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Regulatory hotspots in the malaria parasite genome dictate transcriptional variation.

Gonzales JM, Patel JJ, Ponmee N, Jiang L, Tan A, Maher SP, Wuchty S, Rathod PK, Ferdig MT - PLoS Biol. (2008)

Bottom Line: 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.Nearly 18% of genes were regulated by a significant expression quantitative trait locus.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.

View Article: PubMed Central - PubMed

Affiliation: The Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA.

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.

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Genome-wide Distribution of eQTLsCounts of significant eQTLs are represented for each marker interval across the genome. The dashed horizontal line denotes the 95% confidence threshold for regulatory hotspots, calculated from 1,000 permutations (see Methods). Chr 5 accounted for nearly 50% of the total regulatory variation in the genome. The inset shows the composition of each cluster containing ten or more genes that mapped to the same locus, including those that surpassed the threshold for eQTL hotspots (≥14 genes). Most of these loci regulated the expression of distant genes, but two sets, denoted by one (*) and two (**) asterisks, were composed of mostly local eQTLs. These “local sets” coincide with chromosomal structural events (deletion of a locus at the end of Chr 2 [64] and an amplification event on Chr 12 [41]). The diamond (♦) denotes the two largest hotspots that aligned with the pfmdr1-containing amplicon of Dd2 on Chr 5 [41].
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pbio-0060238-g002: Genome-wide Distribution of eQTLsCounts of significant eQTLs are represented for each marker interval across the genome. The dashed horizontal line denotes the 95% confidence threshold for regulatory hotspots, calculated from 1,000 permutations (see Methods). Chr 5 accounted for nearly 50% of the total regulatory variation in the genome. The inset shows the composition of each cluster containing ten or more genes that mapped to the same locus, including those that surpassed the threshold for eQTL hotspots (≥14 genes). Most of these loci regulated the expression of distant genes, but two sets, denoted by one (*) and two (**) asterisks, were composed of mostly local eQTLs. These “local sets” coincide with chromosomal structural events (deletion of a locus at the end of Chr 2 [64] and an amplification event on Chr 12 [41]). The diamond (♦) denotes the two largest hotspots that aligned with the pfmdr1-containing amplicon of Dd2 on Chr 5 [41].

Mentions: In addition to numbers and effect sizes, the genome-wide distribution of eQTLs can identify the regulatory architecture driving expression variation. Regulatory loci resided on each chromosome, ranging from as few as 17 eQTLs on Chr 6 to 513 on Chr 5 (Figure 2; Table 2). Of the 329 informative positions in the genome defined by recombination in the combined progeny pool [40], 203 loci harbored at least one eQTL, and 122 had multiple eQTLs (Figure 2). The 81 genome positions with a single eQTL (singletons) influenced expression of 32 local genes and 49 distant genes. Local effects were more common than distant effects in the singleton group (40% versus 24% of the total eQTLs, respectively). This could be because local eQTLs contributed to larger genetic effects and were thus more readily detected.


Regulatory hotspots in the malaria parasite genome dictate transcriptional variation.

Gonzales JM, Patel JJ, Ponmee N, Jiang L, Tan A, Maher SP, Wuchty S, Rathod PK, Ferdig MT - PLoS Biol. (2008)

Genome-wide Distribution of eQTLsCounts of significant eQTLs are represented for each marker interval across the genome. The dashed horizontal line denotes the 95% confidence threshold for regulatory hotspots, calculated from 1,000 permutations (see Methods). Chr 5 accounted for nearly 50% of the total regulatory variation in the genome. The inset shows the composition of each cluster containing ten or more genes that mapped to the same locus, including those that surpassed the threshold for eQTL hotspots (≥14 genes). Most of these loci regulated the expression of distant genes, but two sets, denoted by one (*) and two (**) asterisks, were composed of mostly local eQTLs. These “local sets” coincide with chromosomal structural events (deletion of a locus at the end of Chr 2 [64] and an amplification event on Chr 12 [41]). The diamond (♦) denotes the two largest hotspots that aligned with the pfmdr1-containing amplicon of Dd2 on Chr 5 [41].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2553844&req=5

pbio-0060238-g002: Genome-wide Distribution of eQTLsCounts of significant eQTLs are represented for each marker interval across the genome. The dashed horizontal line denotes the 95% confidence threshold for regulatory hotspots, calculated from 1,000 permutations (see Methods). Chr 5 accounted for nearly 50% of the total regulatory variation in the genome. The inset shows the composition of each cluster containing ten or more genes that mapped to the same locus, including those that surpassed the threshold for eQTL hotspots (≥14 genes). Most of these loci regulated the expression of distant genes, but two sets, denoted by one (*) and two (**) asterisks, were composed of mostly local eQTLs. These “local sets” coincide with chromosomal structural events (deletion of a locus at the end of Chr 2 [64] and an amplification event on Chr 12 [41]). The diamond (♦) denotes the two largest hotspots that aligned with the pfmdr1-containing amplicon of Dd2 on Chr 5 [41].
Mentions: In addition to numbers and effect sizes, the genome-wide distribution of eQTLs can identify the regulatory architecture driving expression variation. Regulatory loci resided on each chromosome, ranging from as few as 17 eQTLs on Chr 6 to 513 on Chr 5 (Figure 2; Table 2). Of the 329 informative positions in the genome defined by recombination in the combined progeny pool [40], 203 loci harbored at least one eQTL, and 122 had multiple eQTLs (Figure 2). The 81 genome positions with a single eQTL (singletons) influenced expression of 32 local genes and 49 distant genes. Local effects were more common than distant effects in the singleton group (40% versus 24% of the total eQTLs, respectively). This could be because local eQTLs contributed to larger genetic effects and were thus more readily detected.

Bottom Line: 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.Nearly 18% of genes were regulated by a significant expression quantitative trait locus.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.

View Article: PubMed Central - PubMed

Affiliation: The Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA.

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.

Show MeSH
Related in: MedlinePlus