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121.
MJ Emond T Louie J Emerson W Zhao RA Mathias MR Knowles FA Wright MJ Rieder HK Tabor DA Nickerson KC Barnes;National Heart Lung Blood Institute 《Nature genetics》2012,44(8):886-889
Exome sequencing has become a powerful and effective strategy for the discovery of genes underlying Mendelian disorders. However, use of exome sequencing to identify variants associated with complex traits has been more challenging, partly because the sample sizes needed for adequate power may be very large. One strategy to increase efficiency is to sequence individuals who are at both ends of a phenotype distribution (those with extreme phenotypes). Because the frequency of alleles that contribute to the trait are enriched in one or both phenotype extremes, a modest sample size can potentially be used to identify novel candidate genes and/or alleles. As part of the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP), we used an extreme phenotype study design to discover that variants in DCTN4, encoding a dynactin protein, are associated with time to first P. aeruginosa airway infection, chronic P. aeruginosa infection and mucoid P. aeruginosa in individuals with cystic fibrosis. 相似文献
122.
Autism Genome Project Consortium Szatmari P Paterson AD Zwaigenbaum L Roberts W Brian J Liu XQ Vincent JB Skaug JL Thompson AP Senman L Feuk L Qian C Bryson SE Jones MB Marshall CR Scherer SW Vieland VJ Bartlett C Mangin LV Goedken R Segre A Pericak-Vance MA Cuccaro ML Gilbert JR Wright HH Abramson RK Betancur C Bourgeron T Gillberg C Leboyer M Buxbaum JD Davis KL Hollander E Silverman JM Hallmayer J Lotspeich L Sutcliffe JS Haines JL Folstein SE Piven J Wassink TH Sheffield V Geschwind DH 《Nature genetics》2007,39(3):319-328
Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs. 相似文献
123.
Sotoodehnia N Isaacs A de Bakker PI Dörr M Newton-Cheh C Nolte IM van der Harst P Müller M Eijgelsheim M Alonso A Hicks AA Padmanabhan S Hayward C Smith AV Polasek O Giovannone S Fu J Magnani JW Marciante KD Pfeufer A Gharib SA Teumer A Li M Bis JC Rivadeneira F Aspelund T Köttgen A Johnson T Rice K Sie MP Wang YA Klopp N Fuchsberger C Wild SH Mateo Leach I Estrada K Völker U Wright AF Asselbergs FW Qu J Chakravarti A Sinner MF Kors JA Petersmann A Harris TB Soliman EZ Munroe PB Psaty BM 《Nature genetics》2010,42(12):1068-1076
124.
Ngo VN Young RM Schmitz R Jhavar S Xiao W Lim KH Kohlhammer H Xu W Yang Y Zhao H Shaffer AL Romesser P Wright G Powell J Rosenwald A Muller-Hermelink HK Ott G Gascoyne RD Connors JM Rimsza LM Campo E Jaffe ES Delabie J Smeland EB Fisher RI Braziel RM Tubbs RR Cook JR Weisenburger DD Chan WC Staudt LM 《Nature》2011,470(7332):115-119
The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) remains the least curable form of this malignancy despite recent advances in therapy. Constitutive nuclear factor (NF)-κB and JAK kinase signalling promotes malignant cell survival in these lymphomas, but the genetic basis for this signalling is incompletely understood. Here we describe the dependence of ABC DLBCLs on MYD88, an adaptor protein that mediates toll and interleukin (IL)-1 receptor signalling, and the discovery of highly recurrent oncogenic mutations affecting MYD88 in ABC DLBCL tumours. RNA interference screening revealed that MYD88 and the associated kinases IRAK1 and IRAK4 are essential for ABC DLBCL survival. High-throughput RNA resequencing uncovered MYD88 mutations in ABC DLBCL lines. Notably, 29% of ABC DLBCL tumours harboured the same amino acid substitution, L265P, in the MYD88 Toll/IL-1 receptor (TIR) domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in other DLBCL subtypes and Burkitt's lymphoma, but was observed in 9% of mucosa-associated lymphoid tissue lymphomas. At a lower frequency, additional mutations were observed in the MYD88 TIR domain, occurring in both the ABC and germinal centre B-cell-like (GCB) DLBCL subtypes. Survival of ABC DLBCL cells bearing the L265P mutation was sustained by the mutant but not the wild-type MYD88 isoform, demonstrating that L265P is a gain-of-function driver mutation. The L265P mutant promoted cell survival by spontaneously assembling a protein complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-κB signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-β. Hence, the MYD88 signalling pathway is integral to the pathogenesis of ABC DLBCL, supporting the development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MYD88 mutations. 相似文献
125.
