Two novel loci underlie natural differences in Caenorhabditis elegans abamectin responses.
Two novel loci underlie natural differences in Caenorhabditis elegans abamectin responses.
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两个新的基因座在秀丽隐杆线虫阿维菌素反应的自然差异的基础。
DOI：
10.1371/journal.ppat.1009297
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发表时间：
2021-03
期刊：
影响因子：
6.7
通讯作者：
Andersen EC
中科院分区：
文献类型：
--
作者：
Evans KS;Wit J;Stevens L;Hahnel SR;Rodriguez B;Park G;Zamanian M;Brady SC;Chao E;Introcaso K;Tanny RE;Andersen EC
寄生线虫对人类健康造成巨大的全球性负担，沿着牲畜和农业生产力的损失。驱虫药在治疗寄生线虫方面已取得广泛成功。然而，耐药性正在增加，对大多数这些药物的耐药性的分子和遗传原因知之甚少。自由生活的线虫秀丽隐杆线虫提供了一个易处理的模型，以确定耐药性的基因。与寄生线虫不同，C.秀丽线虫易于在实验室中保存，具有完整且注释良好的基因组，并且具有许多遗传工具。使用野生菌株和一组重组近交系的组合构建的两个遗传和表型不同的菌株杂交，我们确定了三个染色体上的基因组区域V的自然差异的基础大环内酯（ML）阿维菌素。一个基因座是以前确定的，编码谷氨酸门控氯离子通道（glc-1）的α亚基。在这里，我们验证和缩小两个新的基因座使用近等基因系。此外，我们还生成了一个C中确定的优先候选基因列表。线虫和寄生虫捻转血矛线虫的ML抗性位点的比较。这些基因可以代表以前未识别的抗性基因共享线虫物种，并应在未来进行评估。我们的工作突出了使用C的优点。线虫作为模型，以更好地了解寄生线虫的ML抗性。寄生线虫感染植物、动物和人类，在世界范围内造成重大的健康和经济负担。寄生线虫感染通常用称为驱虫剂的一类药物有效治疗。然而，对许多这些驱虫药，包括大环内酯（ML）的耐药性是猖獗和增加。因此，我们必须了解这些药物如何对抗寄生线虫，以及线虫如何获得耐药性，以便在未来更好地治疗这些感染。在这里，我们使用非寄生线虫秀丽隐杆线虫作为模式生物来研究ML抗性。我们利用C. elegans的差异反应阿维菌素，以确定染色体V上的三个基因组区域，每个区域含有一个或多个基因，有助于ML响应。其中两个基因座以前未被发现，可能代表了新的耐药机制。我们还比较了这两个新基因座的基因内发现的基因组区域内的ML抗性寄生虫捻转血矛线虫，发现两个物种之间的重叠的几个案例。总的来说，这项研究突出了使用C的优势。elegans了解寄生线虫的驱虫抗性。
Parasitic nematodes cause a massive worldwide burden on human health along with a loss of livestock and agriculture productivity. Anthelmintics have been widely successful in treating parasitic nematodes. However, resistance is increasing, and little is known about the molecular and genetic causes of resistance for most of these drugs. The free-living roundworm Caenorhabditis elegans provides a tractable model to identify genes that underlie resistance. Unlike parasitic nematodes, C. elegans is easy to maintain in the laboratory, has a complete and well annotated genome, and has many genetic tools. Using a combination of wild isolates and a panel of recombinant inbred lines constructed from crosses of two genetically and phenotypically divergent strains, we identified three genomic regions on chromosome V that underlie natural differences in response to the macrocyclic lactone (ML) abamectin. One locus was identified previously and encodes an alpha subunit of a glutamate-gated chloride channel (glc-1). Here, we validate and narrow two novel loci using near-isogenic lines. Additionally, we generate a list of prioritized candidate genes identified in C. elegans and in the parasite Haemonchus contortus by comparison of ML resistance loci. These genes could represent previously unidentified resistance genes shared across nematode species and should be evaluated in the future. Our work highlights the advantages of using C. elegans as a model to better understand ML resistance in parasitic nematodes. Parasitic nematodes infect plants, animals, and humans, causing major health and economic burdens worldwide. Parasitic nematode infections are generally treated efficiently with a class of drugs named anthelmintics. However, resistance to many of these anthelmintic drugs, including macrocyclic lactones (MLs), is rampant and increasing. Therefore, it is essential that we understand how these drugs act against parasitic nematodes and, conversely, how nematodes gain resistance in order to better treat these infections in the future. Here, we used the non-parasitic nematode Caenorhabditis elegans as a model organism to study ML resistance. We leveraged natural genetic variation between strains of C. elegans with differential responses to abamectin to identify three genomic regions on chromosome V, each containing one or more genes that contribute to the ML response. Two of these loci have not been previously discovered and likely represent novel resistance mechanisms. We also compared the genes in these two novel loci to the genes found within genomic regions linked to ML resistance in the parasite Haemonchus contortus and found several cases of overlap between the two species. Overall, this study highlights the advantages of using C. elegans to understand anthelmintic resistance in parasitic nematodes.
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