Genes and Immunity (2000) 1, 280–287  2000 Macmillan Publishers Ltd All rights reserved 1466-4879/00 $15.00 www.nature.com/gene The centromeric part of the human NK gene complex: linkage of LOX-1 and LY49L with the CD94/NKG2 region C Bull 1 , Y Sobanov 2 , B Ro ¨ hrdanz 1 , J O’Brien 1 , H Lehrach 1 and E Hofer 2 1 Max-Planck-Institute for Molecular Genetics, Ihnestrasse 73, D-14195 Berlin, Germany; 2 Department of Vascular Biology and Thrombosis Research, Vienna International Research Cooperation Center, University of Vienna, Brunnerstrasse 59, A-1235 Vienna, Austria The natural killer (NK) gene complex is a genomic region containing lectin-type receptor genes. We have established a contig of PAC and BAC clones comprising about 1 Mb of the centromeric part of the NK gene complex. This region extends from the LOX-1 gene, which encodes a receptor for oxidized LDL and was found within 100 kb telomeric of the STS marker D12S77, contains the CD94 and NKG2 NK receptor genes and reaches beyond D12S852 on the proximal side. In this part we have mapped the human LY49L gene, a homologue of the rodent Ly49 genes, which encode important MHC class I receptors for the regulation of NK cell activity in rodents. The LY49L gene is localized 100 to 200 kb centromeric of the NKG2 gene cluster and 300 to 400 kb telomeric of the STS marker D12S841. Genomic sequencing of the complete gene including promoter and intron sequences confirmed that the structure is similar to the mouse Ly49 genes. Screening of several cDNA libraries did not detect any transcripts of putative additional human LY49 genes. In addition, in the course of these studies several EST sequences were localized in the region, one immediately upstream of the LY49L gene. Genes and Immunity (2000) 1, 280–287. Keywords: natural killer cells; NK gene complex; chromosome 12; LOX, CD94, NKG2 and LY-49 genes Introduction Cytotoxicity of natural killer (NK) cells towards tumor or virally infected target cells 1 is regulated by inhibitory and activating signals from cell surface receptors. NK cell receptors that recognize MHC class I or related molecules on target cells 2–6 can be grouped into two structurally dis- tinct classes, namely the immunoglobulin-(Ig)-like and the C-type lectin receptors. The killer immunoglobulin- like receptors (KIR) have been found to be expressed on human NK cells and different variants display either repressive or triggering functions. They are encoded by a cluster of genes in a region on chromosome 19 named the leukocyte receptor complex (LRC). 7,8 A gene distantly related to the Ig-like receptor gene family has recently also been detected in mice, but its relevance for rodent NK cell function has not been firmly established. 9 C-type lectin NK receptors, which occur in both inhibi- tory and activating forms and are encoded within a syn- tenic region on human chromosome 12, 10–13 mouse chro- mosome 6 14,15 and rat chromosome 4, 16 called the NK gene complex, can be sub-grouped into different families. Among these are the CD94/NKG2, the Ly49 and the Correspondence: Erhard Hofer, Department of Vascular Biology and Thrombosis Research, Vienna International Research Cooperation Center, University of Vienna, Brunnerstrasse 59, A-1235 Vienna, Austria This work was supported in part by a grant from the Austrian National Bank (Jubila ¨umsfond No. 7567) to E.H. Supplementary material to this paper is available from the author. Received 28 January 2000; revised and accepted 22 February 2000 NKR-P1 families. Whereas members of the CD94/NKG2 and the NKR-P1 families have been found to be expressed in mice, 17–19 rats 20 and humans, 5,21–24 expression of functional Ly49 proteins has so far only been detected in rodents. 15,19 Recently, an aberrantly spliced cDNA coding for a human LY49 molecule (named Ly49L) has been detected 25 in the expressed sequence tags (EST) database and in cDNA libraries derived from human NK cells. Therefore genes related to all different NK cell receptor classes have now been found in rodents and in humans. However, it remains unclear whether intact gene families related to the human KIR receptors and the rodent Ly49 receptors coexist and fulfill similar functions in human as well as in rodent NK cells or whether these two receptor classes, which bind classical MHC class I molecules, have evolved differently from common ancestor genes in humans and rodents. Furthermore, there are additional lectin-type receptors encoded in the NK gene complex which possess different functions in various cell types. The CD69 or AICL recep- tors 26,27 are widely expressed in the hematopoietic lineage and their functions and ligands are not clearly defined. Recently, the lectin-type LLT1 receptor was reported to be broadly expressed in lymphocytes. 28 Furthermore, a member of another lectin-type receptor class, LOX-1, has been implicated as a receptor for oxidized low-density lipoprotein on endothelial cells and monocytes. 29 In order to establish the basis to search for novel forms of lectin-type receptor genes, to link the NKG2 and CD94 NK cell receptor genes 13,23 with the region containing the