Genomic introgression mapping of field-derived multiple-anthelmintic resistance in Teladorsagia circumcincta.
Genomic introgression mapping of field-derived multiple-anthelmintic resistance in Teladorsagia circumcincta.
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DOI：
10.1371/journal.pgen.1006857
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发表时间：
2017-06
期刊：
影响因子：
4.5
通讯作者：
Mitreva M
中科院分区：
文献类型：
--
作者：
Choi YJ;Bisset SA;Doyle SR;Hallsworth-Pepin K;Martin J;Grant WN;Mitreva M
长期以来，预防性化疗一直用于对抗家畜的线虫寄生虫，导致广泛的耐药性，并且越来越多地被用于根除人类寄生线虫，即使它同样可能导致耐药性。鉴于抗性的遗传结构对任何线虫都知之甚少，我们分析了多药耐药的Teladorsagia circumcincta，绵羊的主要寄生虫，作为抗性选择分析的模型。我们将田间来源的多药耐药基因型渗入部分近交的易感遗传背景（通过重复的回交和药物选择），并在回交后代和药物选择的F2群体中进行全基因组扫描，以识别导致多药耐药的主要基因。我们确定了将候选耐药基因与每种药物类别联系起来的变异。推测的机制包括靶位点多态性、可能调控区域的变化和外排转运蛋白的拷贝数变异。本研究首次阐明了寄生线虫多重抗蠕虫药抗性的遗传结构，为人类寄生线虫抗蠕虫药抗性的进一步研究奠定了基础。Teladorsagia circumcincta是一种经济上重要的线虫（蛔虫）病原体，影响世界温带地区的绵羊和山羊。预防性治疗的广泛使用导致了对这种和其他家畜寄生虫的驱虫药（抗蠕虫药物）抗性的快速选择。抗性的机制还没有得到很好的理解，因为大多数研究都集中在候选基因的作用，使用简单的单基因选择模型，尽管有证据表明抗性的进化更为复杂。在这里，我们报告了一个全面的全基因组分析，阐明了抗性相关基因，这是通过开发一对T。circumcincta菌株共享一个很大程度上共同的遗传背景，但显着不同的敏感性驱虫药物。结果显示，多种遗传因素以多种方式促成驱虫剂抗性，包括靶位点敏感性的可能降低/调节、靶位点表达降低和药物外排增加，仅举几例。这表明，这些寄生虫的耐药性是一个多因素的数量性状，而不是一个简单的离散孟德尔性状。通过这项研究，我们建立了一个基于基因组学的实验范式，用于调查驱虫药耐药性，在其医学重要性迅速增加的时候。
Preventive chemotherapy has long been practiced against nematode parasites of livestock, leading to widespread drug resistance, and is increasingly being adopted for eradication of human parasitic nematodes even though it is similarly likely to lead to drug resistance. Given that the genetic architecture of resistance is poorly understood for any nematode, we have analyzed multidrug resistant Teladorsagia circumcincta, a major parasite of sheep, as a model for analysis of resistance selection. We introgressed a field-derived multiresistant genotype into a partially inbred susceptible genetic background (through repeated backcrossing and drug selection) and performed genome-wide scans in the backcross progeny and drug-selected F2 populations to identify the major genes responsible for the multidrug resistance. We identified variation linking candidate resistance genes to each drug class. Putative mechanisms included target site polymorphism, changes in likely regulatory regions and copy number variation in efflux transporters. This work elucidates the genetic architecture of multiple anthelmintic resistance in a parasitic nematode for the first time and establishes a framework for future studies of anthelmintic resistance in nematode parasites of humans. Teladorsagia circumcincta is an economically significant nematode (roundworm) pathogen affecting sheep and goats in temperate regions of the world. The widespread use of prophylactic treatment has resulted in rapid selection for anthelmintic (anti-worm drug) resistance in this and other species of livestock parasites. The mechanism of resistance is not well understood because most studies have focused on the role of candidate genes using simplistic models of single gene selection, despite evidence that the evolution of resistance is more complex. Here, we report on a comprehensive whole-genome analysis that elucidated resistance-associated genes, which was facilitated by developing a pair of T. circumcincta strains sharing a largely common genetic background but differing markedly in their susceptibility to anthelmintic drugs. The results show that multiple genetic factors contribute to anthelmintic resistance in a variety of ways, including possible reduction/modulation in target site sensitivity, reduced target site expression, and increased drug efflux, to name a few. This suggests that drug resistance in these parasites is a multifactorial quantitative trait rather than a simple discrete Mendelian character. With this study, we established a genomics-based experimental paradigm for investigating anthelmintic resistance, at a time when its medical importance is rapidly increasing.
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影响因子：
48
作者：
Engstrom, Par G.;Steijger, Tamara;Sipos, Botond;Grant, Gregory R.;Kahles, Andre;Raetsch, Gunnar;Goldman, Nick;Hubbard, Tim J.;Harrow, Jennifer;Guigo, Roderic;Bertone, Paul
通讯作者：
Bertone, Paul
影响因子：
4.4
作者：
Chevalier, Frederic D.;Valentim, Claudia L. L.;Anderson, Timothy J. C.
通讯作者：
Anderson, Timothy J. C.
影响因子：
7
作者：
Barriere, Antoine;Yang, Shiaw-Pyng;Ruvinsky, Ilya
通讯作者：
Ruvinsky, Ilya
影响因子：
7
作者：
Cantarel, Brandi L.;Korf, Ian;Yandell, Mark
通讯作者：
Yandell, Mark
影响因子：
14.9
作者：
Benson, G
通讯作者：
Benson, G