Abstract
ABSTRACTLeishmania tropica, a unicellular eukaryotic parasite present in North and East Africa, the Middle East, and the Indian subcontinent, has been linked to large outbreaks of cutaneous leishmaniasis in displaced populations in Iraq, Jordan, and Syria. Here, we report the genome sequence of this pathogen and 7,863 identified protein-coding genes, and we show that the majority of clinical isolates possess high levels of allelic diversity, genetic admixture, heterozygosity, and extensive aneuploidy. By utilizing paired genome-wide high-throughput DNA sequencing (DNA-seq) with RNA-seq, we found that gene dosage, at the level of individual genes or chromosomal “somy” (a general term covering disomy, trisomy, tetrasomy, etc.), accounted for greater than 85% of total gene expression variation in genes with a 2-fold or greater change in expression. High gene copy number variation (CNV) among membrane-bound transporters, a class of proteins previously implicated in drug resistance, was found for the most highly differentially expressed genes. Our results suggest that gene dosage is an adaptive trait that confers phenotypic plasticity among natural Leishmania populations by rapid down- or upregulation of transporter proteins to limit the effects of environmental stresses, such as drug selection.
Highlights
Leishmania tropica, a unicellular eukaryotic parasite present in North and East Africa, the Middle East, and the Indian subcontinent, has been linked to large outbreaks of cutaneous leishmaniasis in displaced populations in Iraq, Jordan, and Syria
IMPORTANCE Leishmania is a genus of unicellular eukaryotic parasites that is responsible for a spectrum of human diseases that range from cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL) to life-threatening visceral leishmaniasis (VL)
The present study describes the first comprehensive, high-resolution investigation of intraspecific genetic diversity and heterozygosity within the Old World Leishmania species L. tropica, a species that is responsible for large outbreaks of cutaneous leishmaniasis in the Middle East
Summary
Leishmania tropica, a unicellular eukaryotic parasite present in North and East Africa, the Middle East, and the Indian subcontinent, has been linked to large outbreaks of cutaneous leishmaniasis in displaced populations in Iraq, Jordan, and Syria. Leishmania tropica is a species that has been recently linked to massive epidemics of CL in refugee camps in Syria and neighboring areas of the Middle East, including Iraq, Jordan, Israel, Palestine, and Afghanistan, due to ongoing armed conflict and civil unrest in the region [2,3,4]. This species is highly prevalent in this geographic region and follows an anthroponotic, or human-to-human, transmission cycle, which sets this species apart from the zoonotic and coendemic species Leishmania major. Considerable variation in the response of Leishmania to treatment has been documented in affected patients, with cutaneous lesions due to L. tropica being generally less responsive to treatment and more prone to form satellite lesions than those due to L. major, but the genetic determinants for this variation are still largely unknown [7, 8]
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