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961.
BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice 总被引:17,自引:0,他引:17
Baker DJ Jeganathan KB Cameron JD Thompson M Juneja S Kopecka A Kumar R Jenkins RB de Groen PC Roche P van Deursen JM 《Nature genetics》2004,36(7):744-749
Faithful segregation of replicated chromosomes is essential for maintenance of genetic stability and seems to be monitored by several mitotic checkpoints. Various components of these checkpoints have been identified in mammals, but their physiological relevance is largely unknown. Here we show that mutant mice with low levels of the spindle assembly checkpoint protein BubR1 develop progressive aneuploidy along with a variety of progeroid features, including short lifespan, cachectic dwarfism, lordokyphosis, cataracts, loss of subcutaneous fat and impaired wound healing. Graded reduction of BubR1 expression in mouse embryonic fibroblasts causes increased aneuploidy and senescence. Male and female mutant mice have defects in meiotic chromosome segregation and are infertile. Natural aging of wild-type mice is marked by decreased expression of BubR1 in multiple tissues, including testis and ovary. These results suggest a role for BubR1 in regulating aging and infertility. 相似文献
962.
A transcriptomic analysis of the phylum Nematoda 总被引:1,自引:0,他引:1
Parkinson J Mitreva M Whitton C Thomson M Daub J Martin J Schmid R Hall N Barrell B Waterston RH McCarter JP Blaxter ML 《Nature genetics》2004,36(12):1259-1267
The phylum Nematoda occupies a huge range of ecological niches, from free-living microbivores to human parasites. We analyzed the genomic biology of the phylum using 265,494 expressed-sequence tag sequences, corresponding to 93,645 putative genes, from 30 species, including 28 parasites. From 35% to 70% of each species' genes had significant similarity to proteins from the model nematode Caenorhabditis elegans. More than half of the putative genes were unique to the phylum, and 23% were unique to the species from which they were derived. We have not yet come close to exhausting the genomic diversity of the phylum. We identified more than 2,600 different known protein domains, some of which had differential abundances between major taxonomic groups of nematodes. We also defined 4,228 nematode-specific protein families from nematode-restricted genes: this class of genes probably underpins species- and higher-level taxonomic disparity. Nematode-specific families are particularly interesting as drug and vaccine targets. 相似文献
963.
Kleta R Romeo E Ristic Z Ohura T Stuart C Arcos-Burgos M Dave MH Wagner CA Camargo SR Inoue S Matsuura N Helip-Wooley A Bockenhauer D Warth R Bernardini I Visser G Eggermann T Lee P Chairoungdua A Jutabha P Babu E Nilwarangkoon S Anzai N Kanai Y Verrey F Gahl WA Koizumi A 《Nature genetics》2004,36(9):999-1002
Hartnup disorder, an autosomal recessive defect named after an English family described in 1956 (ref. 1), results from impaired transport of neutral amino acids across epithelial cells in renal proximal tubules and intestinal mucosa. Symptoms include transient manifestations of pellagra (rashes), cerebellar ataxia and psychosis. Using homozygosity mapping in the original family in whom Hartnup disorder was discovered, we confirmed that the critical region for one causative gene was located on chromosome 5p15 (ref. 3). This region is homologous to the area of mouse chromosome 13 that encodes the sodium-dependent amino acid transporter B(0)AT1 (ref. 4). We isolated the human homolog of B(0)AT1, called SLC6A19, and determined its size and molecular organization. We then identified mutations in SLC6A19 in members of the original family in whom Hartnup disorder was discovered and of three Japanese families. The protein product of SLC6A19, the Hartnup transporter, is expressed primarily in intestine and renal proximal tubule and functions as a neutral amino acid transporter. 相似文献
964.
Churchill GA Airey DC Allayee H Angel JM Attie AD Beatty J Beavis WD Belknap JK Bennett B Berrettini W Bleich A Bogue M Broman KW Buck KJ Buckler E Burmeister M Chesler EJ Cheverud JM Clapcote S Cook MN Cox RD Crabbe JC Crusio WE Darvasi A Deschepper CF Doerge RW Farber CR Forejt J Gaile D Garlow SJ Geiger H Gershenfeld H Gordon T Gu J Gu W de Haan G Hayes NL Heller C Himmelbauer H Hitzemann R Hunter K Hsu HC Iraqi FA Ivandic B Jacob HJ Jansen RC Jepsen KJ Johnson DK Johnson TE Kempermann G 《Nature genetics》2004,36(11):1133-1137
The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease. 相似文献
965.
966.
967.
Spicules are dynamic jets propelled upwards (at speeds of approximately 20 km s(-1)) from the solar 'surface' (photosphere) into the magnetized low atmosphere of the Sun. They carry a mass flux of 100 times that of the solar wind into the low solar corona. With diameters close to observational limits (< 500 km), spicules have been largely unexplained since their discovery in 1877: none of the existing models can account simultaneously for their ubiquity, evolution, energetics and recently discovered periodicity. Here we report a synthesis of modelling and high-spatial-resolution observations in which numerical simulations driven by observed photospheric velocities directly reproduce the observed occurrence and properties of individual spicules. Photospheric velocities are dominated by convective granulation (which has been considered before for spicule formation) and by p-modes (which are solar global resonant acoustic oscillations visible in the photosphere as quasi-sinusoidal velocity and intensity pulsations). We show that the previously ignored p-modes are crucial: on inclined magnetic flux tubes, the p-modes leak sufficient energy from the global resonant cavity into the chromosphere to power shocks that drive upward flows and form spicules. 相似文献
968.
Gibbs RA Weinstock GM Metzker ML Muzny DM Sodergren EJ Scherer S Scott G Steffen D Worley KC Burch PE Okwuonu G Hines S Lewis L DeRamo C Delgado O Dugan-Rocha S Miner G Morgan M Hawes A Gill R Celera Holt RA Adams MD Amanatides PG Baden-Tillson H Barnstead M Chin S Evans CA Ferriera S Fosler C Glodek A Gu Z Jennings D Kraft CL Nguyen T Pfannkoch CM Sitter C Sutton GG Venter JC Woodage T Smith D Lee HM Gustafson E Cahill P Kana A Doucette-Stamm L Weinstock K Fechtel K Weiss RB Dunn DM Green ED 《Nature》2004,428(6982):493-521
The laboratory rat (Rattus norvegicus) is an indispensable tool in experimental medicine and drug development, having made inestimable contributions to human health. We report here the genome sequence of the Brown Norway (BN) rat strain. The sequence represents a high-quality 'draft' covering over 90% of the genome. The BN rat sequence is the third complete mammalian genome to be deciphered, and three-way comparisons with the human and mouse genomes resolve details of mammalian evolution. This first comprehensive analysis includes genes and proteins and their relation to human disease, repeated sequences, comparative genome-wide studies of mammalian orthologous chromosomal regions and rearrangement breakpoints, reconstruction of ancestral karyotypes and the events leading to existing species, rates of variation, and lineage-specific and lineage-independent evolutionary events such as expansion of gene families, orthology relations and protein evolution. 相似文献
969.
Söllner C Rauch GJ Siemens J Geisler R Schuster SC Müller U Nicolson T;Tübingen Screen Consortium 《Nature》2004,428(6986):955-959
Hair cells have highly organized bundles of apical projections, or stereocilia, that are deflected by sound and movement. Displacement of stereocilia stretches linkages at the tips of stereocilia that are thought to gate mechanosensory channels. To identify the molecular machinery that mediates mechanotransduction in hair cells, zebrafish mutants were identified with defects in balance and hearing. In sputnik mutants, stereociliary bundles are splayed to various degrees, with individuals displaying reduced or absent mechanotransduction. Here we show that the defects in sputnik mutants are caused by mutations in cadherin 23 (cdh23). Mutations in Cdh23 also cause deafness and vestibular defects in mice and humans, and the protein is present in hair bundles. We show that zebrafish Cdh23 protein is concentrated near the tips of hair bundles, and that tip links are absent in homozygous sputnik(tc317e) larvae. Moreover, tip links are absent in larvae carrying weak alleles of cdh23 that affect mechanotransduction but not hair bundle integrity. We conclude that Cdh23 is an essential tip link component required for hair-cell mechanotransduction. 相似文献
970.
Structure of the signal recognition particle interacting with the elongation-arrested ribosome 总被引:1,自引:0,他引:1
Cotranslational translocation of proteins across or into membranes is a vital process in all kingdoms of life. It requires that the translating ribosome be targeted to the membrane by the signal recognition particle (SRP), an evolutionarily conserved ribonucleoprotein particle. SRP recognizes signal sequences of nascent protein chains emerging from the ribosome. Subsequent binding of SRP leads to a pause in peptide elongation and to the ribosome docking to the membrane-bound SRP receptor. Here we present the structure of a targeting complex consisting of mammalian SRP bound to an active 80S ribosome carrying a signal sequence. This structure, solved to 12 A by cryo-electron microscopy, enables us to generate a molecular model of SRP in its functional conformation. The model shows how the S domain of SRP contacts the large ribosomal subunit at the nascent chain exit site to bind the signal sequence, and that the Alu domain reaches into the elongation-factor-binding site of the ribosome, explaining its elongation arrest activity. 相似文献