There are two main classes of natural killer (NK) cell receptors in mammals, the killer cell immunoglobulin-like receptors (KIR) and the structurally unrelated killer cell lectin-like receptors (KLR). While KIR represent the most diverse group of NK receptors in all primates studied to date, including humans, apes, and Old and New World monkeys, KLR represent the functional equivalent in rodents. Here, we report a first digression from this rule in lemurs, where the KLR (CD94/NKG2) rather than KIR constitute the most diverse group of NK cell receptors. We demonstrate that natural selection contributed to such diversification in lemurs and particularly targeted KLR residues interacting with the peptide presented by MHC class I ligands. We further show that lemurs lack a strict ortholog or functional equivalent of MHC-E, the ligands of non-polymorphic KLR in “higher” primates. Our data support the existence of a hitherto unknown system of polymorphic and diverse NK cell receptors in primates and of combinatorial diversity as a novel mechanism to increase NK cell receptor repertoire.

Basic medical research critically depends on the finished human genome sequence. Two types of gaps are known to exist in the human genome: those associated with heterochromatic sequences and those embedded within euchromatin. We identified and analyzed a euchromatic island within the pericentromeric repeats of the human Y chromosome. This 450-kb island, although not recalcitrant to subcloning and present in 100 tested males from different ethnic origins, was not detected and is not contained within the published Y chromosomal sequence. The entire 450-kb interval is almost completely duplicated and consists predominantly of interchromosomal rather than intrachromosomal duplication events that are usually prevalent on the Y chromosome. We defined the modular structure of this interval and detected a total of 128 underlying pairwise alignments (Ն90% and Ն1 kb in length) to various autosomal pericentromeric and ancestral pericentromeric regions. We also analyzed the putative gene content of this region by a combination of in silico gene prediction and paralogy analysis. We can show that even in this exceptionally duplicated region of the Y chromosome, eight putative genes with open reading frames reside, including fusion transcripts formed by the splicing of exons from two different duplication modules as well as members of the homeobox gene family DUX.

BackgroundAurora kinases and loss of p53 function are implicated in the carcinogenesis of aneuploid esophageal cancers. Their association with occurrence of multipolar mitoses in the two main histotypes of aneuploid esophageal squamous cell carcinoma (ESCC) and Barrett's adenocarcinoma (BAC) remains unclear. Here, we investigated the occurrence of multipolar mitoses, Aurora-A/-B gene copy numbers and expression/activation as well as p53 alterations in aneuploid ESCC and BAC cancer cell lines.ResultsA control esophageal epithelial cell line (EPC-hTERT) had normal Aurora-A and -B gene copy numbers and expression, was p53 wild type and displayed bipolar mitoses. In contrast, both ESCC (OE21, Kyse-410) and BAC (OE33, OE19) cell lines were aneuploid and displayed elevated gene copy numbers of Aurora-A (chromosome 20 polysomy: OE21, OE33, OE19; gene amplification: Kyse-410) and Aurora-B (chromosome 17 polysomy: OE21, Kyse-410). Aurora-B gene copy numbers were not elevated in OE19 and OE33 cells despite chromosome 17 polysomy. Aurora-A expression and activity (Aurora-A/phosphoT288) was not directly linked to gene copy numbers and was highest in Kyse-410 and OE33 cells. Aurora-B expression and activity (Aurora-B/phosphoT232) was higher in OE21 and Kyse-410 than in OE33 and OE19 cells. The mitotic index was highest in OE21, followed by OE33 > OE19 > Kyse-410 and EPC-hTERT cells. Multipolar mitoses occurred with high frequency in OE33 (13.8 ± 4.2%), followed by OE21 (7.7 ± 5.0%) and Kyse-410 (6.3 ± 2.0%) cells. Single multipolar mitoses occurred in OE19 (1.0 ± 1.0%) cells. Distinct p53 mutations and p53 protein expression patterns were found in all esophageal cancer cell lines, but complete functional p53 inactivation occurred in OE21 and OE33 only.ConclusionsHigh Aurora-A expression alone is not associated with overt multipolar mitoses in aneuploid ESCC and BAC cancer cells, as specifically shown here for OE21 and OE33 cells, respectively. Additional p53 loss of function mutations are necessary for this to occur, at least for invasive esophageal cancer cells. Further assessment of Aurora kinases and p53 interactions in cells or tissue specimens derived from non-invasive dysplasia (ESCC) or intestinal metaplasia (BAC) are necessary to disclose a potential causative role of Aurora kinases and p53 for development of aneuploid, invasive esophageal cancers.

