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基因组分析和渐进性的演化改变

2011-08-18
形态演化,卵巢腺癌,癌症基因组,Cancer Genome Atlas,ovarian carcinoma,Physiology Molecular biology Medical research Cell biology,Evolution Genetics and genomics Developmental biology Molecular biology
基因组分析和渐进性的演化改变



Integrated genomic analyses of ovarian carcinoma
The Cancer Genome Atlas Research Network
Affiliations Contributions Corresponding authors Journal name:
Nature Volume: 474, Pages: 609–615
Date published: (30 June 2011)
DOI: doi:10.1038/nature10166
Received 07 September 2010 Accepted 27 April 2011 Published online 29 June 2011
Abstract
Abstract Author information Supplementary information Comments Article tools
Share/bookmarkConnotea Cite U Like Facebook Twitter Delicious Digg A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients’ lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.

Top of page卵巢腺癌的全面分析
Nature 474 (30 Jun 2011)

“癌症基因组图集” (TCGA)项目组在本期Nature上报告了其对489种高等级“浆液性卵巢腺癌”中的mRNA 和 miRNA表达、启动子甲基化、DNA版本数和“外显子组”序列所做的分析。这些分析结果可帮助确定新的肿瘤亚型。该项目组的发现之一是,虽然p53肿瘤抑制因子在几乎所有肿瘤中都发生了突变,但包括NF1、BRCA1、BRCA2、 RB1和 CDK12在内的其他9个位点也携带复发性的、尽管流行度较低的突变。同源重组在约一半的这些肿瘤中是有缺陷的,Notch 和 FOXM1信号作用也牵涉到了病理生理过程中。

MicroRNAs 103 and 107 regulate insulin sensitivity
Mirko Trajkovski,1, 2 Jean Hausser,2, 3 Jürgen Soutschek,4 Bal Bhat,4 Akinc Akin,5 Mihaela Zavolan,3 Markus H. Heim2, 6 & Markus Stoffel1, 2
Affiliations Contributions Corresponding author Journal name:
Nature Volume: 474, Pages: 649–653
Date published: (30 June 2011)
DOI: doi:10.1038/nature10112
Received 22 March 2010 Accepted 13 April 2011 Published online 08 June 2011
Article tools
Share/bookmarkConnotea Cite U Like Facebook Twitter Delicious Digg Defects in insulin signalling are among the most common and earliest defects that predispose an individual to the development of type 2 diabetes1, 2, 3. MicroRNAs have been identified as a new class of regulatory molecules that influence many biological functions, including metabolism4, 5. However, the direct regulation of insulin sensitivity by microRNAs in vivo has not been demonstrated. Here we show that the expression of microRNAs 103 and 107 (miR-103/107) is upregulated in obese mice. Silencing of miR-103/107 leads to improved glucose homeostasis and insulin sensitivity. In contrast, gain of miR-103/107 function in either liver or fat is sufficient to induce impaired glucose homeostasis. We identify caveolin-1, a critical regulator of the insulin receptor, as a direct target gene of miR-103/107. We demonstrate that caveolin-1 is upregulated upon miR-103/107 inactivation in adipocytes and that this is concomitant with stabilization of the insulin receptor, enhanced insulin signalling, decreased adipocyte size and enhanced insulin-stimulated glucose uptake. These findings demonstrate the central importance of miR-103/107 to insulin sensitivity and identify a new target for the treatment of type 2 diabetes and obesity.

Subject terms:Physiology Molecular biology Medical research Cell biology
Top of page糖尿病和肥胖症的一个新的治疗目标
Nature 474 (30 Jun 2011)

对两个肥胖症小鼠模型的肝脏所做的一个微RNA(miRNA)微阵列分析表明,miRNA-103 和 miRNA-103 107的表达水平在肥胖症中被提高。使这些miRNA沉默,可以改善葡萄糖体内平衡和提高胰岛素敏感性。激活肝脏或脂肪中的miRNA足以损害葡萄糖体内平衡。Caveolin-1(胰岛素信号作用调控中所涉及的一种蛋白)是miRNA的一个直接目标基因。这些发现表明miR-103/107调控胰岛素敏感性,同时也为2-型糖尿病和肥胖症的治疗识别出一个新的潜在目标。

Morphological evolution caused by many subtle-effect substitutions in regulatory DNA
Nicolás Frankel,1, 4 Deniz F. Erezyilmaz,1, 4 Alistair P. McGregor,2 Shu Wang,1 Fran?ois Payre3 & David L. Stern1
Affiliations Contributions Corresponding author Journal name:
Nature Volume: 474,
Pages: 598–603 Date published: (30 June 2011)
DOI:
doi:10.1038/nature10200
Received 04 February 2011 Accepted 13 May 2011 Published online 29 June 2011
Abstract
Abstract Author information Supplementary information Comments Article tools

Share/bookmarkConnotea Cite U Like Facebook Twitter Delicious Digg Morphology evolves often through changes in developmental genes, but the causal mutations, and their effects, remain largely unknown. The evolution of naked cuticle on larvae of Drosophila sechellia resulted from changes in five transcriptional enhancers of shavenbaby (svb), a transcript of the ovo locus that encodes a transcription factor that governs morphogenesis of microtrichiae, hereafter called ‘trichomes’. Here we show that the function of one of these enhancers evolved through multiple single-nucleotide substitutions that altered both the timing and level of svb expression. The consequences of these nucleotide substitutions on larval morphology were quantified with a novel functional assay. We found that each substitution had a relatively small phenotypic effect, and that many nucleotide changes account for this large morphological difference. In addition, we observed that the substitutions had non-additive effects. These data provide unprecedented resolution of the phenotypic effects of substitutions and show how individual nucleotide changes in a transcriptional enhancer have caused morphological evolution.

Subject terms:Evolution Genetics and genomics Developmental biology Molecular biology

Top of page渐进性的演化改变
Nature 474 (30 Jun 2011)

形态演化经常涉及发育基因的变化,但造成这些演化的突变的数量和效应在很大程度上却仍不知道。Frankel等人利用果蝇的shavenbaby基因作为一个模型系统,来研究这一现象的遗传学。他们发现,shavenbaby基因的5个顺位调控增强子之一所发生的演化变化来自很多核苷酸替代,这些替代既改变了该基因表达的时机,又改变了其水平。因此,这种果蝇要形成一种无毛的幼虫,将需要很多有较小影响的突变(而不是一个有较大影响的突变)。这项工作在单核苷酸替代水平上为达尔文所赞同的关于存在一个渐进性演化过程的观点提供了定量支持。

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本栏目主要介绍基因工程方面,包括人类基因组计划、转基因、基因技术、基因组分析和渐进性的演化改变等。特别关注有关人与文化方面的研究。

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