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191.
Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing 总被引:1,自引:0,他引:1
Stark MS Woods SL Gartside MG Bonazzi VF Dutton-Regester K Aoude LG Chow D Sereduk C Niemi NM Tang N Ellis JJ Reid J Zismann V Tyagi S Muzny D Newsham I Wu Y Palmer JM Pollak T Youngkin D Brooks BR Lanagan C Schmidt CW Kobe B MacKeigan JP Yin H Brown KM Gibbs R Trent J Hayward NK 《Nature genetics》2012,44(2):165-169
We sequenced eight melanoma exomes to identify new somatic mutations in metastatic melanoma. Focusing on the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, we found that 24% of melanoma cell lines have mutations in the protein-coding regions of either MAP3K5 or MAP3K9. Structural modeling predicted that mutations in the kinase domain may affect the activity and regulation of these protein kinases. The position of the mutations and the loss of heterozygosity of MAP3K5 and MAP3K9 in 85% and 67% of melanoma samples, respectively, together suggest that the mutations are likely to be inactivating. In in vitro kinase assays, MAP3K5 I780F and MAP3K9 W333* variants had reduced kinase activity. Overexpression of MAP3K5 or MAP3K9 mutants in HEK293T cells reduced the phosphorylation of downstream MAP kinases. Attenuation of MAP3K9 function in melanoma cells using siRNA led to increased cell viability after temozolomide treatment, suggesting that decreased MAP3K pathway activity can lead to chemoresistance in melanoma. 相似文献
192.
Griffith E Walker S Martin CA Vagnarelli P Stiff T Vernay B Al Sanna N Saggar A Hamel B Earnshaw WC Jeggo PA Jackson AP O'Driscoll M 《Nature genetics》2008,40(2):232-236
Large brain size is one of the defining characteristics of modern humans. Seckel syndrome (MIM 210600), a disorder of markedly reduced brain and body size, is associated with defective ATR-dependent DNA damage signaling. Only a single hypomorphic mutation of ATR has been identified in this genetically heterogeneous condition. We now report that mutations in the gene encoding pericentrin (PCNT)--resulting in the loss of pericentrin from the centrosome, where it has key functions anchoring both structural and regulatory proteins--also cause Seckel syndrome. Furthermore, we find that cells of individuals with Seckel syndrome due to mutations in PCNT (PCNT-Seckel) have defects in ATR-dependent checkpoint signaling, providing the first evidence linking a structural centrosomal protein with DNA damage signaling. These findings also suggest that other known microcephaly genes implicated in either DNA repair responses or centrosomal function may act in common developmental pathways determining human brain and body size. 相似文献
193.
Tarpey PS Raymond FL Nguyen LS Rodriguez J Hackett A Vandeleur L Smith R Shoubridge C Edkins S Stevens C O'Meara S Tofts C Barthorpe S Buck G Cole J Halliday K Hills K Jones D Mironenko T Perry J Varian J West S Widaa S Teague J Dicks E Butler A Menzies A Richardson D Jenkinson A Shepherd R Raine K Moon J Luo Y Parnau J Bhat SS Gardner A Corbett M Brooks D Thomas P Parkinson-Lawrence E Porteous ME Warner JP Sanderson T Pearson P Simensen RJ Skinner C Hoganson G Superneau D Wooster R Bobrow M 《Nature genetics》2007,39(9):1127-1133
194.
New models of collaboration in genome-wide association studies: the Genetic Association Information Network 总被引:7,自引:0,他引:7
GAIN Collaborative Research Group Manolio TA Rodriguez LL Brooks L Abecasis G;Collaborative Association Study of Psoriasis Ballinger D Daly M Donnelly P Faraone SV;International Multi-Center ADHD Genetics Project Frazer K Gabriel S Gejman P;Molecular Genetics of Schizophrenia Collaboration Guttmacher A Harris EL Insel T Kelsoe JR;Bipolar Genome Study Lander E McCowin N Mailman MD Nabel E Ostell J Pugh E Sherry S 《Nature genetics》2007,39(9):1045-1051
The Genetic Association Information Network (GAIN) is a public-private partnership established to investigate the genetic basis of common diseases through a series of collaborative genome-wide association studies. GAIN has used new approaches for project selection, data deposition and distribution, collaborative analysis, publication and protection from premature intellectual property claims. These demonstrate a new commitment to shared scientific knowledge that should facilitate rapid advances in understanding the genetics of complex diseases. 相似文献
195.