126.
Summary Allozyme electrophoresis was used to determine the hybrid parentage of the triploid parthenogenetic speciesCnemidophorus exsanguis. 19 of 33 loci were polymorphic inC. exsanguis and/or the 7 potential bisexual progenitors. It was determined from allele distributions thatC. exsanguis containes genomes form 3 different species, probablyC. costatus, C. inornatus andC. septemvittatus.Acknowledgments. We thank R.L. Bezy, W.M. Brown, A.E. Greer, C.S. Lieb, J.L. Patton and K.L. Wright for assistance in the field; the Departments of Game and Fish of Arizona and New Mexico and the Direccion General de la Fauna Silvestre, Mexico for providing collecting permits; and R.L. Bezy, H.W. Greene and D.B. Wake for discussions and criticisms. This research was supported in part by NSF Grants DEB 76-20599 and DEB 81-05615 and by a Research Fellowship in Herpetology from the Natural History Museum of Los Angeles County to DAG. 相似文献
127.
128.
Urogastrone-epidermal growth factor is trophic to the intestinal epithelium of parenterally fed rats 总被引:4,自引:0,他引:4
R A Goodlad T J Wilson W Lenton H Gregory K G McCullough N A Wright 《Experientia》1985,41(9):1161-1163
The weight of the stomach, small intestine and colon and the mucosal crypt cell production rate of these tissues were significantly decreased after 10 days on an isocaloric TPN diet when compared to orally fed controls. Continuous infusion of recombinant beta urogastrone, at a dose below that needed to inhibit gastric acid secretion, largely prevented this decrease in crypt cell production rate and gastrointestinal tissue weights. 相似文献
129.
Transmission of chromosomal instability after plutonium alpha-particle irradiation. 总被引:15,自引:0,他引:15
M A Kadhim D A Macdonald D T Goodhead S A Lorimore S J Marsden E G Wright 《Nature》1992,355(6362):738-740
When investigating the biological effects of ionizing radiation on the haemopoietic system, a confounding problem lies in possible differences between the biological effects of sparsely ionizing, low linear energy transfer radiation such as X-, beta- or gamma-rays, and densely ionizing, high linear energy transfer radiation such as alpha-particles. To address this problem we have developed novel techniques for studying haemopoietic cells irradiated with environmentally relevant doses of alpha-particles from a plutonium-238 source. Using a clonogenic culture system, cytogenetic aberrations in individual colonies of haemopoietic cells derived from irradiated stem cells have been studied. Exposure to alpha-particles (but not X-rays) produced a high frequency of non-clonal aberrations in the clonal descendants, compatible with alpha-emitters inducing lesions in stem cells that result in the transmission of chromosomal instability to their progeny. Such unexpected instability may have important implications for radiation leukaemogenesis. 相似文献
130.
Zusammenfassung Es wurde mit Hilfe der Papier- und Dünnschichtchromatographie und der Isotopen-Verdünnungstechnik des C14-markierten Materials gezeigt, dass diein vivo-Hydroxylierung von Carbazol sowohl im Ratten- als auch im Kaninchenorganismus am Ort der höchsten Elektronenstauung stattfindet und zur Bildung von 3-Hydroxycarbazol führt.
This work was supported by a Burroughs Wellcome (Aust.) Research Fellowship (S.R.J.). 相似文献
This work was supported by a Burroughs Wellcome (Aust.) Research Fellowship (S.R.J.). 相似文献