Human chromosomal regions enriched in segmental duplications are subject to extensive genomic reorganization. Such regions are particularly informative for illuminating the evolutionary history of a given chromosome. We have analyzed 866 kb of Y-chromosomal non-palindromic segmental duplications delineating four euchromatin/heterochromatin transition regions (Yp11.2/Yp11.1, Yq11.1/Yq11.21, Yq11.23/Yq12, and Yq12/PAR2). Several computational methods were applied to decipher the segmental duplication architecture and identify the ancestral origin of the 41 different duplicons. Combining computational and comparative FISH analysis, we reconstruct the evolutionary history of these regions. Our analysis indicates a continuous process of transposition of duplicated sequences onto the evolving higher primate Y chromosome, providing unique insights into the development of species-specific Y-chromosomal and autosomal duplicons. Phylogenetic sequence comparisons show that duplicons of the human Yp11.2/Yp11.1 region were already present in the macaque-human ancestor as multiple paralogs located predominantly in subtelomeric regions. In contrast, duplicons from the Yq11.1/Yq11.21, Yq11.23/Yq12, and Yq12/PAR2 regions show no evidence of duplication in rhesus macaque, but map to the pericentromeric regions in chimpanzee and human. This suggests an evolutionary shift in the direction of duplicative transposition events from subtelomeric in Old World monkeys to pericentromeric in the human/ape lineage. Extensive chromosomal relocation of autosomal-duplicated sequences from euchromatin/heterochromatin transition regions to interstitial regions as demonstrated on the pygmy chimpanzee Y chromosome support a model in which substantial reorganization and amplification of duplicated sequences may contribute to speciation.

The male-specific regions of the Y chromosome (MSY) of the human and the chimpanzee (Pan troglodytes) are fully sequenced. The most striking difference is the dramatic rearrangement of large parts of their respective MSYs. These non-recombining regions include ampliconic gene families that are known to be important for male reproduction,and are consequently under significant selective pressure. However, whether the published Y-chromosomal pattern of ampliconic fertility genes is invariable within P. troglodytes is an open but fundamental question pertinent to discussions of the evolutionary fate of the Y chromosome in different primate mating systems. To solve this question we applied fluorescence in situ hybridisation (FISH) of testis-specific expressed ampliconic fertility genes to metaphase Y chromosomes of 17 chimpanzees derived from 11 wild-born males and 16 bonobos representing seven wild-born males. We show that of eleven P. troglodytes Y-chromosomal lines, ten Y-chromosomal variants were detected based on the number and arrangement of the ampliconic fertility genes DAZ (deleted in azoospermia) and CDY (chromodomain protein Y)—a so-far never-described variation of a species' Y chromosome. In marked contrast, no variation was evident among seven Y-chromosomal lines of the bonobo, P. paniscus, the chimpanzee's closest living relative. Although, loss of variation of the Y chromosome in the bonobo by a founder effect or genetic drift cannot be excluded, these contrasting patterns might be explained in the context of the species' markedly different social and mating behaviour. In chimpanzees, multiple males copulate with a receptive female during a short period of visible anogenital swelling, and this may place significant selection on fertility genes. In bonobos, however, female mate choice may make sperm competition redundant (leading to monomorphism of fertility genes), since ovulation in this species is concealed by the prolonged anogenital swelling, and because female bonobos can occupy high-ranking positions in the group and are thus able to determine mate choice more freely.