Modulation of gene expression in drug resistant Leishmania is associated with gene amplification, gene deletion and chromosome aneuploidy.
Modulation of gene expression in drug resistant Leishmania is associated with gene amplification, gene deletion and chromosome aneuploidy.
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DOI：
10.1186/gb-2008-9-7-r115
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发表时间：
2008
期刊：
影响因子：
12.3
通讯作者：
Ouellette M
中科院分区：
文献类型：
--
作者：
Ubeda JM;Légaré D;Raymond F;Ouameur AA;Boisvert S;Rigault P;Corbeil J;Tremblay MJ;Olivier M;Papadopoulou B;Ouellette M
利用利什曼原虫全基因组寡核苷酸微阵列进行基因表达和DNA拷贝数分析，揭示了利什曼原虫耐甲氨蝶呤的分子机制。耐药可能很复杂，导致耐药的几种突变可以在耐药细胞中共存。转录谱分析非常适合研究复杂的耐药基因型，并有可能导致新的发现。我们为人类原生动物寄生虫大利什曼原虫和幼利什曼原虫的所有蛋白编码基因构建了全基因组70-mer寡核苷酸微阵列。这些阵列用于监测抗甲氨蝶呤寄生虫的基因表达。利什曼原虫是一种在转录起始水平上控制最小的真核生物，很少有基因差异表达而DNA拷贝数没有变化。在大利什曼原虫中发现了一个例外，其中整个染色体的表达下调。微阵列强调了几种机制，通过这些机制，参与抗性的基因拷贝数被改变；这些包括基因缺失，染色体外圆形或线性扩增子的形成，以及多余染色体的存在。在基因缺失或基因扩增的情况下，重排发生在重复（直接或反向）序列的位点。这些重复序列在两种物种中表现出高度保守，以促进关键基因在环境变化期间的扩增。当具有选择优势的基因附近没有直接或反向重复序列时，利什曼原虫就会求助于多余的染色体来增加基因产物的水平。非整倍体已被认为是几种生物耐药的重要原因，进一步的研究应揭示这一现象在利什曼原虫耐药中的潜在重要性。
Gene expression and DNA copy number analyses using full genome oligonucleotide microarrays of Leishmania reveal molecular mechanisms of methotrexate resistance. Drug resistance can be complex, and several mutations responsible for it can co-exist in a resistant cell. Transcriptional profiling is ideally suited for studying complex resistance genotypes and has the potential to lead to novel discoveries. We generated full genome 70-mer oligonucleotide microarrays for all protein coding genes of the human protozoan parasites Leishmania major and Leishmania infantum. These arrays were used to monitor gene expression in methotrexate resistant parasites. Leishmania is a eukaryotic organism with minimal control at the level of transcription initiation and few genes were differentially expressed without concomitant changes in DNA copy number. One exception was found in Leishmania major, where the expression of whole chromosomes was down-regulated. The microarrays highlighted several mechanisms by which the copy number of genes involved in resistance was altered; these include gene deletion, formation of extrachromosomal circular or linear amplicons, and the presence of supernumerary chromosomes. In the case of gene deletion or gene amplification, the rearrangements have occurred at the sites of repeated (direct or inverted) sequences. These repeats appear highly conserved in both species to facilitate the amplification of key genes during environmental changes. When direct or inverted repeats are absent in the vicinity of a gene conferring a selective advantage, Leishmania will resort to supernumerary chromosomes to increase the levels of a gene product. Aneuploidy has been suggested as an important cause of drug resistance in several organisms and additional studies should reveal the potential importance of this phenomenon in drug resistance in Leishmania.
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影响因子：
7
作者：
Drummelsmith, J;Brochu, V;Ouellette, M
通讯作者：
Ouellette, M
DOI：
10.1073/pnas.80.8.2132
发表时间：
1983-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
CODERRE, JA;BEVERLEY, SM;SANTI, DV
通讯作者：
SANTI, DV
影响因子：
3.3
作者：
Albrecht, EB;Hunyady, AB;Patterson, TE
通讯作者：
Patterson, TE
影响因子：
1.5
作者：
Cunningham, ML;Beverley, SM
通讯作者：
Beverley, SM
影响因子：
1.5
作者：
DEWES, H;OSTERGAARD, HL;SIMPSON, L
通讯作者：
SIMPSON, L