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51.
Jakobsson M Scholz SW Scheet P Gibbs JR VanLiere JM Fung HC Szpiech ZA Degnan JH Wang K Guerreiro R Bras JM Schymick JC Hernandez DG Traynor BJ Simon-Sanchez J Matarin M Britton A van de Leemput J Rafferty I Bucan M Cann HM Hardy JA Rosenberg NA Singleton AB 《Nature》2008,451(7181):998-1003
Genome-wide patterns of variation across individuals provide a powerful source of data for uncovering the history of migration, range expansion, and adaptation of the human species. However, high-resolution surveys of variation in genotype, haplotype and copy number have generally focused on a small number of population groups. Here we report the analysis of high-quality genotypes at 525,910 single-nucleotide polymorphisms (SNPs) and 396 copy-number-variable loci in a worldwide sample of 29 populations. Analysis of SNP genotypes yields strongly supported fine-scale inferences about population structure. Increasing linkage disequilibrium is observed with increasing geographic distance from Africa, as expected under a serial founder effect for the out-of-Africa spread of human populations. New approaches for haplotype analysis produce inferences about population structure that complement results based on unphased SNPs. Despite a difference from SNPs in the frequency spectrum of the copy-number variants (CNVs) detected--including a comparatively large number of CNVs in previously unexamined populations from Oceania and the Americas--the global distribution of CNVs largely accords with population structure analyses for SNP data sets of similar size. Our results produce new inferences about inter-population variation, support the utility of CNVs in human population-genetic research, and serve as a genomic resource for human-genetic studies in diverse worldwide populations. 相似文献
52.
Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome 总被引:7,自引:0,他引:7
Arts HH Doherty D van Beersum SE Parisi MA Letteboer SJ Gorden NT Peters TA Märker T Voesenek K Kartono A Ozyurek H Farin FM Kroes HY Wolfrum U Brunner HG Cremers FP Glass IA Knoers NV Roepman R 《Nature genetics》2007,39(7):882-888
Protein-protein interaction analyses have uncovered a ciliary and basal body protein network that, when disrupted, can result in nephronophthisis (NPHP), Leber congenital amaurosis, Senior-L?ken syndrome (SLSN) or Joubert syndrome (JBTS). However, details of the molecular mechanisms underlying these disorders remain poorly understood. RPGRIP1-like protein (RPGRIP1L) is a homolog of RPGRIP1 (RPGR-interacting protein 1), a ciliary protein defective in Leber congenital amaurosis. We show that RPGRIP1L interacts with nephrocystin-4 and that mutations in the gene encoding nephrocystin-4 (NPHP4) that are known to cause SLSN disrupt this interaction. RPGRIP1L is ubiquitously expressed, and its protein product localizes to basal bodies. Therefore, we analyzed RPGRIP1L as a candidate gene for JBTS and identified loss-of-function mutations in three families with typical JBTS, including the characteristic mid-hindbrain malformation. This work identifies RPGRIP1L as a gene responsible for JBTS and establishes a central role for cilia and basal bodies in the pathophysiology of this disorder. 相似文献
53.
54.
Chiang C Jacobsen JC Ernst C Hanscom C Heilbut A Blumenthal I Mills RE Kirby A Lindgren AM Rudiger SR McLaughlan CJ Bawden CS Reid SJ Faull RL Snell RG Hall IM Shen Y Ohsumi TK Borowsky ML Daly MJ Lee C Morton CC MacDonald ME Gusella JF Talkowski ME 《Nature genetics》2012,44(4):390-7, S1
We defined the genetic landscape of balanced chromosomal rearrangements at nucleotide resolution by sequencing 141 breakpoints from cytogenetically interpreted translocations and inversions. We confirm that the recently described phenomenon of 'chromothripsis' (massive chromosomal shattering and reorganization) is not unique to cancer cells but also occurs in the germline, where it can resolve to a relatively balanced state with frequent inversions. We detected a high incidence of complex rearrangements (19.2%) and substantially less reliance on microhomology (31%) than previously observed in benign copy-number variants (CNVs). We compared these results to experimentally generated DNA breakage-repair by sequencing seven transgenic animals, revealing extensive rearrangement of the transgene and host genome with similar complexity to human germline alterations. Inversion was the most common rearrangement, suggesting that a combined mechanism involving template switching and non-homologous repair mediates the formation of balanced complex rearrangements that are viable, stably replicated and transmitted unaltered to subsequent generations. 相似文献
55.
