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PubMed2001

The human genome: an immuno-centric view of evolutionary strategies.

A hallmark of modern biology is the realization of the fundamental unity of biological processes in all life forms. Consequently, the complete genome sequencing of various bacteria, yeast (Saccharomyces cerevisiae), fly (Drosophila melanogaster) and worm (Caenorhabditis elegans) over the past five years has already had an impact on all of biology. "Model organisms" have contributed a great deal to immunology; for example, the Toll receptors of the fly provided the impetus for the investigation of Toll-like receptors, which proved to be fundamental elements in the mammalian innate immune system. The recent release of a draft sequence of the human genome provides the first panoramic view of the 30000-35000 human genes in the human genetic blueprint and provides a plethora of new details, the significance of which will take some time to appreciate. The over-riding concepts that emerge from these studies relate primarily to general evolutionary processes that are equally as relevant to immunology as they are to other disciplines of biology.

Amino Acid Sequence↗

PubMed2001

High-resolution mapping of the human 4q21 and the mouse 5E3 SCYB chemokine cluster by fiber-fluorescence in situ hybridization.

The CXC chemokine or small inducible cytokine B (SCYB) subfamily includes the T-cell chemoattractants MIG (CXCL9, SCYB9), IP-10 (CXCL10, SCYB10), and I-TAC (CXCL11, SCYB11). These three highly homologous chemokines lack the glutamic acid-leucine-arginine (ELR) motif and signal via the CXCR3 receptor. Previous work showed that the genes encoding these chemokines are localized in an individual mini-cluster on human Chromosome (Chr) 4 at position 4q21.2. Recently, we identified mouse Scyb11 and mapped this gene by fluorescence in situ hybridization (FISH) to mouse Chr 5E3, the orthologous locus to human 4q21 where the other two homologous mouse genes, Scyb9 and Scyb10, have also been localized. Since SCYB10 and SCYB11 are not represented in the recently published draft sequence of the human genome, we wanted to clarify exactly the order and distances of the three chemokine genes using two-color FISH on stretched DNA fiber preparations. Here, we report the simultaneous localization of all three genes and provide high-resolution visual maps of this chemokine cluster from both mouse and human. The three chemokine genes were found within a range of 32 kb on mouse and 29 kb on human DNA fiber targets. The precise physical distances were defined, and an almost identical arrangement of the human and mouse homologues was identified, indicating that this CXC chemokine mini-cluster has been completely conserved evolutionarily since the divergence of mouse and human. Our results refine previous maps of the three genes, support the hypothesis that they resulted from gene duplication that took place in a common ancestor of mouse and human, and provide complementary information on a region of the draft sequence of human Chr 4 that is not yet covered.

Animals↗

PubMed2002

Primer on medical genomics part I: History of genetics and sequencing of the human genome.

In comparison with most other disciplines of science, the field of genetics is still in its youth. The majority of scientific work in genetics has been done in the past 150 years. The successful preliminary sequencing of the human genome was announced in 2001. Nonetheless, interest in heredity and in other concepts within the field of genetics has existed since the beginning of humanity. This article provides an account of the history of genetics, spanning from humankind's initial attempts to understand and influence heredity, to the early scientific work in the field of genetics, and subsequently to the advancements in modern genetics. Additionally, the Human Genome Project is summarized, from inception to publication of the 'first draft" of the human genome sequence.

Forecasting↗

PubMed2002

Entire sequence of a mouse chromosomal segment containing the gene Rhced and a comparative analysis of the homologous human sequence.

The mouse genomic sequence of the region containing the gene Rhced, the orthologue to the human gene RH30, was determined to elucidate the structure of Rhced and its flanking regions and to compare these with the corresponding human genomic region. Two genes, Smp1 and AK003528 (an orthologue of FLJ10747), flank Rhced. Neither sequences homologous to the characteristic nucleotide elements flanking the RHD gene in humans (rhesus boxes) nor an additional Rh gene were found within the mouse region sequenced. This result and that of a previous report demonstrate that this chromosomal region of the mouse comprises five genes (FLJ10747-RHCE-SMP1-NPD014-P29) that exhibit syntenic homology with the corresponding human region, which suggests that the RHD gene and rhesus boxes were inserted later. Evaluations of tissue distribution and subcellular localization of these genes indicate that the SMP1 orthologue has a ubiquitous tissue distribution and cytoplasmic localization, whereas AK003528 is expressed slightly higher in testis with a strong subcellular localization in the nucleus. Despite the steady improvements in the draft sequence of the human genome, this study demonstrates the continuing benefits of comparative genetic analyses in increasing our understanding of human genomic structure.

3' Flanking Region↗

PubMed2006

Shedding genomic light on Aristotle's lantern.

