Heterogeneous but conserved natural killer receptor gene complexes in four major orders of mammals

Abstract

The natural killer (NK) receptor gene complex (NKC) encodes a large number of C-type lectin-like receptors, which are expressed on NK and other immune-related cells. These receptors play an important role in regulating NK-cell cytolytic activity, protecting cells against virus infection and tumorigenesis. To understand the evolutionary history of the NKC, we characterized the C-type lectin-like NKC genes and their organization from four major orders of placental mammals, primates (human), rodents (mouse and rat), carnivores (dog), and artiodactyls (cattle) and then conducted phylogenetic analysis of these genes. The results indicate that the NKC of placental mammals is highly heterogeneous in terms of the gene content and rates of birth and death of different gene lineages, but the NKC is also remarkably conserved in its gene organization and persistence of orthologous gene lineages. Among the 28 identified NKC gene lineages, 4, KLRA1, KLRB1, CLEC2D, and CLEC4A͞B͞C, have expanded rapidly in rodents only. The high birth and death rate of these 4 gene families might be due to functional differentiation driven by positive selection. Identification of putative NKC sequences in opossum and chicken genomes implies that the expansion of the NKC gene families might have occurred before the radiation of placental mammals but after the divergence of birds from mammals.contraction-expansion ͉ evolution ͉ genomic organization

Two major groups of rat NKR‐P1 receptors can be distinguished based on chromosomal localization, phylogenetic analysis and Clr ligand binding

“…The Nkrp1g gene is situated at a different locus in the two rodent species, likely due to a translocation event in the mouse also involving the Clrf gene. A phylogenetic analysis shows that Clrf is the ortholog of Clr9 in the rat (our unpublished data and [6]). Although the Nkrp1g and Clr9 genes are located just downstream of Nkrp1f in the rat, their mouse orthologs are located more proximally in the NKC, between the Nkrp1a and -b genes but in an inverted configuration, i.e.…”

“…Here we have isolated cDNAs for six of the ten complete Clrs (Clr2, -3, -4, -6, -7, and -11) and expressed and tested their ability to stimulate various NKR-P1 reporters. It should be noted that Clr7 is not a pseudogene as suggested by Hao et al [6], but a fully functional gene. Of the remaining members, Clr5 has been reported previously [23,25].…”

“…A recent analysis of the genomic sequence in BN concluded that the rat NKC harbors 11 Clr genes, 2 of which were supposedly pseudogenes (Clr7 and -8) [6]. As stated in the Introduction section, we do not think that Clr8 should have been counted as a pseudogene, as it appears to be a gene fragment containing only part of the lectin-like domain (L. Hao, personal communication and our own observation), but to avoid further nomenclature confusion, we have decided to stick to the suggested numbering.…”

“…A recent analysis concluded that there are 11 Clr/Clec2d genes in the rat BN strain genome, which were numbered consecutively from proximal to distal. One of these (Clr8) is most likely only a gene fragment, which could have been excluded, but we will nevertheless adhere to the Clr numbering suggested by Hao et al [6].…”

“…The NKR-P1 molecules (KLRB or CD161) were among the first KLR to be characterized, but their function long remained elusive [3][4][5]. Although the NKR-P1 family has expanded to include both activating and inhibitory members in rodents, it consists of only one member in several other mammalian species, including in human [6]. The nature of their ligands has been controversial [7,8], but it has recently been shown that members of another KLR-related receptor family, the C-type lectin-related (Clr) molecules [9], also termed C-type lectin 2D (CLEC2D), can act as ligands for certain NKR-P1 molecules [10,11].…”