BACKGROUND Determining the factors involved in the likelihood of a gene being under adaptive selection is still a challenging goal in Evolutionary Biology. Here, we perform an evolutionary analysis of the human metabolic genes to explore the associations between network structure and the presence and strength of natural selection in the genes whose products are involved in metabolism. Purifying and positive selection are estimated at interspecific (among mammals) and intraspecific (among human populations) levels, and the connections between enzymatic reactions are differentiated between incoming (in-degree) and outgoing (out-degree) links. RESULTS We confirm that purifying selection has been stronger in highly connected genes. Long-term positive selection has targeted poorly connected enzymes, whereas short-term positive selection has targeted different enzymes depending on whether the selective sweep has reached fixation in the population: genes under a complete selective sweep are poorly connected, whereas those under an incomplete selective sweep have high out-degree connectivity. The last steps of pathways are more conserved due to stronger purifying selection, with long-term positive selection targeting preferentially enzymes that catalyze the first steps. However, short-term positive selection has targeted enzymes that catalyze the last steps in the metabolic network. Strong signals of positive selection have been found for metabolic processes involved in lipid transport and membrane fluidity and permeability. CONCLUSIONS Our analysis highlights the importance of analyzing the same biological system at different evolutionary timescales to understand the evolution of metabolic genes and of distinguishing between incoming and outgoing links in a metabolic network. Short-term positive selection has targeted enzymes with a different connectivity profile depending on the completeness of the selective sweep, while long-term positive selection has targeted genes with fewer connections that code for enzymes that catalyze the first steps in the network. REVIEWERS This article was reviewed by Diamantis Sellis and Brandon Invergo.

中文翻译：

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人类代谢网络中的基因连通性和酶进化。

背景技术确定基因处于适应选择之下的可能性的因素仍然是进化生物学中的挑战性目标。在这里，我们进行人类代谢基因的进化分析，以探索网络结构与产物参与代谢的基因中自然选择的存在和强度之间的关联。在种间（在哺乳动物之间）和种内（在人群之间）水平上估计纯化和阳性选择，并且酶反应之间的联系在传入（进度）和传出（出度）之间有所区别。结果我们证实，在高度连接的基因中，纯化选择更强。长期的积极选择针对的是连接不良的酶，短期正向选择针对不同的酶，这取决于选择性扫描是否已在种群中达到固定：完全选择性扫描下的基因连接不良，而不完全选择性扫描下的基因具有较高的连通度。由于更强的纯化选择，途径的最后一步更加保守，长期的阳性选择优先针对催化第一步的酶。但是，短期的积极选择已针对了催化代谢网络中最后一步的酶。对于涉及脂质转运以及膜流动性和渗透性的代谢过程，已经发现强烈的正选择信号。结论我们的分析强调了在不同的进化时间尺度上分析同一生物系统以了解代谢基因的进化以及区分代谢网络中传入和传出链接的重要性。短期正向选择的目标酶具有不同的连通性，取决于选择性扫描的完整性，而长期正向选择的目标基因具有较少的连接性，这些基因编码的酶催化网络中的第一步。审阅者本文由Diamantis Sellis和Brandon Invergo审阅。短期正向选择的目标酶具有不同的连通性，取决于选择性扫描的完整性，而长期正向选择的目标基因具有较少的连接性，这些基因编码的酶催化网络中的第一步。审阅者本文由Diamantis Sellis和Brandon Invergo审阅。短期正向选择的目标酶具有不同的连通性，取决于选择性扫描的完整性，而长期正向选择的目标基因具有较少的连接性，这些基因编码的酶催化网络中的第一步。审阅者本文由Diamantis Sellis和Brandon Invergo审阅。