The human T-cell receptor alpha-chain gene maps to chromosome 14

The T-cell receptor for antigen has been identified as a disulphide-linked heterodimeric glycoprotein of relative molecular mass (Mr) 90,000 comprising an alpha- and a beta-chain. The availability of complementary DNA clones encoding mouse and human beta-chains has allowed a detailed characterization of the genomic organization of the beta-chain gene family and has revealed that functional beta-chain genes in T cells are generated from recombination events involving variable (V), diversity (D), joining (J) and constant (C) gene segments. Recently, cDNA clones encoding mouse and human alpha-chains have been described; the sequences of these clones have indicated that functional alpha-chain genes are also generated from multiple gene segments. It is possible that chromosomal translocations involving T-cell receptor alpha- and beta-chain genes have a role in T-cell neoplasms in much the same way as translocations involving immunoglobulin genes are associated with oncogenic transformation in B cells. In the latter case, the chromosomal localization of the immunoglobulin genes provided one of the first indications of the involvement of such translocations in oncogenic transformation. The chromosomal assignment of the alpha- and beta-chain genes may, therefore, provide equally important clues for T-cell neoplastic transformation. The chromosomal location of the mouse and human beta-chain gene family has been determined: the murine gene lies on chromosome 6 (refs 12, 13) whereas the human gene is located on chromosome 7 (refs 13, 14). Here we use a cDNA clone encoding the human alph-chain to map the corresponding gene to chromosome 14.     

Deficient pheromone responses in mice lacking a cluster of vomeronasal receptor genes

The mammalian vomeronasal organ (VNO), a part of the olfactory system, detects pheromones--chemical signals that modulate social and reproductive behaviours. But the molecular receptors in the VNO that detect these chemosensory stimuli remain undefined. Candidate pheromone receptors are encoded by two distinct and complex superfamilies of genes, V1r and V2r (refs 3 and 4), which code for receptors with seven transmembrane domains. These genes are selectively expressed in sensory neurons of the VNO. However, there is at present no functional evidence for a role of these genes in pheromone responses. Here, using chromosome engineering technology, we delete in the germ line of mice an approximately 600-kilobase genomic region that contains a cluster of 16 intact V1r genes. These genes comprise two of the 12 described V1r gene families, and represent approximately 12% of the V1r repertoire. The mutant mice display deficits in a subset of VNO-dependent behaviours: the expression of male sexual behaviour and maternal aggression is substantially altered. Electrophysiologically, the epithelium of the VNO of such mice does not respond detectably to specific pheromonal ligands. The behavioural impairment and chemosensory deficit support a role of V1r receptors as pheromone receptors.     

The gene encoding the T-cell receptor alpha-chain maps close to the Np-2 locus on mouse chromosome 14

Serological and molecular genetic analyses of T-cell clones have shown that the T-cell antigen receptor apparently comprises two glycosylated, disulphide-linked polypeptide chains (alpha and beta), both of which span the cell membrane. Cloning of the genes encoding the two chains from mouse and human DNA has shown that the alpha- and beta-chains are composed of variable (V) and conserved (C) regions in agreement with peptide mapping data. Gene segments encoding variable and conserved domains of the beta-chain have been identified and undergo rearrangements during T-cell differentiation. The genes encoding the alpha-chain, so far described at the level of complementary DNA clones, also identify DNA rearrangements. Thus, the genes encoding the T-cell receptor show the same structure and dynamic behaviour as immunoglobulin genes, indicating that the two gene families belong to the same supergene family; this evolutionary relationship is supported by the fact that the genes encoding the beta-chain of the T-cell receptor are closely linked to immunoglobulin kappa light-chain genes on chromosome 6 in mouse. In man, however, the beta genes map to chromosome 7 (ref. 14) whereas the kappa-chain genes are located on chromosome 2, indicating that linkage between the two gene families is not needed for proper expression. Here we describe genomic clones encoding the constant portion of the T-cell receptor alpha-chain and map the gene to chromosome 14 in mouse, close to the gene for purine nucleoside phosphorylase (Np-2) which, in man, has been associated with T-cell immunodeficiencies.     

Molecular organization of vomeronasal chemoreception

The vomeronasal organ (VNO) has a key role in mediating the social and defensive responses of many terrestrial vertebrates to species- and sex-specific chemosignals. More than 250 putative pheromone receptors have been identified in the mouse VNO, but the nature of the signals detected by individual VNO receptors has not yet been elucidated. To gain insight into the molecular logic of VNO detection leading to mating, aggression or defensive responses, we sought to uncover the response profiles of individual vomeronasal receptors to a wide range of animal cues. Here we describe the repertoire of behaviourally and physiologically relevant stimuli detected by a large number of individual vomeronasal receptors in mice, and define a global map of vomeronasal signal detection. We demonstrate that the two classes (V1R and V2R) of vomeronasal receptors use fundamentally different strategies to encode chemosensory information, and that distinct receptor subfamilies have evolved towards the specific recognition of certain animal groups or chemical structures. The association of large subsets of vomeronasal receptors with cognate, ethologically and physiologically relevant stimuli establishes the molecular foundation of vomeronasal information coding, and opens new avenues for further investigating the neural mechanisms underlying behaviour specificity.     