Sea urchins have proved fascinating to biologists since the time of Aristotle who compared the appearance of their bony mouth structure to a lantern in The History of Animals. Throughout modern times it has been a model system for research in developmental biology. Now, the genome of the sea urchin Strongylocentrotus purpuratus is the first echinoderm genome to be sequenced. A high quality draft sequence assembly was produced using the Atlas assembler to combine whole genome shotgun sequences with sequences from a collection of BACs selected to form a minimal tiling path along the genome. A formidable challenge was presented by the high degree of heterozygosity between the two haplotypes of the selected male representative of this marine organism. This was overcome by use of the BAC tiling path backbone, in which each BAC represents a single haplotype, as well as by improvements in the Atlas software. Another innovation introduced in this project was the sequencing of pools of tiling path BACs rather than individual BAC sequencing. The Clone-Array Pooled Shotgun Strategy greatly reduced the cost and time devoted to preparing shotgun libraries from BAC clones. The genome sequence was analyzed with several gene prediction methods to produce a comprehensive gene list that was then manually refined and annotated by a volunteer team of sea urchin experts. This latter annotation community edited over 9000 gene models and uncovered many unexpected aspects of the sea urchin genetic content impacting transcriptional regulation, immunology, sensory perception, and an organism's development. Analysis of the basic deuterostome genetic complement supports the sea urchin's role as a model system for deuterostome and, by extension, chordate development.

Animals↗

PubMed2001

[Identification and characterization of histamine H4 receptor].

Recently, we and other groups have identified cDNA encoding the novel histamine H4 receptor. All of the groups have initially found a clue for the H4 receptor-nucleotides sequence in the human draft genomic DNA database. The primary structure of H4 receptor reveals the highest homology with H3 receptor among known G-protein coupled receptors (37.4%). H4 receptor binds to histamine with high affinity, which results in the down-regulation of intracellular cAMP level. H4 receptor is activated not only by histamine, but also R-(alpha)-methylhistamine (H3 receptor agonist), clobenpropit (H3 receptor antagonist), clozapine (neuroleptic) and other histaminergic compounds, while it is antagonized by thioperamide (H3 receptor antagonist). The H4 receptor is localized in the peripheral blood leukocytes, spleen, thymus, small intestine, colon, bone marrow and so on. The tissue distribution of the H4 receptor and known physiological function of histamine tempts us to speculate about its function as an immune modulator. Although there needs much additional work on characterization of the H4 receptor, the discovery of this receptor subtype will unveil a new phase for determining the physiological role of histamine.

Amino Acid Sequence↗

PubMed2003

The genome sequence of the filamentous fungus Neurospora crassa.

Neurospora crassa is a central organism in the history of twentieth-century genetics, biochemistry and molecular biology. Here, we report a high-quality draft sequence of the N. crassa genome. The approximately 40-megabase genome encodes about 10,000 protein-coding genes--more than twice as many as in the fission yeast Schizosaccharomyces pombe and only about 25% fewer than in the fruitfly Drosophila melanogaster. Analysis of the gene set yields insights into unexpected aspects of Neurospora biology including the identification of genes potentially associated with red light photobiology, genes implicated in secondary metabolism, and important differences in Ca2+ signalling as compared with plants and animals. Neurospora possesses the widest array of genome defence mechanisms known for any eukaryotic organism, including a process unique to fungi called repeat-induced point mutation (RIP). Genome analysis suggests that RIP has had a profound impact on genome evolution, greatly slowing the creation of new genes through genomic duplication and resulting in a genome with an unusually low proportion of closely related genes.

Calcium Signaling↗

PubMed2001

A BAC-based STS-content map spanning a 35-Mb region of human chromosome 1p35-p36.

We have devised a mapping method for rapid assembly and ordering of bacterial artificial chromosome (BAC) clones on a radiation hybrid (RH) panel, using sequence-tagged sites (STSs) and PCR. The protocol consists of two rounds of two-dimensional screening from a limited number of BACs to correspond each to an STS. In the first round, STSs are assembled in the RH bins and ordered according to PCR signals derived from 384-well microtiter plates (MTPs) in which BAC clones have been arrayed. In the second round, individual BAC clones are isolated from the MTPs to build a contig. We applied this method to a 35-Mb region spanning human chromosome 1p35-p36 and assembled 1366 BACs in 11 contigs, the longest being about 20 Mb. The working draft sequences of the human genome have been integrated into the contigs to validate the accuracy.

Chromosome Mapping↗

PubMed2002

Physical and transcript map of a 2-Mb region in Xp22.1 containing candidate genes for X-linked mental retardation and short stature.

