Ludwig Institute for Cancer Research, Uppsala University, Box 595, SE-751 24 Uppsala, Sweden.
BMC Biol. 2010 Dec 13;8:146. doi: 10.1186/1741-7007-8-146.
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.
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，通过多倍体化使所有基因同时复制。两次全基因组复制（2R-WGD）发生在脊椎动物的基础上，产生了大量的遗传新颖性，但这一事件的功能后果尚未进行系统分析。
我们表明，2R-WGD 影响了绝大多数（74%）的信号基因，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。与串联重复基因相比，2R 保留基因在 Ras 和丝裂原激活蛋白激酶级联的蛋白质相互作用结构域和多功能信号模块中富集。2R-WGD 对细胞周期机制产生了根本影响，重新定义了神经元突触的分子构建块，并为脊椎动物大脑的形成奠定了基础。我们在人类信号网络的背景下以及在推断的前 2R（AP2R）网络中研究了与 2R 相关的节点，发现（特别是涉及负调节的）枢纽优先保留，高连接性驱动保留。最后，微阵列和蛋白质组学证明，逐渐的平行表达分化趋势独立于复制机制，但推断的祖先表达状态表明 2R-ohnologs（2ROs）之间存在优先的亚功能化。
2R 事件在脊椎动物信号和细胞周期上留下了不可磨灭的印记。我们表明，2R-WGD 优先保留的基因与更高的生物体复杂性相关（例如，运动、神经系统、形态发生），而与基本细胞功能相关的基因（例如，翻译、复制、剪接、重组；细胞周期除外）则倾向于被排除。2R-WGD 为关键的脊椎动物功能新颖性（如复杂大脑、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。对 2R 对脊椎动物信号网络进化、功能和信息流的影响的全面解释很可能对再生医学、干细胞疗法和癌症治疗具有实际意义。
