Recent Duplication and Functional Divergence in Parasitic Nematode Levamisole-Sensitive Acetylcholine Receptors
Recent Duplication and Functional Divergence in Parasitic Nematode Levamisole-Sensitive Acetylcholine Receptors
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DOI：
10.1371/journal.pntd.0004826
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发表时间：
2016-07-01
影响因子：
3.8
通讯作者：
Beech, Robin N.
中科院分区：
文献类型：
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作者：
Duguet, Thomas B.;Charvet, Claude L.;Beech, Robin N.
蠕虫寄生虫依靠其神经肌肉组织中的快速突触传递来体验外部世界并对其做出反应。乙酰胆碱在其中发挥着关键作用，其受体是用于人类健康和控制的各种天然和合成化合物的目标寄生虫疾病。秀丽隐杆线虫模型的特征在于大量的乙酰胆碱受体亚基基因，这是线虫共有的特征。这个动态家族的特点是物种之间的基因复制和丢失。五聚体左旋咪唑敏感的乙酰胆碱受体已被鉴定为来自C。elegans，由五个不同的亚基组成。最近，同源受体已被重建从多种寄生线虫，发现不同的亚基组成。为了了解受体组成变化的影响和潜在的新型药物靶点的起源，我们研究了一个具体的例子，亚基重复的基础上分析的基因组数据的25种蠕虫基因组计划。我们发现unc29，乙酰胆碱受体亚基，密码子置换率分析确定积极的，定向选择作用于与亚基组装相关的氨基酸位置的多个独立的重复。对转基因捻转血矛线虫（Haemonchuscontortus）的4个基因拷贝的分析表明，每个拷贝都具有独特的功能特征，这是基于转基因C.非洲爪蟾卵母细胞中重组受体的电生理学研究。我们发现的证据表明，一个特定的不相容性已经演变为两个亚基共表达的肌肉。我们证明，乙酰胆碱受体的功能分歧，驱动的定向选择，可以发生更迅速地比以前认为，并可能介导的受体组装的改变。这种现象在进化枝V寄生线虫中很常见，这项工作为理解寄生线虫中改变驱虫药物靶点的更广泛背景提供了基础。
Helminth parasites rely on fast-synaptic transmission in their neuromusculature to experience the outside world and respond to it. Acetylcholine plays a pivotal role in this and its receptors are targeted by a wide variety of both natural and synthetic compounds used in human health and for the control of parasitic disease. The model, Caenorhabditis elegans is characterized by a large number of acetylcholine receptor subunit genes, a feature shared across the nematodes. This dynamic family is characterized by both gene duplication and loss between species. The pentameric levamisole-sensitive acetylcholine receptor has been characterized from C. elegans, comprised of five different subunits. More recently, cognate receptors have been reconstituted from multiple parasitic nematodes that are found to vary in subunit composition. In order to understand the implications of receptor composition change and the origins of potentially novel drug targets, we investigated a specific example of subunit duplication based on analysis of genome data for 25 species from the 50 helminth genome initiative. We found multiple independent duplications of the unc29, acetylcholine receptor subunit, where codon substitution rate analysis identified positive, directional selection acting on amino acid positions associated with subunit assembly. Characterization of four gene copies from a model parasitic nematode, Haemonchus contortus, demonstrated that each copy has acquired unique functional characteristics based on phenotype rescue of transgenic C. elegans and electrophysiology of receptors reconstituted in Xenopus oocytes. We found evidence that a specific incompatibility has evolved for two subunits co-expressed in muscle. We demonstrated that functional divergence of acetylcholine receptors, driven by directional selection, can occur more rapidly than previously thought and may be mediated by alteration of receptor assembly. This phenomenon is common among the clade V parasitic nematodes and this work provides a foundation for understanding the broader context of changing anthelmintic drug targets across the parasitic nematodes.