Complexity of human T-cell antigen receptor beta-chain constant- and variable-region genes

Immune systems of vertebrates function via two types of effector cells, B and T cells, which are capable of antigen-specific recognition. The immunoglobulins, which serve as antigen receptors on B cells, have been well characterized with respect to gene structure, unlike the T-cell receptors. Recently, cDNA clones thought to correspond to the beta-chain locus of the human and mouse T-cell receptor have been described. The presumptive beta-chain clones detect gene rearrangement specifically in T-cell DNA and show homology with immunoglobulin light chains. The similarity of the T-cell beta-chain gene system to the immunoglobulin genes has been further demonstrated by the recent observation of variable- and constant-region gene segments as well as joining segments and putative diversity segments. We report here the characterization of cDNA and genomic clones encoding human T-cell receptor beta-chain genes. There are two constant-region genes (C beta 1 and C beta 2), each capable of rearrangement and expression as RNA. The gene arrangement, analogous to that of mouse beta-chain genes, shows strong evolutionary conservation of the dual C beta gene system in these two species.     

A maternally inherited superantigen encoded by a mammary tumour virus.

A collection of superantigens, molecules which in combination with class II major histocompatibility complex (MHC) engage T cells bearing particular V beta chains as part of their alpha beta receptors, have recently been described. The mouse self superantigen, Mls-1a, for example, in conjunction with many MHC class II proteins, engages mouse T cells bearing V beta 6, 7, 8.1 and 9, almost regardless of the sequences of the other variable components of the receptors on the T cells. Two types of superantigen have been identified so far: first, superantigens encoded in the mouse genome, such as Mls-1a; second, superantigens produced by bacteria, such as the staphylococcal enterotoxins. Although the latter type of superantigens are in many cases known to be proteins of about 220 amino acids, nothing is known about the structures of any of the superantigens encoded in mouse. Here we describe the properties of a new mouse superantigen. The antigen is maternally transmitted in milk and is probably encoded by a mammary tumour virus (MTV). Given the known genetic linkage between at least one of the mouse genomic superantigens and endogenous MTV integration sites, it is tempting to speculate that the superantigen described here and some of the endogenous mouse superantigens are encoded by MTVs.     

一株拮抗纹枯病菌放线菌的筛选及鉴定

从采自金华市各地的68份土样中分离得到了放线菌406株,以水稻纹枯病菌为指示菌,利用平皿对峙法筛选到42株具有较好拮抗作用的放线菌菌株．其中,Sh-43菌株的拮抗作用最强,抑菌带宽度为28．3mm．根据培养特征、形态特征、生理生化特征及16S rDNA序列比对分析,鉴定Sh-43菌株为吸水链霉菌（Streptomyces hygroscopicus）．     

Rearrangement of two distinct T-cell gamma-chain variable-region genes in human DNA

Selective cloning procedures for T-cell-specific complementary DNAs have revealed the existence of a gene designated gamma as well as the main antigen receptor alpha- and beta-chain genes. The gamma-chain genes undergo rearrangement during T-cell differentiation but the patterns and complexity of such rearrangements differ markedly in mouse and human. In mouse, a panel of cytotoxic T-lymphocyte clones exhibit the same rearrangement pattern with a gamma-chain gene probe and a set of three gamma-chain variable (V) genes have been identified in the DNA. Clonal diversity in mouse seems to be confined to V-J (joining) regions. In contrast, human T-cell lines exhibit diverse rearrangements suggestive of a family of differing V gamma genes variously rearranging to the two gamma-chain constant (C) region genes. Here we report the cloning of two very different V gamma genes rearranged to J segments upstream of the two human C gamma genes. Both V gamma genes are rearranged productively but nucleotide sequence comparison shows that they possess very little homology with each other. This shows that human T-cell V gamma genes exist which differ significantly from each other at the nucleotide level and that such diverse genes can be usefully rearranged in different T cells.     

