Haplotype selection as an adaptive mechanism in the protozoan pathogen Leishmania donovani

Abstract

The parasite Leishmania  donovani causes a fatal disease termed visceral leishmaniasis. The process through which the parasite adapts to environmental change remains largely unknown. Here we show that aneuploidy is integral for parasite adaptation and that karyotypic fluctuations allow for selection of beneficial haplotypes, which impact transcriptomic output and correlate with phenotypic variations in proliferation and infectivity. To avoid loss of diversity following karyotype and haplotype selection, L. donovani utilizes two mechanisms: polyclonal selection of beneficial haplotypes to create coexisting subpopulations that preserve the original diversity, and generation of new diversity as aneuploidy-prone chromosomes tolerate higher mutation rates. Our results reveal high aneuploidy turnover and haplotype selection as a unique evolutionary adaptation mechanism that L. donovani uses to preserve genetic diversity under strong selection. This unexplored process may function in other human diseases, including fungal infection and cancer, and stimulate innovative treatment options.

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Fig. 1: Genome instability, aneuploidy co-occurrence and haplotype selection in 204 L. donovani field isolates.
Fig. 2: In vivo aneuploidy dynamics.
Fig. 3: In vitro aneuploidy dynamics.
Fig. 4: Fluctuations of allele frequency during culture adaptation.
Fig. 5: Aneuploidies and haplotype selection correlate with phenotype and fitness.
Fig. 6: Aneuploidy influence on heterozygosity.

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Acknowledgements

Work on samples from the Indian subcontinent was supported by the European Union 7th Framework Programme (EU FP7) (Kaladrug-R, contract 222895), the Belgian Science Policy Office (TRIT, P7/41), the Department of Economy, Science and Innovation in Flanders (ITM-SOFIB) and the Flemish Fund for Scientific Research (G.0.B81.12). We thank Life Science Editors for editing assistance. This study recieved funding from Plan Nacional (BFU2011-28575 to C.N., P.P.B. and D.K.), Center for Genomic Regulation (CRG), Spanish Ministry of Economy and Competitiveness, ‘Centro de Excelencia Severo Ochoa 2013–2017’ (SEV-2012–0208), a grant from the Institut Pasteur International Department strategic fund to the LeiSHield consortium (P.P.B., P.P, C.N., G.F.S., G.B. and Y.S.), Agence Nationale de la Recherche (ANR) within the framework of the 'Investissements d’avenir' programme (ANR-11-LABX-0024-01 “PARAFRAP”) (V.C., M.P. and Y.S.), the EU FP7 (Kaladrug-R, contract 222895), the Belgian Science Policy Office (TRIT, P7/41), the Department of Economy, Science and Innovation in Flanders (ITM-SOFIB) and the Flemish Fund for Scientific Research (G.0.B81.12) (J.C.D., F.D., H.I. and M.D.).

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P.P.B., P.P, C.N. and G.F.S worked on all aspects of work, contributed to the design of the project and wrote the article. G.B contributed to in silico analysis. F.D. and M.D. managed the hamster infection experiment with field isolates. H.I., M.D. and J.-C.D. contributed to the field isolates analyses and revised the paper. D.K. helped analyse the sequencing data. H.H. was responsible for the genomic sequencing of the in vitro clones. V.C., M.P. and Y.S. contributed the DNA-FISH analysis.

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Correspondence to Cedric Notredame or Gerald Frank Späth.

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Prieto Barja, P., Pescher, P., Bussotti, G. et al. Haplotype selection as an adaptive mechanism in the protozoan pathogen Leishmania donovani . Nat Ecol Evol 1, 1961–1969 (2017). https://doi.org/10.1038/s41559-017-0361-x

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