Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Ecology & Evolution volume 1, pages 1961–1969 (2017)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Pallen, M. J. & Wren, B. W. Bacterial pathogenomics. Nature 449, 835–842 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Torres, E. M. et al. Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science 317, 916–924 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Pavelka, N. et al. Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast. Nature 468, 321–325 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Pavelka, N., Rancati, G. & Li, R. Dr Jekyll and Mr Hyde: role of aneuploidy in cellular adaptation and cancer. Curr. Opin. Cell Biol. 22, 809–815 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Selmecki, A. M., Dulmage, K., Cowen, L. E., Anderson, J. B. & Berman, J. Acquisition of aneuploidy provides increased fitness during the evolution of antifungal drug resistance. PLoS Genet. 5, e1000705 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Sabeti, P. C. et al. Detecting recent positive selection in the human genome from haplotype structure. Nature 419, 832–837 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Staaf, J. et al. Landscape of somatic allelic imbalances and copy number alterations in human lung carcinoma. Int. J. Cancer 132, 2020–2031 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. Scheinfeldt, L. B. & Tishkoff, S. A. Recent human adaptation: genomic approaches, interpretation and insights. Nat. Rev. Genet. 14, 692–702 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Gao, R. et al. Punctuated copy number evolution and clonal stasis in triple-negative breast cancer. Nat. Genet. 48, 1119–1130 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sterkers, Y., Crobu, L., Lachaud, L., Pagès, M. & Bastien, P. Parasexuality and mosaic aneuploidy in Leishmania: alternative genetics. Trends Parasitol. 30, 429–435 (2014).

    Article  PubMed  Google Scholar 

  11. Imamura, H. et al. Evolutionary genomics of epidemic visceral leishmaniasis in the Indian subcontinent. Elife 5, e12613 (2016).

  12. Alvar, J. et al. Leishmaniasis worldwide and global estimates of its incidence. PLoS ONE 7, e35671 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zilberstein, D. & Shapira, M. The role of pH and temperature in the development of Leishmania parasites. Annu. Rev. Microbiol. 48, 449–470 (1994).

    Article  CAS  PubMed  Google Scholar 

  14. Leprohon, P., Fernandez-Prada, C., Gazanion, É., Monte-Neto, R. & Ouellette, M. Drug resistance analysis by next generation sequencing in Leishmania. Int. J. Parasitol. Drugs Drug Resist. 5, 26–35 (2015).

    Article  PubMed  Google Scholar 

  15. Downing, T. et al. Whole genome sequencing of multiple Leishmania donovani clinical isolates provides insights into population structure and mechanisms of drug resistance. Genome Res. 21, 2143–2156 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dujardin, J.-C., Mannaert, A., Durrant, C. & Cotton, J. A. Mosaic aneuploidy in Leishmania: the perspective of whole genome sequencing. Trends Parasitol. 30, 554–555 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. Rogers, M. B. et al. Chromosome and gene copy number variation allow major structural change between species and strains of Leishmania. Genome Res. 21, 2129–2142 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sterkers, Y., Lachaud, L., Crobu, L., Bastien, P. & Pagès, M. FISH analysis reveals aneuploidy and continual generation of chromosomal mosaicism in Leishmania major. Cell. Microbiol. 13, 274–283 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Dumetz, F. et al. Modulation of aneuploidy in Leishmania donovani during adaptation to different in vitro and in vivo environments and its impact on gene expression. MBio 8, e00599-17 (2017).

  20. Legrand, M. et al. Haplotype mapping of a diploid non-meiotic organism using existing and induced aneuploidies. PLoS Genet. 4, e1 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Yona, A. H. et al. Chromosomal duplication is a transient evolutionary solution to stress. Proc. Natl Acad. Sci. USA 109, 21010–21015 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sterkers, Y. et al. Novel insights into genome plasticity in eukaryotes: mosaic aneuploidy in Leishmania. Mol. Microbiol. 86, 15–23 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Rougeron, V., De Meeûs, T., Kako Ouraga, S., Hide, M. & Bañuls, A.-L. ‘Everything you always wanted to know about sex (but were afraid to ask)’ in Leishmania after two decades of laboratory and field analyses. PLoS Pathog. 6, e1001004 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Lande, R. Natural selection and random genetic drift in phenotypic evolution. Evolution 30, 314–334 (1976).

