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Mills RE Walter K Stewart C Handsaker RE Chen K Alkan C Abyzov A Yoon SC Ye K Cheetham RK Chinwalla A Conrad DF Fu Y Grubert F Hajirasouliha I Hormozdiari F Iakoucheva LM Iqbal Z Kang S Kidd JM Konkel MK Korn J Khurana E Kural D Lam HY Leng J Li R Li Y Lin CY Luo R Mu XJ Nemesh J Peckham HE Rausch T Scally A Shi X Stromberg MP Stütz AM Urban AE Walker JA Wu J Zhang Y Zhang ZD Batzer MA Ding L Marth GT McVean G Sebat J Snyder M Wang J Ye K Eichler EE Gerstein MB Hurles ME Lee C McCarroll SA 《Nature》2011,470(7332):59-65
Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies. 相似文献
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Ghoreschi K Laurence A Yang XP Tato CM McGeachy MJ Konkel JE Ramos HL Wei L Davidson TS Bouladoux N Grainger JR Chen Q Kanno Y Watford WT Sun HW Eberl G Shevach EM Belkaid Y Cua DJ Chen W O'Shea JJ 《Nature》2010,467(7318):967-971
CD4(+) T-helper cells that selectively produce interleukin (IL)-17 (T(H)17), are critical for host defence and autoimmunity. Although crucial for T(H)17 cells in vivo, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been proposed to be the factors responsible for initiating specification. Here we show that T(H)17 differentiation can occur in the absence of TGF-β signalling. Neither IL-6 nor IL-23 alone efficiently generated T(H)17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naive precursors, independently of TGF-β. Epigenetic modification of the Il17a, Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed RORγt (encoded by Rorc) and T-bet. T-bet(+)RORγt(+) T(H)17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred T(H)17 cells generated with IL-23 without TGF-β1 were pathogenic in this disease model. These data indicate an alternative mode for T(H)17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore may have therapeutic implications. 相似文献
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