystroglycan 1; FcɛRI-γ, receptor for Fc fragment of IgE, high affinity I, gamma polypeptide; GRB2, growth factor receptor-bound protein 2; INPP5D, inositol polyphosphate-5-phosphatase, 145kDa (also called SHIP); ITPKB, inositol 1,4,5-trisphosphate 3-kinase B (also called IP3KB); LAT, linker for activation of T cells; LCP2, lymphocyte cytosolic protein 2 (also called SLP76); P, phosphate group; PAK1, p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast); PIK3CG, phosphoinositide-3-kinase, catalytic, gamma polypeptide (also called phosphatidylinositol 3-kinase); PLCG1, phospholipase C, gamma 1; PTEN, phosphatase and tensin homolog; PTPN6, protein tyrosine phosphatase, nonreceptor type 6 (also called SHP1); RAF, raf protein; RAS, rat sarcoma viral oncogene homolog; SH3BP2, SH3 domain–binding protein 2; SHC1, SHC (SH2 domain–containing) transforming protein 1; SOS1, son of sevenless homolog 1; VAV1, vav 1 oncogene; YINM, tyrosine-containing motif (YINM).

Figure 2. Comparative Genomics of Natural Killer Cell Receptor Complexes

This figure, showing LRCs and NKCs in various species, is not drawn to scale; however, the linear arrangement of genes is correct and is aligned vertically by homology within each region, where possible. Colors indicate genes related by gene organization, structure, and phylogeny. Gray indicates genes that are not considered NK receptors. White boxes mark pseudogenes. Slash marks represent large distances in the genomic sequence. Some non-NK receptor genes that are located within this region may not be represented in this figure. A question mark indicates that the gene has been mapped to the corresponding chromosome, but the specific chromosomal position is not known. An “X” indicates that the gene is not homologous with genes sharing its vertical alignment. The linear organization of these genes was taken from literature sources as described in the text and from NCBI's MapViewer [123]. Similar to in human, only one Ly49 gene has been found in baboon, orangutan, dog, cat, cow, and pig. However, the horse has multiple Ly49 genes, as does the rodent lineage [96]. The chicken contains two sequences similar to NKC-encoded genes within its MHC [102], again suggesting an evolutionary relationship between MHC and NK receptor genes. The chicken also possesses multiple genes for Ig domain–containing NK receptors: the CHIR genes [100]; however, the chicken arrangement is from data assembled from whole genome sequence and will be refined as more accurate annotation is applied. While the zebrafish contains NK receptors containing Ig or C-type lectin domains, the genomic organization does not resemble the mammalian pattern of clustering into two main regions [104].

Figure 3. Differences in Organization of KIR Genes in Human Haplotypes and Ly49 Genes in Various Mouse Strains

This figure is not drawn to scale, but it illustrates the presence of framework genes and the variable gene content in Ly49 genes in different mouse strains [72] and KIR sequences in human haplotypes. The vertical arrangement of genes within a family shows allelic relationships. White boxes indicate known pseudogenes. Please note that while many KIR haplotypes are possible, only a small selection has been shown here.