2R and remodeling of vertebrate signal transduction engine.
2R and remodeling of vertebrate signal transduction engine.
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2R和脊椎动物信号转导引擎的重塑。
DOI：
10.1186/1741-7007-8-146
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发表时间：
2010-12-13
期刊：
影响因子：
5.4
通讯作者：
Heldin CH
中科院分区：
文献类型：
--
作者：
Huminiecki L;Heldin CH
全基因组复制(WGD)是基因复制的一种特殊情况，在动物中很少观察到，即所有基因通过多倍化同时复制。两轮WGD(2R-WGD)发生在脊椎动物的底部，引发了一波巨大的遗传新奇浪潮，但对这一事件的功能后果尚未进行系统分析。我们发现，2R-WGD影响绝大多数(74%)信号基因，特别是涉及受体酪氨酸激酶、Wnt和转化生长因子-β配体、G蛋白偶联受体和细胞凋亡途径的发育途径。与串联复制相比，保留2R的基因在RAS和丝裂原活化蛋白激酶级联的蛋白相互作用结构域和多功能信号模块中得到了丰富。2R-WGD对细胞周期机制产生了根本性的影响，重新定义了神经元突触的分子构建块，并对脊椎动物的大脑形成了影响。我们在人类信令网络以及推断的祖先前2R(AP2R)网络中研究了2R相关节点，发现枢纽(特别是涉及负调控)被优先保留，高连接性驱动保持。最后，微阵列和蛋白质组学显示出一种与复制机制无关的逐渐平行对数表达差异的趋势，但推测祖先表达状态表明2R-Ohnologs(2RO)之间有优先的亚功能化。2R事件在脊椎动物的信号传递和细胞周期上留下了不可磨灭的印记。我们发现2R-WGD优先保留的基因与较高的组织复杂性(例如运动、神经系统、形态发生)有关，而与基本细胞功能(例如翻译、复制、剪接、重组；细胞周期显著例外)相关的基因往往被排除在外。2R-WGD为脊椎动物的关键功能创新(如复杂的大脑、循环系统、心脏、骨骼、软骨、肌肉和脂肪组织)的出现奠定了基础。完全解释2R对脊椎动物信号网络中的进化、功能和信息流的影响，可能会对再生医学、干细胞疗法和癌症治疗产生实际影响。
Whole genome duplication (WGD) is a special case of gene duplication, observed rarely in animals, whereby all genes duplicate simultaneously through polyploidisation. Two rounds of WGD (2R-WGD) occurred at the base of vertebrates, giving rise to an enormous wave of genetic novelty, but a systematic analysis of functional consequences of this event has not yet been performed. We show that 2R-WGD affected an overwhelming majority (74%) of signalling genes, in particular developmental pathways involving receptor tyrosine kinases, Wnt and transforming growth factor-β ligands, G protein-coupled receptors and the apoptosis pathway. 2R-retained genes, in contrast to tandem duplicates, were enriched in protein interaction domains and multifunctional signalling modules of Ras and mitogen-activated protein kinase cascades. 2R-WGD had a fundamental impact on the cell-cycle machinery, redefined molecular building blocks of the neuronal synapse, and was formative for vertebrate brains. We investigated 2R-associated nodes in the context of the human signalling network, as well as in an inferred ancestral pre-2R (AP2R) network, and found that hubs (particularly involving negative regulation) were preferentially retained, with high connectivity driving retention. Finally, microarrays and proteomics demonstrated a trend for gradual paralog expression divergence independent of the duplication mechanism, but inferred ancestral expression states suggested preferential subfunctionalisation among 2R-ohnologs (2ROs). The 2R event left an indelible imprint on vertebrate signalling and the cell cycle. We show that 2R-WGD preferentially retained genes are associated with higher organismal complexity (for example, locomotion, nervous system, morphogenesis), while genes associated with basic cellular functions (for example, translation, replication, splicing, recombination; with the notable exception of cell cycle) tended to be excluded. 2R-WGD set the stage for the emergence of key vertebrate functional novelties (such as complex brains, circulatory system, heart, bone, cartilage, musculature and adipose tissue). A full explanation of the impact of 2R on evolution, function and the flow of information in vertebrate signalling networks is likely to have practical consequences for regenerative medicine, stem cell therapies and cancer treatment.
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影响因子：
4.4
作者：
Huminiecki L;Lloyd AT;Wolfe KH
通讯作者：
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