Gene expression modulation is associated with gene amplification, supernumerary chromosomes and chromosome loss in antimony-resistant Leishmania infantum.
Gene expression modulation is associated with gene amplification, supernumerary chromosomes and chromosome loss in antimony-resistant Leishmania infantum.
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DOI：
10.1093/nar/gkn1069
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发表时间：
2009-04
影响因子：
14.9
通讯作者：
Ouellette M
中科院分区：
文献类型：
--
作者：
Leprohon P;Légaré D;Raymond F;Madore E;Hardiman G;Corbeil J;Ouellette M
锑剂仍然是对抗原生动物寄生虫利什曼原虫的第一线药物，但其疗效受到耐药性的威胁。我们进行了RNA表达谱分析比较锑敏感和耐药（Sb 2000.1）株婴儿利什曼原虫使用全基因组70聚体寡核苷酸微阵列。两种菌株之间的几个基因差异表达，其中几个被发现在基因组中物理连锁。MRPA是一种已知参与锑抗性的ATP结合盒（ABC）基因，在锑抗性突变体中与23号染色体上的其他三个串联基因一起过表达。这四个基因位点的侧翼是1.4 kb的重复序列，从该重复序列在抗性细胞中产生染色体外环状扩增子。有趣的是，整个染色体的基因表达调制发生在抗锑突变体。Southern印迹分析和比较基因组杂交表明，这是由于存在额外的染色体或一个染色体的损失。单倍体利什曼原虫是活的。这些染色体中的一些的拷贝数的变化在另一个抗锑菌株中得到证实。部分回复突变株系的选择与抗体抗性水平和非整倍体染色体的拷贝数相关，表明利什曼原虫的非整倍体和耐药性之间存在假定的联系。
Antimonials remain the first line drug against the protozoan parasite Leishmania but their efficacy is threatened by resistance. We carried out a RNA expression profiling analysis comparing an antimony-sensitive and -resistant (Sb2000.1) strain of Leishmania infantum using whole-genome 70-mer oligonucleotide microarrays. Several genes were differentially expressed between the two strains, several of which were found to be physically linked in the genome. MRPA, an ATP-binding cassette (ABC) gene known to be involved in antimony resistance, was overexpressed in the antimony-resistant mutant along with three other tandemly linked genes on chromosome 23. This four gene locus was flanked by 1.4 kb repeated sequences from which an extrachromosomal circular amplicon was generated in the resistant cells. Interestingly, gene expression modulation of entire chromosomes occurred in the antimony-resistant mutant. Southern blots analyses and comparative genomic hybridizations revealed that this was either due to the presence of supernumerary chromosomes or to the loss of one chromosome. Leishmania parasites with haploid chromosomes were viable. Changes in copy number for some of these chromosomes were confirmed in another antimony-resistant strain. Selection of a partial revertant line correlated antimomy resistance levels and the copy number of aneuploid chromosomes, suggesting a putative link between aneuploidy and drug resistance in Leishmania.
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影响因子：
56.9
作者：
Ivens, AC;Peacock, CS;Myler, PJ
通讯作者：
Myler, PJ
影响因子：
1.5
作者：
Holzer, TR;McMaster, WR;Forney, JD
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影响因子：
4.8
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Gourbal, B;Sonuc, N;Mukhopadhyay, R
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Mukhopadhyay, R
影响因子：
4.9
作者：
El Fadili, K;Messier, N;Oullette, M
通讯作者：
Oullette, M
影响因子：
14.9
作者：
Guimond, C;Trudel, N;Ouellette, M
通讯作者：
Ouellette, M