Identical V beta T-cell receptor genes used in alloreactive cytotoxic and antigen plus I-A specific helper T cells

T lymphocytes involved in the cellular immune response carry cell-surface receptors responsible for antigen and self recognition. This T-cell receptor molecule is a heterodimeric protein consisting of disulphide-linked alpha- and beta-chains with variable (V) and constant (C) regions. Several complementary DNA and genomic DNA clones have been isolated and characterized. These analyses showed that the genomic arrangement and rearrangement of T-cell receptor genes using VT, diversity (DT), joining (JT) and CT gene segments is very similar to the structure of the known immunoglobulin genes. We have isolated two cDNA clones from an allospecific cytotoxic T cell, one of which shows a productive V beta-J beta-C beta 1 rearrangement without an intervening D beta segment. This V beta gene segment is identical to the V beta gene expressed in a helper T-cell clone specific for chicken red blood cells and H-21. The other clone carries the C beta 2 gene of the T-cell receptor, but the C beta 2 sequence is preceded by a DNA sequence that does not show any similarity to V beta or J beta sequences.     

Two tandemly organized human genes encoding the T-cell gamma constant-region sequences show multiple rearrangement in different T-cell types

The recent detailed analysis of genes that undergo rearrangement in T cells has shown that the T-cell receptor genes encoding alpha- and beta-chains are involved in specific alterations in T-cell DNA analogous to the immunoglobulin genes. A third type of gene, designated gamma, has been isolated from mouse cytotoxic T lymphocytes, and evidence suggest that the mouse displays very limited diversity in this gene system, having only three variable-region (V) genes and three constant-region (C) genes. The function of the so-called T-cell gamma gene is unknown. We have isolated genomic genes encoding the human homologue of the mouse T-cell gamma gene; as there is no evidence that this T-cell rearranging gene is anything to do with the T3 molecule, we have designated the human T-cell rearranging gene as TRG gamma (ref. 13), to avoid confusion with the T3 gamma-chain, and have shown that the gene locus maps to chromosome 7 in humans. We now report that human DNA contains two tandemly arranged TRG gamma constant-region genes about 16 kilobases apart. These two genes show multiple rearrangement patterns in a variety of T cells, including helper and cytotoxic/suppressor type, as well as in all forms of T-cell leukaemia. Our results indicate variability of this T-cell gene system in man compared with the analogous system in mouse.     

A cloned cell with NK function resembles basophils by ultrastructure and expresses IgE receptors

Natural killer (NK) cells are defined by their ability to lyse certain tumour cells in vitro without previous exposure to them, and have been postulated as effectors of immune surveillance against spontaneous neoplasms. Because they kill some non-neoplastic lymphoid cells, they may also have a role in immunoregulation. NK cell activity resides in a small proportion of normal mouse spleen cells (less than 5%) that have been difficult to characterize completely. They may represent a heterogeneous group of effector cells whose precise relationship to other myelopoietic or immunological cells has remained obscure. We have previously described a cloned mouse cell line (Cl. Ly 1-2-NK-1+/11) with the functional characteristics of natural killer cells activated by interferon or other factors. We now find that this cloned line, like basophils and mast cells, expresses high-affinity plasma membrane receptors (Fc epsilon R) specific for IgE antibody. In addition, the clone contains cytoplasmic granules similar by ultrastructure to those of basophils of the mouse and other species. Our findings indicate that cells sharing morphological and biochemical features of basophilic granulocytes can mediate NK lysis.     

Numerous potentially functional but non-genic conserved sequences on human chromosome 21

The use of comparative genomics to infer genome function relies on the understanding of how different components of the genome change over evolutionary time. The aim of such comparative analysis is to identify conserved, functionally transcribed sequences such as protein-coding genes and non-coding RNA genes, and other functional sequences such as regulatory regions, as well as other genomic features. Here, we have compared the entire human chromosome 21 with syntenic regions of the mouse genome, and have identified a large number of conserved blocks of unknown function. Although previous studies have made similar observations, it is unknown whether these conserved sequences are genes or not. Here we present an extensive experimental and computational analysis of human chromosome 21 in an effort to assign function to sequences conserved between human chromosome 21 (ref. 8) and the syntenic mouse regions. Our data support the presence of a large number of potentially functional non-genic sequences, probably regulatory and structural. The integration of the properties of the conserved components of human chromosome 21 to the rapidly accumulating functional data for this chromosome will improve considerably our understanding of the role of sequence conservation in mammalian genomes.     

Identification of D segments of immunoglobulin heavy-chain genes and their rearrangement in T lymphocytes

The finding that the diversity (D) and joining (JH) but not the variable (VH) DNA segments of mouse immunoglobulin heavy-chain genes are joined in the DNA of some cloned cytolytic T cells, led to identification and sequencing of three different D DNA segments. Two segments identified on the embryo DNA carry on both the 5' and 3' sides two sets of characteristic sequences separated by a 12-base pair spacer, which have been implicated as recognition signals for a recombinase. The third segment, identified in a form joined with a JHDNA segment in a T cell, carries the recognition signal on the 5' side. These results support the 12/23-base pair model for somatic generation of immunoglobulin V genes, and rule out the possibility that the cytolytic T cells use assembled VH, D and JH sequences to encode their antigen receptors.     