Genetic loci for several diseases, including X-linked nonspecific mental retardation and short stature, have been mapped to Xp22.1. In spite of the recent publications of two draft sequences for the human genome, this region seems to be largely unmapped and unsequenced. Here we report an integrated physical and transcript map of approximately 2-Mb from DXS8004 to DXS365. Using sequence tagged site (STS)-content mapping and chromosome walking, we assembled a genomic clone contig of 54 BACs and one cosmid with an estimated 4.5-fold coverage of this region. The minimum tiling path consists of 23 BACs and one cosmid. Onto this contig, we mapped 30 new STSs derived from the unique end-sequences of the BACs, three expressed sequence tags, five genes, and seven CpG islands. This integrated map provides a unique resource for the positional cloning of candidate disease genes mapping to Xp22.1 and is therefore of value for the completion of the genomic sequence of this region.

Base Sequence↗

PubMed2003

Mouse genetic approaches to access pathways important in retinal function.

The laboratory mouse is a premier research tool for understanding human biology and disease. With the availability of the first complete draft sequences of the mouse genome and ongoing large scale screens for new mouse mutations to serve as novel models, the usefulness of the mouse will only increase. The vision research field, in particular, which has identified many human diseases for which no models are yet available, will benefit from the newly developed tools in mouse molecular genetics.

Animals↗

PubMed2005

Adaptive diversification of vomeronasal receptor 1 genes in rodents.

The vomeronasal receptor 1 (V1R) are believed to be pheromone receptors in rodents. Here we used computational methods to identify 95 and 62 new putative V1R genes from the draft rat and mouse genome sequence, respectively. The rat V1R repertoire consists of 11 subfamilies, 10 of which are shared with the mouse, while rat appears to lack the H and I subfamilies found in mouse and possesses one unique subfamily (M). The estimations of the relative divergence times suggest that many subfamilies originated after the split of rodents and primates. The analysis also reveals that these clusters underwent an expansion very close to the split of mouse and rat. In addition, maximum likelihood analysis showed that the nonsynonymous and synonymous rate ratio for most of these clusters was much higher than one, suggesting the role of positive selection in the diversification of these duplicated V1R genes. Because V1R are thought to mediate the process of signal transduction in response to pheromone detection, we speculate that the V1R genes have evolved under positive Darwinian selection to maintain the ability to discriminate between large and complex pheromonal mixtures.

Adaptation, Physiological↗

PubMed2004

Cloning, expression, and characterization of fugu CD4, the first ectothermic animal CD4.

We have cloned and sequenced the first ectothermic animal CD4 gene from fugu, Takifugu rubripes, using a public database of the third draft sequence of the fugu genome. The fugu CD4 gene encodes a predicted protein of 463 amino acids containing four extracellular immunoglobulin (Ig)-like domains, a transmembrane region, and a cytoplasmic tail. Fugu CD4 shares low identity of about 15-20% with avian and mammalian CD4 proteins. Unlike avian and mammalian CD4, fugu CD4 lacks the Cys pair of the first Ig-like domain, but has a unique possible disulfide bond in the third domain. These differences suggest that fugu CD4 may have a different structure that could affect binding of major histocompatibility complex class II molecules and subsequent T-cell activation. In the putative fugu cytoplasmic region, the protein tyrosine kinase p56lck binding motif is conserved. The predicted fugu CD4 gene is composed of 12 exons, differing from other CD4 genes, but showing conserved synteny and many conserved sequence motifs in the promoter region. RT-PCR analysis demonstrated that the fugu CD4 gene is expressed predominantly in lymphoid tissues. We also show that fugu CD4 can be expressed on the surface of cells via transfection. Molecular characterization of CD4 in fish provides insights into the evolution of both the CD4 molecule and the immune system.

Amino Acid Sequence↗

PubMed2001

CD2F-10: a new member of the CD2 subset of the immunoglobulin superfamily.

The CD2 subset of the immunoglobulin superfamily consists of a rapidly expanding family of leukocyte cell surface receptors, at least five of which (CD2, CD48, CD58, CD150, and CD244) are involved in lymphocyte activation as either receptors or ligands. Completion of the draft sequence of the human genome offers the possibility of systematically identifying the full set of proteins and interactions of this important family. Here we describe the identification and characterization of the first new member of the subset, CD2F-10, found exclusively by genome searching.

Amino Acid Sequence↗

PubMed2002

Microdeletions of a Y-specific marker, Yfm1, and implications for a role in spermatogenesis.

