High regulatability favors genetic selection in SLC18A2, a vesicular monoamine transporter essential for life
High regulatability favors genetic selection in SLC18A2, a vesicular monoamine transporter essential for life
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DOI：
10.1096/fj.09-140368
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发表时间：
2010-07-01
期刊：
影响因子：
4.8
通讯作者：
Isacson, Ole
中科院分区：
文献类型：
--
作者：
Lin, Zhicheng;Zhao, Ying;Isacson, Ole
SLC18A2编码囊泡单胺转运体2蛋白，该蛋白调节神经传递并降低单胺的胞浆毒性。该基因的缺失会导致小鼠死亡，该基因的DNA序列变异与酒精中毒和帕金森氏症等疾病有关。高加索人SLC18A2启动子至少有20个单倍型(A-T)，其中A代表1460条染色体的三分之二。目前尚不清楚为什么A会被选入人类谱系。为了理解选择，我们采取了功能的方法，调查了17个代理人对4种有代表性的单倍型(A、C、G和T)的调节。我们发现，76.5%的药物能够调控A，但只有11.8%-23.5%的药物能够调控其他3种不常见的药物，观察到单倍型频率与可调性呈正相关。途径和分子分析揭示了五个信号枢纽，它们可能通过靶向多态的核心启动子区域，对四种单倍型进行不同的调控。这些发现表明，转录调控的更大多样性是SLC18A2单倍型选择的驱动力。-Lin，Z.，赵，Y.，Chung，Cy，周，Y.，熊，N，Glatt，C.E.，Isacson，O。高度的可调性有利于SLC18A2的遗传选择，SLC18A2是一种对生命至关重要的囊泡单胺转运蛋白。FASE B J.24,2191-2200(2010)。Www.fasebj.org
SLC18A2 encodes the vesicular monoamine transporter 2 protein that regulates neurotransmission and reduces cytosolic toxicity of monoamines. Deletion of this gene causes lethality in mice, and DNA sequence variation in this gene is associated with alcoholism and Parkinson's disease, among other disorders. The Caucasian SLC18A2 promoter has at least 20 haplotypes (A-T), with A representing two-thirds of 1460 chromosomes. It is not known why A is selected in the human lineage. To understand the selection, here we took a functional approach by investigating the regulations of 4 representative haplotypes (A, C, G, and T) by 17 agents. We show that 76.5% of the agents were able to regulate A but only 11.8-23.5% of them regulated the 3 other infrequent ones, observing a positive correlation between haplotype frequency and regulatability. Pathway and molecular analyses revealed five signaling hubs that regulate the four haplotypes differentially, probably through targeting the polymorphic core promoter region. These findings suggest that greater diversity of transcriptional regulations is the driving force for the haplotype selection in SLC18A2.-Lin, Z., Zhao, Y., Chung, C. Y., Zhou, Y., Xiong, N., Glatt, C. E., Isacson, O. High regulatability favors genetic selection in SLC18A2, a vesicular monoamine transporter essential for life. FASEB J. 24, 2191-2200 (2010). www.fasebj.org