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.

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