Anthropogenic ocean acidification over the twenty-first century and its impact on calcifying organisms 总被引:15,自引:0,他引:15
Orr JC Fabry VJ Aumont O Bopp L Doney SC Feely RA Gnanadesikan A Gruber N Ishida A Joos F Key RM Lindsay K Maier-Reimer E Matear R Monfray P Mouchet A Najjar RG Plattner GK Rodgers KB Sabine CL Sarmiento JL Schlitzer R Slater RD Totterdell IJ Weirig MF Yamanaka Y Yool A 《Nature》2005,437(7059):681-686
Today's surface ocean is saturated with respect to calcium carbonate, but increasing atmospheric carbon dioxide concentrations are reducing ocean pH and carbonate ion concentrations, and thus the level of calcium carbonate saturation. Experimental evidence suggests that if these trends continue, key marine organisms--such as corals and some plankton--will have difficulty maintaining their external calcium carbonate skeletons. Here we use 13 models of the ocean-carbon cycle to assess calcium carbonate saturation under the IS92a 'business-as-usual' scenario for future emissions of anthropogenic carbon dioxide. In our projections, Southern Ocean surface waters will begin to become undersaturated with respect to aragonite, a metastable form of calcium carbonate, by the year 2050. By 2100, this undersaturation could extend throughout the entire Southern Ocean and into the subarctic Pacific Ocean. When live pteropods were exposed to our predicted level of undersaturation during a two-day shipboard experiment, their aragonite shells showed notable dissolution. Our findings indicate that conditions detrimental to high-latitude ecosystems could develop within decades, not centuries as suggested previously. 相似文献
56.
RNAi-mediated gene silencing in non-human primates 总被引:2,自引:0,他引:2
Zimmermann TS Lee AC Akinc A Bramlage B Bumcrot D Fedoruk MN Harborth J Heyes JA Jeffs LB John M Judge AD Lam K McClintock K Nechev LV Palmer LR Racie T Röhl I Seiffert S Shanmugam S Sood V Soutschek J Toudjarska I Wheat AJ Yaworski E Zedalis W Koteliansky V Manoharan M Vornlocher HP MacLachlan I 《Nature》2006,441(7089):111-114
The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg(-1). A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs. 相似文献
57.
伊恩·维尔穆特 《科技导报(北京)》2019,37(2):29-30
从1865年到世界上首个克隆动物--"克隆羊"诞生的100多年间,人类一直在进行相关研究。有一个问题直到现在仍未得到完全的回答--人类来自于一个单一的细胞,但现在还不完全清楚的是,这样一个单个细胞是如何产生胚胎并形成其他器官的。1865年,著名科学家韦斯曼(Weissmann)认为,细胞的分裂是不平均的,这样导致在细胞分裂之后所获得的结果有各自不同的特点。那么,把细胞分离进行移植到底会产生什么样的结果?正是这样一种对换,导致了克隆技术的研发和发展。 相似文献
58.
Alterations in the composition and function of the gut microbiome have been implicated in a range of conditions and diseases. Culture-dependent and culture-independent studies both showed that older people harbour a gut microbiome that differs in composition from that of younger adults. Detailed analyses have identified discrete microbiota subtypes that characterize intermediates between a high diversity microbiota found in healthy community-dwelling subjects and a low diversity microbiota typical for elderly living in long-term residential care. There are also alterations in the microbiome composition associated with biological age, independent of health status. Even after adjusting for confounding factors such as age and medication, trends in microbiota composition correlate with gradients in clinical metadata particularly frailty and inflammatory status. There are few known mechanisms by which these associations might be causative rather than consequential, and this is a subject of intensive research. The strongest candidate effectors are microbial metabolites that could impact host energy balance, act as signalling molecules to modulate host metabolism or inflammation, and potentially also impact on the gut–brain axis. 相似文献
59.
In this paper a high-quality disaggregate database is utilized to examine whether individual forecasters produce efficient exchange rate predictions and also if the properties of the forecasts change when they are combined. The paper links a number of themes in the exchange rate literature and examines various methods of forecast combination. It is demonstrated, inter alia, that some forecasters are better than others, but that most are not as good as a naive no-change prediction. Combining forecasts adds to the accuracy of the predictions, but the gains mainly reflect the removal of systematic and unstable bias. 相似文献
60.