title: Regulatory hotspots in the malaria parasite genome dictate transcriptional variation.
abstract: 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.
authors.affiliation: The Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Gonzales
authors.forename: Jigar J
authors.initials: JJ
authors.lastname: Patel
authors.forename: Napawan
authors.initials: N
authors.lastname: Ponmee
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.forename: Asako
authors.initials: A
authors.lastname: Tan
authors.forename: Steven P
authors.initials: SP
authors.lastname: Maher
authors.forename: Stefan
authors.initials: S
authors.lastname: Wuchty
authors.forename: Pradipsinh K
authors.initials: PK
authors.lastname: Rathod
authors.forename: Michael T
authors.initials: MT
authors.lastname: Ferdig
mesh_terms: D000483:Alleles; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002875:Chromosomes; D004351:Drug Resistance / Q000235:genetics; D005784:Gene Amplification; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D006801:Humans; D016778:Malaria, Falciparum; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D010963:Plasmodium falciparum / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D040641:Quantitative Trait Loci; D014158:Transcription, Genetic
chemical_list: D015800:Protozoan Proteins