We have detected deletions of a Y-specific microsatellite marker, Yfm1, located on the Y chromosome (Yq) within interval 6 and near the DAZ (deleted in azoospermia) genes, in 9/89 oligospermic and 17/68 azoospermic Japanese men. No Yfm1 deletions were detected in the 150 normal fertile males examined as controls. Yfm1 deletions in the oligo- and azoospermic males were associated with other deletions that removed entire DAZ genes in those infertile men. These deletions indicated that all Yfm1 loci are located within azoospermia factor c (AZFc) in interval 6 on the long arm of the Y chromosome. Mapping Yfm1 on the Y chromosome using the draft sequence of the human genome revealed that at least three Yfm1 loci are located within about 25-30 kbp of the DAZ genes. Moreover, the Yfm1 marker showed the least number of copies in Japanese males derived from a Y chromosomal lineage called haplotype II, defined by having the Y Alu polymorphism (YAP) insertion. Males from this haplotype II lineage are known from our previous studies to have lower spermatogenic abilities, with higher rates of oligo- and azoospermia than other haplotypes. The least number of Yfm1 loci, whose copy number may correspond to that of the DAZ genes, may be a risk factor predisposing an individual to azoospermia or oligospermia.

Alu Elements↗

PubMed2004

Towards a mutant map of the mouse--new models of neurological, behavioural, deafness, bone, renal and blood disorders.

With the completion of the first draft of the human genome sequence, the next major challenge is assigning function to genes. One approach is genome-wide random chemical mutagenesis, followed by screening for mutant phenotypes of interest and subsequent mapping and identification of the mutated genes in question. We (a consortium made up of GlaxoSmithKline, the MRC Mammalian Genetics Unit and Mouse Genome Centre, Harwell, Imperial College, London, and the Royal London Hospital) have used ENU mutagenesis in the mouse for the rapid generation of novel mutant phenotypes for use as animal models of human disease and for gene function assignment (Nolan et al., 2000). As of 2003, 35,000 mice have been produced to date in a genome-wide screen for dominant mutations and screened using a variety of screening protocols. Nearly 200 mutants have been confirmed as heritable and added to the mouse mutant catalogue and, overall, we can extrapolate that we have recovered over 700 mutants from the screening programme. For further information on the project and details of the data, see http://www.mgu.har.mrc.ac.uk/mutabase.

Animals↗

PubMed2004

The future of genetic research on appetitive behavior.

The risk for developing obesity has a significant genetic component. Several quantitative trait loci and candidate genes have been identified using current methodological approaches however the information gained thus far is insufficient to adequately explain the genetics underlying human obesity. The completion of a draft of the human genome sequence, the potential benefit of single nucleotide polymorphisms association studies for identifying risk conferring alleles, and developing functional genomics technologies promise to accelerate obesity gene discovery. These advances, used with current evaluative tools (murine molecular genetic techniques), may increase our understanding of human obesity, and ultimately provide better approaches to diagnosis and treatment.

Appetite↗

PubMed2005

Characterization of the AMP-activated protein kinase pathway in chickens.

In mammals, AMP-activated protein kinase (AMPK) is involved in the regulation of cellular energy homeostasis and, on the whole animal level, in regulating energy balance and food intake. Because the chicken is a valuable experimental animal model and considering that a first draft of the chicken genome sequence has recently been completed, we were interested in verifying the genetic basis for the LKB1/AMPK pathway in chickens. We identified distinct gene homologues for AMPK alpha, beta and gamma subunits and for LKB1, MO25 and STRAD. Analysis of gene expression by RT-PCR showed that liver, brain, kidney, spleen, pancreas, duodenum, abdominal fat and hypothalamus from 3 wk-old broiler chickens preferentially expressed AMPK alpha-1, beta-2 and gamma-1 subunit isoforms. Heart predominantly expressed alpha-2, beta-2 and gamma-1, whereas skeletal muscle expressed alpha-2, beta-2 and gamma-3 preferentially. Moreover, the AMPK gamma-3 gene was only expressed in heart and skeletal muscle. Genes encoding LKB1, MO25 alpha, MO25 beta, and STRAD beta were expressed in all examined tissues, whereas STRAD alpha was expressed exclusively in brain, hypothalamus, heart and skeletal muscle. Alterations in energy status (fasting and refeeding) produced little significant change in AMPK subunit gene transcription. We also determined the level of phosphorylated (active) AMPK in different tissues and in different states of energy balance. Immunocytochemical analysis of the chicken hypothalamus showed that activated AMPK was present in hypothalamic nuclei involved in regulation of food intake and energy balance. Together, these findings suggest a functional LKB1/AMPK pathway exists in chickens similar to that observed in mammals.

AMP-Activated Protein Kinases↗

PubMed2003

Role of evolutionary history on haplotype block structure in the human genome: implications for disease mapping.

With the completion of the first draft of the human genome sequencing project, a new challenge is to characterize patterns of linkage disequilibrium and haplotype structure across genomic regions to identify mutations associated with complex disease. Recent work shows considerable linkage disequilibrium heterogeneity, where genomic regions of extended haplotype blocks are punctuated by recombination hotspots. In this review we explore some of the current approaches to defining and characterizing 'hapblocks', mechanisms by which hapblocks may be generated, and the implications this block-like structure may have for successfully mapping mutations associated with complex disease.

Biological Evolution↗