Dudek, K. | Search bioRxiv

bioRxiv2018

Validation of the protein kinase PfCLK3 as a multi-stage cross species malarial drug target

The requirement for next generation anti-malarials to be both curative and transmission blockers necessitate the identification of molecular pathways essential for viability of both asexual and sexual parasite life stages. Here we identify a selective inhibitor to the Plasmodium falciparum protein kinase PfCLK3 which we use in combination with chemogenetics, whole genome sequencing and transcriptomics to validate PfCLK3 as a druggable target acting at multiple parasite life stages. Consistent with the proposed role of PfCLK3 as a regulator of RNA splicing, inhibition results in the down-regulation of >400 genes essential for parasite survival. Through this mechanism, blocking PfCLK3 activity not only results in rapid killing of asexual blood stage parasites but is also effective on sporozoites and gametocytes as well as showing parasiticidal activity in all Plasmodium species tested. Hence, our data establishes PfCLK3 as a target with the potential to deliver both symptomatic treatment and transmission blocking in malaria.

microbiology↗

bioRxiv2016

Isolation and Gene Flow in a Speciation Continuum in Newts

Because reproductive isolation often evolves gradually, differentiating lineages may retain the potential for genetic exchange for prolonged periods, providing an opportunity to quantify and understand the fundamental role of gene flow during speciation. Here we delimit taxa, reconstruct the phylogeny and infer gene flow in newts of the Lissotriton vulgaris species complex based on 74 nuclear markers sampled from 127 localities. We demonstrate that distinct lineages along the speciation continuum in newts exchange nontrivial amounts of genes, affecting their evolutionary trajectories. By integrating a wide array of methods, we delimit nine taxa and show that two principle factors have driven their genetic differentiation: time since the last common ancestor determining levels of shared ancestral polymorphism, and shifts in geographic distributions determining the extent of secondary contact. Post-divergence gene flow, indicative of evolutionary non-independence, has been most extensive between sister and non-sister taxa in Central Europe, while four southern European lineages have acquired the population genetic hallmarks of independent species (L. graecus, L. kosswigi, L. lantzi, L. schmidtleri). We obtained strong statistical support for widespread mtDNA introgression, previously suggested by discordance between mtDNA phylogeny and morphology. Our study suggests that long-term evolution in structured populations that may periodically exchange genes may be common: although some of these populations may become extinct or fuse, others will acquire complete reproductive isolation and will carry signatures of this complex history in their genomes.

evolutionary biology↗