Aberrant rearrangement of the kappa light-chain locus involving the heavy-chain locus and chromosome 15 in a mouse plasmacytoma

The creation of a functional antibody gene requires the precise recombination of gene segments initially separated on the chromosome. Frequently errors occur in the process, resulting in the formation of a non-functional gene. The non-functional genes can be generated by incomplete rearrangements, frameshifts, or the use of pseudo V or J joining segments. It is likely that these aberrant rearrangements arise by the same mechanism as is used in generating functional genes, a process which we have suggested may involve unequal sister chromatid exchange. Aberrant rearrangements of immunoglobulin genes occur in normal lymphocytes and play a major part in allelic exclusion. However, it has recently been suggested that aberrant rearrangements involving immunoglobulin and non-immunoglobulin genes may be involved in tumorigenesis. This suggestion has been stimulated by the frequent occurrence of translocations involving chromosomes known to carry immunoglobulin genes in B-cell malignancies. The rearrangement of non-immunoglobulin DNA to the heavy-chain locus has recently been reported. Some aberrant rearrangements of the kappa locus appear to be due to rearrangements to sites that do not include the conventional sequence for V gene segment joining. Here we describe an aberrant kappa rearrangement that has led to the joining of DNA from chromosomes 15, 6 and 12, and so appears to be the result of chromosomal translocations or transpositions. As 15/6 or 15/12 translocations have frequently been found in mouse plasmacytomas (as have analogous translocations in human lymphocyte tumours) this aberrant kappa rearrangement may be unique to the plasmacytoma from which it was isolated.     

Comparative chromosome mapping of a conserved homoeo box region in mouse and human

Specific genes are assumed to regulate pattern formation in the mammalian embryo, but as yet none has been identified unequivocally. It is possible that such genes in mammals may be identified by virtue of a conserved coding sequence, because many of the Drosophila melanogaster homoeotic and segmentation genes, which have crucial roles in the regulation of segmental pattern formation during embryonic development, contain a 180-base pair (bp) DNA sequence, the homoeo box, and that sequences homologous to the Drosophila homoeo box are also present in 6-10 copies in higher animals, including mammals. Although the assumption that the homoeo box identifies genes responsible for pattern formation in mammals remains to be validated, it is a particularly attractive hypothesis given the strong conservation of homoeo boxes over vast evolutionary distances. Here we report the localization of a human homoeo box region, previously cloned and shown to contain two homoeo boxes within a sequence of 5-kilobases (kb), to the long arm of chromosome 17. We show that two single-copy homoeo box-flanking probes derived from this region strongly hybridize to single-copy restriction fragments in mouse genomic DNA and that these conserved homoeo box-flanking sequences map to mouse chromosome 11. This may be significant as several genes that map to chromosome 17 in human also map to chromosome 11 in the mouse, implying that a segment of mouse chromosome 11 is homologous to a region of human chromosome 17. Taken together, these data suggest that the homoeo box region detected with our probes is highly conserved in human and mouse.     

核酸序列的信道容量

生命是一个进化的信息系统.本文分析了核酸序列作为生命的原型在存储和传递信息中的特征,指出生命信息的‘载波’是随机序列或独立序列,讨论了从中提取信息的问题,得到了信道容量定理,着重分析了镶嵌保守区的随机序列信道和{D_l}统计信道.     

Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development

How environmental cues regulate adult stem cell and cancer cell activity through surface receptors is poorly understood. Angiopoietin-like proteins (ANGPTLs), a family of seven secreted glycoproteins, are known to support the activity of haematopoietic stem cells (HSCs) in vitro and in vivo. ANGPTLs also have important roles in lipid metabolism, angiogenesis and inflammation, but were considered 'orphan ligands' because no receptors were identified. Here we show that the immune-inhibitory receptor human leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse orthologue paired immunoglobulin-like receptor (PIRB) are receptors for several ANGPTLs. LILRB2 and PIRB are expressed on human and mouse HSCs, respectively, and the binding of ANGPTLs to these receptors supported ex vivo expansion of HSCs. In mouse transplantation acute myeloid leukaemia models, a deficiency in intracellular signalling of PIRB resulted in increased differentiation of leukaemia cells, revealing that PIRB supports leukaemia development. Our study indicates an unexpected functional significance of classical immune-inhibitory receptors in maintenance of stemness of normal adult stem cells and in support of cancer development.