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311.
Enucleated oocytes have the distinctive ability to reprogram somatic nuclei back to totipotency. Here, we investigate genome-scale DNA methylation patterns after nuclear transfer and compare them to the dynamics at fertilization. We identify specific targets for DNA demethylation after nuclear transfer, such as germline-associated promoters, as well as unique limitations that include certain repetitive element classes. 相似文献
312.
Zhang Z Lee JC Lin L Olivas V Au V LaFramboise T Abdel-Rahman M Wang X Levine AD Rho JK Choi YJ Choi CM Kim SW Jang SJ Park YS Kim WS Lee DH Lee JS Miller VA Arcila M Ladanyi M Moonsamy P Sawyers C Boggon TJ Ma PC Costa C Taron M Rosell R Halmos B Bivona TG 《Nature genetics》2012,44(8):852-860
Human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer. 相似文献
313.
RK Koenekoop H Wang J Majewski X Wang I Lopez H Ren Y Chen Y Li GA Fishman M Genead J Schwartzentruber N Solanki EI Traboulsi J Cheng CV Logan M McKibbin BE Hayward DA Parry CA Johnson M Nageeb;Finding of Rare Disease Genes 《Nature genetics》2012,44(9):1035-1039
Leber congenital amaurosis (LCA) is a blinding retinal disease that presents within the first year after birth. Using exome sequencing, we identified mutations in the nicotinamide adenine dinucleotide (NAD) synthase gene NMNAT1 encoding nicotinamide mononucleotide adenylyltransferase 1 in eight families with LCA, including the family in which LCA was originally linked to the LCA9 locus. Notably, all individuals with NMNAT1 mutations also have macular colobomas, which are severe degenerative entities of the central retina (fovea) devoid of tissue and photoreceptors. Functional assays of the proteins encoded by the mutant alleles identified in our study showed that the mutations reduce the enzymatic activity of NMNAT1 in NAD biosynthesis and affect protein folding. Of note, recent characterization of the slow Wallerian degeneration (Wld(s)) mouse model, in which prolonged axonal survival after injury is observed, identified NMNAT1 as a neuroprotective protein when ectopically expressed. Our findings identify a new disease mechanism underlying LCA and provide the first link between endogenous NMNAT1 dysfunction and a human nervous system disorder. 相似文献
314.
Maize HapMap2 identifies extant variation from a genome in flux 总被引:3,自引:0,他引:3
Chia JM Song C Bradbury PJ Costich D de Leon N Doebley J Elshire RJ Gaut B Geller L Glaubitz JC Gore M Guill KE Holland J Hufford MB Lai J Li M Liu X Lu Y McCombie R Nelson R Poland J Prasanna BM Pyhäjärvi T Rong T Sekhon RS Sun Q Tenaillon MI Tian F Wang J Xu X Zhang Z Kaeppler SM Ross-Ibarra J McMullen MD Buckler ES Zhang G Xu Y Ware D 《Nature genetics》2012,44(7):803-807
Whereas breeders have exploited diversity in maize for yield improvements, there has been limited progress in using beneficial alleles in undomesticated varieties. Characterizing standing variation in this complex genome has been challenging, with only a small fraction of it described to date. Using a population genetics scoring model, we identified 55 million SNPs in 103 lines across pre-domestication and domesticated Zea mays varieties, including a representative from the sister genus Tripsacum. We find that structural variations are pervasive in the Z. mays genome and are enriched at loci associated with important traits. By investigating the drivers of genome size variation, we find that the larger Tripsacum genome can be explained by transposable element abundance rather than an allopolyploid origin. In contrast, intraspecies genome size variation seems to be controlled by chromosomal knob content. There is tremendous overlap in key gene content in maize and Tripsacum, suggesting that adaptations from Tripsacum (for example, perennialism and frost and drought tolerance) can likely be integrated into maize. 相似文献
315.