Meilang Xue Nikita Minhas Shu-Oi Chow Suat Dervish Philip N. Sambrook Lyn March Christopher J. Jackson 《Cellular and molecular life sciences : CMLS》2010,67(9):1537-1546
Circulating protein C (PC) plays a vital role as an anti-coagulant and anti-inflammatory mediator. We show here that human endothelial cells produce PC that acts through novel mediators to enhance their own functional integrity. When endogenous PC or its receptor, endothelial protein C receptor (EPCR), was suppressed by small interfering (si) RNA, human umbilical cord endothelial cell (HUVEC) proliferation was decreased and apoptosis elevated. Interestingly, PC or EPCR siRNA significantly increased HUVEC permeability, which is likely via reduction of the angiopoietin (Ang)1/Ang2 ratio and inhibition of the peripheral localization of the tight junction protein, zona occludins-1. In addition, PC or EPCR siRNA inhibited type IV collagen and matrix metalloproteinase-2, providing the first evidence that PC contributes to vascular basement membrane formation. These newly described actions of endogenous PC act to stabilize endothelial cells and enhance barrier function, to potentially promote the functional integrity of blood vessels. 相似文献
196.
Heid IM Jackson AU Randall JC Winkler TW Qi L Steinthorsdottir V Thorleifsson G Zillikens MC Speliotes EK Mägi R Workalemahu T White CC Bouatia-Naji N Harris TB Berndt SI Ingelsson E Willer CJ Weedon MN Luan J Vedantam S Esko T Kilpeläinen TO Kutalik Z Li S Monda KL Dixon AL Holmes CC Kaplan LM Liang L Min JL Moffatt MF Molony C Nicholson G Schadt EE Zondervan KT Feitosa MF Ferreira T Lango Allen H Weyant RJ Wheeler E Wood AR;MAGIC Estrada K Goddard ME Lettre G Mangino M Nyholt DR Purcell S 《Nature genetics》2010,42(11):949-960
Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10?? to P = 1.8 × 10???) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10?3 to P = 1.2 × 10?13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions. 相似文献
197.
The developmental transcriptome of Drosophila melanogaster 总被引:2,自引:0,他引:2
Graveley BR Brooks AN Carlson JW Duff MO Landolin JM Yang L Artieri CG van Baren MJ Boley N Booth BW Brown JB Cherbas L Davis CA Dobin A Li R Lin W Malone JH Mattiuzzo NR Miller D Sturgill D Tuch BB Zaleski C Zhang D Blanchette M Dudoit S Eads B Green RE Hammonds A Jiang L Kapranov P Langton L Perrimon N Sandler JE Wan KH Willingham A Zhang Y Zou Y Andrews J Bickel PJ Brenner SE Brent MR Cherbas P Gingeras TR Hoskins RA Kaufman TC Oliver B Celniker SE 《Nature》2011,471(7339):473-479
198.
The blackbrush vegetation type is dominated by Coleogyne ramossisima , which is thought to preclude the coexistence of many other plant species. Fire can remove blackbrush cover and possibly increase plant species richness and evenness. Fire also may increase the frequency and cover of alien annual grasses, thereby intensifying landscape flammability. We tested these predictions in unburned and burned (6-14 years postfire) blackbrush at 3 sites spanning the range of this vegetation type in the Mojave Desert. Species richness in unburned blackbrush was similar to published values for vegetation types in western North America, bur richness varied significantly among the 3 sites and 4 spatial scales (1, 10, 100, and 1000 m 2 ). Richness values declined in order from annual forbs, woody perennials, herbaceous perennials, annual grasses, cacti, to perennial grasses. Fire reduced Coleogyne cover, thus boosting species evenness. In contrast, species richness decreased after burning, although the results varied among spatial scales. Total cover was unaffected by fire because cover of wood perennials decreased, while cover of annual forbs, annual grasses, herbaceous perennials, and perennial grasses increased. Native species richness and cover decreased, whereas alien richness and cover increased after burning especially where the alien forb Erodium cicutarium was present. Fire had no effect on frequency and variable effects on cover of alien annual grasses. These results indicate that in blackbrush species richness can vary among sites and local spatial scales, and effects of fires can vary among plant life-forms and between natives and aliens. 相似文献
199.
200.
I J Jackson 《Nature genetics》2001,28(3):198-200
Large-scale mutagenesis of the mouse genome is an essential task associated with the Human Genome Project. The two opposing schools of direct and reverse genetics have demonstrated comparable advantages, and yet large numbers of mutant lines have mostly been the prerogative of direct genetics. An improved gene-trapping resource now brings reverse genetics one step closer. 相似文献