Authors

J Dujardin¹;  ¹ Institute of Tropical Medicine, UK

Discussion

During this presentation, I will try to summarize four decades of genomic research at ITM, with a focus on the karyotype variability in Leishmania. Initially after exploring the molecular karyotype (as revealed by Pulsed Field Gel Electrophoresis) as a source of biomarkers of virulence and drug resistance, our research surfed on the wave of NGS and led us to unexpected findings on Leishmania biology. Sequencing the whole genome of hundreds of in vitro cultivated clinical isolates (promastigotes) revealed unprecedented aneuploidy -with 2 to 4 copies of each chromosome- which we initially could not associate with parasites’ phenotypes (chance?). Experimental research was conducted to understand this phenomenon and we first found that the degree of aneuploidy was significantly lower in intracellular amastigotes in vivo and that it had a deep impact on gene expression, suggesting an adaptive role of chromosome number modulation. This was supported by in vitro selection of miltefosine resistance, which showed that aneuploidy was the first line of genomic adaptation before the emergence of key point mutations (necessity?). A next finding was made possible by the development of single cell genome sequencing, which revealed a high degree of mosaic aneuploidy (chance?) probably with a pre-adaptive role (necessity?). These observations led us to revisit our early studies on parasite genome diversity in natural populations. We used genome capture to sequence parasites directly in host tissues (bone marrows, biopsies…) without isolating and cultivating them. As expected, aneuploidy was much lower in patients and even monosomy was reported, fitting with the need for a stringent metabolic response in amastigotes. A lot more is to be studied, but in response to the question in the title, we believe that aneuploidy modulation in Leishmania illustrates Monod’s fundamental hypothesis: “chance creates diversity and necessity keeps it”.
Website: https://www.itg.be/en/research/research-themes/leishmaniasis