Elia J Glessner JT Wang K Takahashi N Shtir CJ Hadley D Sleiman PM Zhang H Kim CE Robison R Lyon GJ Flory JH Bradfield JP Imielinski M Hou C Frackelton EC Chiavacci RM Sakurai T Rabin C Middleton FA Thomas KA Garris M Mentch F Freitag CM Steinhausen HC Todorov AA Reif A Rothenberger A Franke B Mick EO Roeyers H Buitelaar J Lesch KP Banaschewski T Ebstein RP Mulas F Oades RD Sergeant J Sonuga-Barke E Renner TJ Romanos M Romanos J Warnke A Walitza S Meyer J Pálmason H Seitz C Loo SK Smalley SL 《Nature genetics》2012,44(1):78-84
Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ~10% of the cases (P = 4.38 × 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts. 相似文献
316.
A new study reports comparative genomic analysis of 52 geographically diverse strains of Chlamydia trachomatis. The authors reconstruct a genome-wide phylogeny of the species and report extensive genome-wide recombination across multiple lineages of this intracellular bacterial pathogen. 相似文献
317.
Gauthier LR Granotier C Hoffschir F Etienne O Ayouaz A Desmaze C Mailliet P Biard DS Boussin FD 《Cellular and molecular life sciences : CMLS》2012,69(4):629-640
Functional telomeres are protected from non-homologous end-joining (NHEJ) and homologous recombination (HR) DNA repair pathways.
Replication is a critical period for telomeres because of the requirement for reconstitution of functional protected telomere
conformations, a process that involves DNA repair proteins. Using knockdown of DNA-PKcs and Rad51 expression in three different
cell lines, we demonstrate the respective involvement of NHEJ and HR in the formation of telomere aberrations induced by the
G-quadruplex ligand 360A during or after replication. HR contributed to specific chromatid-type aberrations (telomere losses
and doublets) affecting the lagging strand telomeres, whereas DNA-PKcs-dependent NHEJ was responsible for sister telomere
fusions as a direct consequence of G-quadruplex formation and/or stabilization induced by 360A on parental telomere G strands.
NHEJ and HR activation at telomeres altered mitotic progression in treated cells. In particular, NHEJ-mediated sister telomere
fusions were associated with altered metaphase-anaphase transition and anaphase bridges and resulted in cell death during
mitosis or early G1. Collectively, these data elucidate specific molecular and cellular mechanisms triggered by telomere targeting
by the G-quadruplex ligand 360A, leading to cancer cell death. 相似文献
318.
We observed a breeding Bald Eagle ( Haliaeetus leucocephalus ) pair nesting in a short-grass prairie and agricultural community on the southern Great Plains of the Texas Panhandle in 2004 and 2005. The nesting eagles produced 1 fledgling in 2004 and 2 fledglings in 2005. Our assessment of landcover types within a 5-km radius of the nest indicated that grasslands accounted for most of the area (90%), followed by agricultural lands (8%). Black-tailed prairie dog ( Cynomys ludovicianus ) colonies occupied 2.5% of the area, and single human residences with associated structures (i.e., barns) occupied 2.5 ha in surface area was 51 km from the nest. An analysis of regurgitated castings collected near the nest revealed a mammalian-dominated, breeding-season diet with black-tailed prairie dogs occurring in 80.9% of the castings. Other identified prey included cottontails ( Sylvilagus spp., 15.9%), black-tailed jackrabbits ( Lepus californicus , 3.2%), pronghorn ( Antilocapra americana , 3.2%), and plains pocket gopher ( Geomys bursarius , 1.6%). Bird remains were also present in 34.9% of the castings. This is the first reported successful nesting of Bald Eagles in the panhandle region of Texas since 1916; the nest is particularly unique because of its distance from any substantial body of water. 相似文献
319.
Normal 0 false false false EN-US X-NONE X-NONE MicrosoftInternetExplorer4 st1\:*{behavior:url(#ieooui) } /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} A rodenticide, zinc phosphide, was applied to remove black-tailed prairie dogs ( Cynomys ludovicianus ) from 6 ha of a prairie dog colony in southwestern South Dakota. Another adjacent 6 ha was left untreated. The removal experiment was repeated two consecutive years. Contingency table analysis showed that the resultant population was not homogeneous; age classes by sex of the immigrant and resident subpopulations were different (P 相似文献
320.
Normal 0 false false false EN-US X-NONE X-NONE MicrosoftInternetExplorer4 st1\:*{behavior:url(#ieooui) } /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} A range extension of the pygmy rabbit, Brachylagus idahoensis, into the Colorado River basin and a hypothesis as to its route of emigration. 相似文献