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Fidock, D. A.

Publications and source records attributed to Fidock, D. A..

2 recordsLinked to original sources

Changes in genome organization of parasite-specific gene families during the Plasmodium transmission stages

The development of malaria parasites throughout their various life cycle stages is controlled by coordinated changes in gene expression. We previously showed that the three-dimensional organization of the P. falciparum genome is strongly associated with gene expression during its replication cycle inside red blood cells. Here, we analyzed genome organization in the P. falciparum and P. vivax transmission stages. Major changes occurred in the localization and interactions of genes involved in pathogenesis and immune evasion, erythrocyte and liver cell invasion, sexual differentiation and master regulation of gene expression. In addition, we observed reorganization of subtelomeric heterochromatin around genes involved in host cell remodeling. Depletion of heterochromatin protein 1 (PfHP1) resulted in loss of interactions between virulence genes, confirming that PfHP1 is essential for maintenance of the repressive center. Overall, our results suggest that the three-dimensional genome structure is strongly connected with transcriptional activity of specific gene families throughout the life cycle of human malaria parasites.

systems biology

Mapping The Malaria Parasite Drug-Able Genome Using In Vitro Evolution And Chemogenomics

Chemogenetic characterization through in vitro evolution combined with whole genome analysis is a powerful tool to discover novel antimalarial drug targets and identify drug resistance genes. Our comprehensive genome analysis of 262 Plasmodium falciparum parasites treated with 37 diverse compounds reveals how the parasite evolves to evade the action of small molecule growth inhibitors. This detailed data set revealed 159 gene amplifications and 148 nonsynonymous changes in 83 genes which developed during resistance acquisition. Using a new algorithm, we show that gene amplifications contribute to 1/3 of drug resistance acquisition events. In addition to confirming known multidrug resistance mechanisms, we discovered novel multidrug resistance genes. Furthermore, we identified promising new drug target-inhibitor pairs to advance the malaria elimination campaign, including: thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This deep exploration of the P. falciparum resistome and drug-able genome will guide future drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms of the deadliest malaria parasite.\n\nOne Sentence SummaryWhole genome sequencing reveals how Plasmodium falciparum evolves resistance to diverse compounds and identifies new antimalarial drug targets.

genomics