    Article  PubMed  Google Scholar 

  25. Lynch, M. & Conery, J. S. The evolutionary fate and consequences of duplicate genes. Science 290, 1151–1155 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Victoir, K. & Dujardin, J.-C. How to succeed in parasitic life without sex? Asking Leishmania. Trends Parasitol. 18, 81–85 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Bastien, P., Blaineau, C. & Pages, M. Leishmania: sex, lies and karyotype. Parasitol. Today 8, 174–177 (1992).

    Article  CAS  PubMed  Google Scholar 

  28. Dujardin, J.-C. et al. Clonal propagation and the fast generation of karyotype diversity: an in vitro Leishmania model. Parasitology 134, 33–39 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Gazanion, É., Fernández-Prada, C., Papadopoulou, B., Leprohon, P. & Ouellette, M. Cos-Seq for high-throughput identification of drug target and resistance mechanisms in the protozoan parasite Leishmania. Proc. Natl Acad. Sci. USA 113, E3012–E3021 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pescher, P., Blisnick, T., Bastin, P. & Späth, G. F. Quantitative proteome profiling informs on phenotypic traits that adapt Leishmania donovani for axenic and intracellular proliferation. Cell. Microbiol. 13, 978–991 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  33. McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Quinlan, A. R. & Hall, I. M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mortazavi, A., Williams, B. A., McCue, K., Schaeffer, L. & Wold, B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat. Methods 5, 621–628 (2008).

    Article  CAS  PubMed  Google Scholar 

Download references

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.).

Author information

Author notes

  1. These authors contributed equally to this work: Pablo Prieto Barja, Pascale Pescher.

Authors and Affiliations

  1. Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, 08002, Barcelona, Spain

    Pablo Prieto Barja, Darek Kedra, Heinz Himmelbauer & Cedric Notredame

  2. Universitat Pompeu Fabra (UPF), 08002, Barcelona, Spain

    Pablo Prieto Barja & Cedric Notredame

  3. Institut Pasteur, INSERM U1201, Unité de Parasitologie Moléculaire et Signalisation, 75015, Paris, France

    Pascale Pescher & Gerald Frank Späth

  4. HUB de Bioinformatique et Biostatistiques, Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur, 75015, Paris, France

    Giovanni Bussotti

  5. Institute of Tropical Medicine, Molecular Parasitology Unit, B-2000, Antwerp, Belgium

    Franck Dumetz, Hideo Imamura, Malgorzata Domagalska & Jean-Claude Dujardin

  6. University Montpellier, Faculty of Medicine, Laboratory of Parasitology–Mycology, CNRS 5290, IRD 224, University Montpellier (UMR ‘MiVEGEC’) and Centre Hospitalier Universitaire, 34295, Montpellier cedex 5, France

    Victor Chaumeau, Michel Pages & Yvon Sterkers

  7. Institute of Biotechnology, 1190, Vienna, Austria

    Heinz Himmelbauer

  8. Department of Biomedical Sciences, University of Antwerp, B-2610, Antwerp, Belgium

    Jean-Claude Dujardin

Authors
  1. Pablo Prieto Barja
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pascale Pescher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giovanni Bussotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Franck Dumetz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hideo Imamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Darek Kedra
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Malgorzata Domagalska
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Victor Chaumeau
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Heinz Himmelbauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Michel Pages
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yvon Sterkers
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jean-Claude Dujardin
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Cedric Notredame
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Gerald Frank Späth
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding authors

Correspondence to Cedric Notredame or Gerald Frank Späth.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Supplementary Information

Supplementary Figures 1–12, Supplementary Tables 1–2.

Life Sciences Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41559-017-0361-x

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing