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11.
Germline KRAS mutations cause Noonan syndrome 总被引:22,自引:0,他引:22
Schubbert S Zenker M Rowe SL Böll S Klein C Bollag G van der Burgt I Musante L Kalscheuer V Wehner LE Nguyen H West B Zhang KY Sistermans E Rauch A Niemeyer CM Shannon K Kratz CP 《Nature genetics》2006,38(3):331-336
Noonan syndrome (MIM 163950) is characterized by short stature, facial dysmorphism and cardiac defects. Heterozygous mutations in PTPN11, which encodes SHP-2, cause approximately 50% of cases of Noonan syndrome. The SHP-2 phosphatase relays signals from activated receptor complexes to downstream effectors, including Ras. We discovered de novo germline KRAS mutations that introduce V14I, T58I or D153V amino acid substitutions in five individuals with Noonan syndrome and a P34R alteration in a individual with cardio-facio-cutaneous syndrome (MIM 115150), which has overlapping features with Noonan syndrome. Recombinant V14I and T58I K-Ras proteins show defective intrinsic GTP hydrolysis and impaired responsiveness to GTPase activating proteins, render primary hematopoietic progenitors hypersensitive to growth factors and deregulate signal transduction in a cell lineage-specific manner. These studies establish germline KRAS mutations as a cause of human disease and infer that the constellation of developmental abnormalities seen in Noonan syndrome spectrum is, in large part, due to hyperactive Ras. 相似文献
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The Plasmodium genome database 总被引:8,自引:0,他引:8
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Healthy elderly subjects (greater than or equal to 65 years) did not show the prominent low frequency (0.07-0.09 Hz) heart rate oscillations (Mayer waves) recorded in young adults immediately following passive upright tilt. This difference may be related to altered autonomic function with physiologic aging. 相似文献
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Mikkelsen TS Wakefield MJ Aken B Amemiya CT Chang JL Duke S Garber M Gentles AJ Goodstadt L Heger A Jurka J Kamal M Mauceli E Searle SM Sharpe T Baker ML Batzer MA Benos PV Belov K Clamp M Cook A Cuff J Das R Davidow L Deakin JE Fazzari MJ Glass JL Grabherr M Greally JM Gu W Hore TA Huttley GA Kleber M Jirtle RL Koina E Lee JT Mahony S Marra MA Miller RD Nicholls RD Oda M Papenfuss AT Parra ZE Pollock DD Ray DA Schein JE Speed TP Thompson K VandeBerg JL Wade CM Walker JA Waters PD Webber C 《Nature》2007,447(7141):167-177
We report a high-quality draft of the genome sequence of the grey, short-tailed opossum (Monodelphis domestica). As the first metatherian ('marsupial') species to be sequenced, the opossum provides a unique perspective on the organization and evolution of mammalian genomes. Distinctive features of the opossum chromosomes provide support for recent theories about genome evolution and function, including a strong influence of biased gene conversion on nucleotide sequence composition, and a relationship between chromosomal characteristics and X chromosome inactivation. Comparison of opossum and eutherian genomes also reveals a sharp difference in evolutionary innovation between protein-coding and non-coding functional elements. True innovation in protein-coding genes seems to be relatively rare, with lineage-specific differences being largely due to diversification and rapid turnover in gene families involved in environmental interactions. In contrast, about 20% of eutherian conserved non-coding elements (CNEs) are recent inventions that postdate the divergence of Eutheria and Metatheria. A substantial proportion of these eutherian-specific CNEs arose from sequence inserted by transposable elements, pointing to transposons as a major creative force in the evolution of mammalian gene regulation. 相似文献
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Roger M Morris DJ Tennant DA Gutmann MJ Goff JP Hoffmann JU Feyerherm R Dudzik E Prabhakaran D Boothroyd AT Shannon N Lake B Deen PP 《Nature》2007,445(7128):631-634
Sodium cobaltate (Na(x)CoO2) has emerged as a material of exceptional scientific interest due to the potential for thermoelectric applications, and because the strong interplay between the magnetic and superconducting properties has led to close comparisons with the physics of the superconducting copper oxides. The density x of the sodium in the intercalation layers can be altered electrochemically, directly changing the number of conduction electrons on the triangular Co layers. Recent electron diffraction measurements reveal a kaleidoscope of Na+ ion patterns as a function of concentration. Here we use single-crystal neutron diffraction supported by numerical simulations to determine the long-range three-dimensional superstructures of these ions. We show that the sodium ordering and its associated distortion field are governed by pure electrostatics, and that the organizational principle is the stabilization of charge droplets that order long range at some simple fractional fillings. Our results provide a good starting point to understand the electronic properties in terms of a Hubbard hamiltonian that takes into account the electrostatic potential from the Na superstructures. The resulting depth of potential wells in the Co layer is greater than the single-particle hopping kinetic energy and as a consequence, holes preferentially occupy the lowest potential regions. Thus we conclude that the Na+ ion patterning has a decisive role in the transport and magnetic properties. 相似文献
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Jones FC Grabherr MG Chan YF Russell P Mauceli E Johnson J Swofford R Pirun M Zody MC White S Birney E Searle S Schmutz J Grimwood J Dickson MC Myers RM Miller CT Summers BR Knecht AK Brady SD Zhang H Pollen AA Howes T Amemiya C;Broad Institute Genome Sequencing Platform & Whole Genome Assembly Team Baldwin J Bloom T Jaffe DB Nicol R Wilkinson J Lander ES Di Palma F Lindblad-Toh K Kingsley DM 《Nature》2012,484(7392):55-61
Marine stickleback fish have colonized and adapted to thousands of streams and lakes formed since the last ice age, providing an exceptional opportunity to characterize genomic mechanisms underlying repeated ecological adaptation in nature. Here we develop a high-quality reference genome assembly for threespine sticklebacks. By sequencing the genomes of twenty additional individuals from a global set of marine and freshwater populations, we identify a genome-wide set of loci that are consistently associated with marine-freshwater divergence. Our results indicate that reuse of globally shared standing genetic variation, including chromosomal inversions, has an important role in repeated evolution of distinct marine and freshwater sticklebacks, and in the maintenance of divergent ecotypes during early stages of reproductive isolation. Both coding and regulatory changes occur in the set of loci underlying marine-freshwater evolution, but regulatory changes appear to predominate in this well known example of repeated adaptive evolution in nature. 相似文献
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Yooseph S Nealson KH Rusch DB McCrow JP Dupont CL Kim M Johnson J Montgomery R Ferriera S Beeson K Williamson SJ Tovchigrechko A Allen AE Zeigler LA Sutton G Eisenstadt E Rogers YH Friedman R Frazier M Venter JC 《Nature》2010,468(7320):60-66
The understanding of marine microbial ecology and metabolism has been hampered by the paucity of sequenced reference genomes. To this end, we report the sequencing of 137 diverse marine isolates collected from around the world. We analysed these sequences, along with previously published marine prokaryotic genomes, in the context of marine metagenomic data, to gain insights into the ecology of the surface ocean prokaryotic picoplankton (0.1-3.0?μm size range). The results suggest that the sequenced genomes define two microbial groups: one composed of only a few taxa that are nearly always abundant in picoplanktonic communities, and the other consisting of many microbial taxa that are rarely abundant. The genomic content of the second group suggests that these microbes are capable of slow growth and survival in energy-limited environments, and rapid growth in energy-rich environments. By contrast, the abundant and cosmopolitan picoplanktonic prokaryotes for which there is genomic representation have smaller genomes, are probably capable of only slow growth and seem to be relatively unable to sense or rapidly acclimate to energy-rich conditions. Their genomic features also lead us to propose that one method used to avoid predation by viruses and/or bacterivores is by means of slow growth and the maintenance of low biomass. 相似文献
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Badano JL Leitch CC Ansley SJ May-Simera H Lawson S Lewis RA Beales PL Dietz HC Fisher S Katsanis N 《Nature》2006,439(7074):326-330
Epistatic interactions have an important role in phenotypic variability, yet the genetic dissection of such phenomena remains challenging. Here we report the identification of a novel locus, MGC1203, that contributes epistatic alleles to Bardet-Biedl syndrome (BBS), a pleiotropic, oligogenic disorder. MGC1203 encodes a pericentriolar protein that interacts and colocalizes with the BBS proteins. Sequencing of two independent BBS cohorts revealed a significant enrichment of a heterozygous C430T mutation in patients, and a transmission disequilibrium test (TDT) showed strong over-transmission of this variant. Further analyses showed that the 430T allele enhances the use of a cryptic splice acceptor site, causing the introduction of a premature termination codon (PTC) and the reduction of steady-state MGC1203 messenger RNA levels. Finally, recapitulation of the human genotypes in zebrafish shows that modest suppression of mgc1203 exerts an epistatic effect on the developmental phenotype of BBS morphants. Our data demonstrate how the combined use of biochemical, genetic and in vivo tools can facilitate the dissection of epistatic phenomena, and enhance our appreciation of the genetic basis of phenotypic variability. 相似文献