Regulatory hotspots in the malaria parasite genome dictate transcriptional variation.
Regulatory hotspots in the malaria parasite genome dictate transcriptional variation.
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DOI：
10.1371/journal.pbio.0060238
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发表时间：
2008-09-30
期刊：
影响因子：
9.8
通讯作者：
Ferdig MT
中科院分区：
文献类型：
--
作者：
Gonzales JM;Patel JJ;Ponmee N;Jiang L;Tan A;Maher SP;Wuchty S;Rathod PK;Ferdig MT
疟疾寄生虫转录调控的决定因素仍然难以捉摸。不同恶性疟原虫菌株共享的一个特征明确的基因表达级联的存在可能意味着转录调控及其自然变异对寄生虫耐药性的进化没有显著贡献。为了阐明转录变异在最致命的疟疾物种中作为染色特异性多样性来源的作用，并找到指示基因表达变异的遗传位点，我们在表型不同的寄生虫克隆之间的遗传杂交中检测了全基因组表达水平多态性（ELPs）。通过对不同恶性疟原虫克隆的RNA进行直接共杂交，观察到基因表达的显著差异。近18%的基因受一个显著表达的数量性状位点调控。大多数elp的遗传决定因素存在于离其靶标物理距离较远的热点地区。最突出的调控位点，影响269个转录本，与携带耐药基因pfmdr1和其他13个基因的第5染色体扩增事件一致。Dd2亲本克隆谱系中的药物选择压力不仅导致pfmdr1基因的拷贝数变化，还导致假定的邻近调节因子的拷贝数增加，进而广泛影响转录网络。以前未被认识到的转录变异，由多态调控基因和可能在大拷贝数变异中的主调控基因控制，有助于耐药性疟疾寄生虫的全面表型进化。疟原虫恶性疟原虫在血液中的发展是由在不同时间和不同水平上表达的许多不同基因驱动的。究竟是什么影响了这种转录变化仍然难以捉摸，特别是在一些重要的表型方面，如耐药性。利用从疟原虫遗传杂交后代中提取的cDNA微阵列杂交技术，我们定位了实验疟原虫群体的基因表达数量性状位点（eQTLs）。每个基因的转录水平被用作分离表型，以确定疟原虫基因组中决定转录变异的区域。几个调控热点控制了大多数基因表达变异，主要通过反式作用机制。其中一个影响转录本数量最多，与传统上与多重耐药性（MDR）相关的基因组扩增区域相吻合。总体而言，两种功能基因组工具（基因定位和转录物定量）的整合揭示了寄生虫转录网络的全系统重新布线：由基因组结构的药物选择驱动的多效表型变异，这在很大程度上可归因于寄生虫的适应性拷贝数多态性。这些结构变异改变了扩增子内基因的表达以及分散在疟原虫基因组中的许多基因。遗传水平的转录变异主要由基因组拷贝数变异通过反机制调节，在耐药疟疾寄生虫中惊人地丰富。
The determinants of transcriptional regulation in malaria parasites remain elusive. The presence of a well-characterized gene expression cascade shared by different Plasmodium falciparum strains could imply that transcriptional regulation and its natural variation do not contribute significantly to the evolution of parasite drug resistance. To clarify the role of transcriptional variation as a source of stain-specific diversity in the most deadly malaria species and to find genetic loci that dictate variations in gene expression, we examined genome-wide expression level polymorphisms (ELPs) in a genetic cross between phenotypically distinct parasite clones. Significant variation in gene expression is observed through direct co-hybridizations of RNA from different P. falciparum clones. Nearly 18% of genes were regulated by a significant expression quantitative trait locus. The genetic determinants of most of these ELPs resided in hotspots that are physically distant from their targets. The most prominent regulatory locus, influencing 269 transcripts, coincided with a Chromosome 5 amplification event carrying the drug resistance gene, pfmdr1, and 13 other genes. Drug selection pressure in the Dd2 parental clone lineage led not only to a copy number change in the pfmdr1 gene but also to an increased copy number of putative neighboring regulatory factors that, in turn, broadly influence the transcriptional network. Previously unrecognized transcriptional variation, controlled by polymorphic regulatory genes and possibly master regulators within large copy number variants, contributes to sweeping phenotypic evolution in drug-resistant malaria parasites. Development of the malaria parasite, Plasmodium falciparum, in the blood is driven by a number of different genes expressed at different times and at different levels. Exactly what influences such transcriptional changes remains elusive, particularly in regard to important phenotypes like drug resistance. Using cDNA microarray hybridizations from the progeny of a Plasmodium genetic cross, we mapped gene expression quantitative trait loci (eQTLs) in an experimental population of malaria parasites. Each gene's transcript level was used as a segregating phenotype to identify regions of the Plasmodium genome dictating transcriptional variation. Several regulatory hotspots controlled the majority of gene expression variation, mostly via trans-acting mechanisms. One, influencing the largest number of transcripts, coincided with an amplified region of the genome traditionally associated with multiple drug resistance (MDR). Overall, integration of two functional genomic tools (gene mapping and transcript quantitation) has revealed a system-wide rewiring of the parasite transcription network: pleiotropic phenotypic variation, driven by drug selection on genome structure that may be attributed in large part to adaptive copy number polymorphisms in the parasite. These structural variants alter the expression of genes within the amplicon as well as many genes scattered across the Plasmodium genome. Heritable levels of transcriptional variation, predominantly regulated by genomic copy number variants via trans mechanisms, are surprisingly abundant in drug-resistant malaria parasites.
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