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Comparative genomic analysis of three Leishmania species that cause diverse human disease

Nature Genetics volume 39, pages 839–847 (2007)Cite this article

Abstract

Leishmania parasites cause a broad spectrum of clinical disease. Here we report the sequencing of the genomes of two species of Leishmania: Leishmania infantum and Leishmania braziliensis. The comparison of these sequences with the published genome of Leishmania major reveals marked conservation of synteny and identifies only ∼200 genes with a differential distribution between the three species. L. braziliensis, contrary to Leishmania species examined so far, possesses components of a putative RNA-mediated interference pathway, telomere-associated transposable elements and spliced leader–associated SLACS retrotransposons. We show that pseudogene formation and gene loss are the principal forces shaping the different genomes. Genes that are differentially distributed between the species encode proteins implicated in host-pathogen interactions and parasite survival in the macrophage.

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Figure 1: Chromosome 32 of L. major showing the positions of genes with a differential distribution between the three Leishmania species analyzed.
Figure 2: Conserved pseudogenes in Leishmania species.

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References

  1. Marsden, P.D. Mucosal leishmaniasis ('espundia' Escomel, 1911). Trans. R. Soc. Trop. Med. Hyg. 80, 859–876 (1986).

    Article  CAS  PubMed  Google Scholar 

  2. Lipoldova, M. & Demant, P. Genetic susceptibility to infectious disease: lessons from mouse models of leishmaniasis. Nat. Rev. Genet. 7, 294–305 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Ivens, A.C. et al. The genome of the kinetoplastid parasite, Leishmania major. Science 309, 436–442 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Berriman, M. et al. The genome of the African trypanosome Trypanosoma brucei. Science 309, 416–422 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. El-Sayed, N.M. et al. The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease. Science 309, 409–415 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. El-Sayed, N.M. et al. Comparative genomics of trypanosomatid parasitic protozoa. Science 309, 404–409 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Myler, P.J. et al. Leishmania major Friedlin chromosome 1 has an unusual distribution of protein-coding genes. Proc. Natl. Acad. Sci. USA 96, 2902–2906 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Depledge, D.P. et al. A database of amino acid repeats present in lower eukaryotic pathogens. BMC Bioinformatics 8, 122 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kedzierski, L. et al. A leucine-rich repeat motif of Leishmania parasite surface antigen 2 binds to macrophages through the complement receptor 3. J. Immunol. 172, 4902–4906 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Kerr, S.F. Molecular trees of trypanosomes incongruent with fossil records of hosts. Mem. Inst. Oswaldo Cruz 101, 25–30 (2006).

    Article  PubMed  Google Scholar 

  11. Momen, H. & Cupolillo, E. Speculations on the origin and evolution of the genus Leishmania. Mem. Inst. Oswaldo Cruz 95, 583–588 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Britto, C. et al. Conserved linkage groups associated with large-scale chromosomal rearrangements between Old World and New World Leishmania genomes. Gene 222, 107–117 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. 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 

  14. Bringaud, F. et al. Evolution of non-LTR retrotransposons in the trypanosomatid genomes: Leishmania major has lost the active elements. Mol. Biochem. Parasitol. 145, 158–170 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Aksoy, S., Williams, S., Chang, S. & Richards, F.F. SLACS retrotransposon from Trypanosoma brucei gambiense is similar to mammalian LINEs. Nucleic Acids Res. 18, 785–792 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Villanueva, M.S., Williams, S.P., Beard, C.B., Richards, F.F. & Aksoy, S. A new member of a family of site-specific retrotransposons is present in the spliced leader RNA genes of Trypanosoma cruzi. Mol. Cell. Biol. 11, 6139–6148 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ngo, H., Tschudi, C., Gull, K. & Ullu, E. Double-stranded RNA induces mRNA degradation in Trypanosoma brucei. Proc. Natl. Acad. Sci. USA 95, 14687–14692 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Robinson, K.A. & Beverley, S.M. Improvements in transfection efficiency and tests of RNA interference (RNAi) approaches in the protozoan parasite Leishmania. Mol. Biochem. Parasitol. 128, 217–228 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Shi, H., Tschudi, C. & Ullu, E. An unusual Dicer-like1 protein fuels the RNA interference pathway in Trypanosoma brucei. RNA 12, 2063–2072 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Durand-Dubief, M., Kohl, L. & Bastin, P. Efficiency and specificity of RNA interference generated by intra- and intermolecular double stranded RNA in Trypanosoma brucei. Mol. Biochem. Parasitol. 129, 11–21 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Shi, H., Tschudi, C. & Ullu, E. Functional replacement of Trypanosoma brucei Argonaute by the human slicer Argonaute2. RNA 12, 943–947 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Shi, H., Ullu, E. & Tschudi, C. Function of the trypanosome Argonaute 1 protein in RNA interference requires the N-terminal RGG domain and arginine 735 in the Piwi domain. J. Biol. Chem. 279, 49889–49893 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Stuart, K.D., Weeks, R., Guilbride, L. & Myler, P.J. Molecular organization of Leishmania RNA virus 1. Proc. Natl. Acad. Sci. USA 89, 8596–8600 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhang, W.W. et al. Comparison of the A2 gene locus in Leishmania donovani and Leishmania major and its control over cutaneous infection. J. Biol. Chem. 278, 35508–35515 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Carver, T.J. et al. ACT: the Artemis Comparison Tool. Bioinformatics 21, 3422–3423 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Kooij, T.W. et al. A Plasmodium whole-genome synteny map: indels and synteny breakpoints as foci for species-specific genes. PLoS Pathog. 1, e44 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Waterston, R.H. et al. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Rochette, A. et al. Characterization and developmental gene regulation of a large gene family encoding amastin surface proteins in Leishmania spp. Mol. Biochem. Parasitol. 140, 205–220 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Yao, C., Donelson, J.E. & Wilson, M.E. The major surface protease (MSP or GP63) of Leishmania sp. Biosynthesis, regulation of expression, and function. Mol. Biochem. Parasitol. 132, 1–16 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Cassago, A. et al. Identification of Leishmania selenoproteins and SECIS element. Mol. Biochem. Parasitol. (2006).

  31. Bankaitis, V.A., Malehorn, D.E., Emr, S.D. & Greene, R. The Saccharomyces cerevisiae SEC14 gene encodes a cytosolic factor that is required for transport of secretory proteins from the yeast Golgi complex. J. Cell Biol. 108, 1271–1281 (1989).

    Article  CAS  PubMed  Google Scholar 

  32. Hall, B.S. et al. TbVps34, the trypanosome orthologue of Vps34, is required for Golgi complex segregation. J. Biol. Chem. 281, 27600–27612 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Jones, S.M., Alb, J.G. Jr., Phillips, S.E., Bankaitis, V.A. & Howell, K.E. A phosphatidylinositol 3-kinase and phosphatidylinositol transfer protein act synergistically in formation of constitutive transport vesicles from the trans-Golgi network. J. Biol. Chem. 273, 10349–10354 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Oza, S.L., Tetaud, E., Ariyanayagam, M.R., Warnon, S.S. & Fairlamb, A.H. A single enzyme catalyses formation of Trypanothione from glutathione and spermidine in Trypanosoma cruzi. J. Biol. Chem. 277, 35853–35861 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Oza, S.L., Shaw, M.P., Wyllie, S. & Fairlamb, A.H. Trypanothione biosynthesis in Leishmania major. Mol. Biochem. Parasitol. 139, 107–116 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Beach, D.H., Holz, G.G. Jr. & Anekwe, G.E. Lipids of Leishmania promastigotes. J. Parasitol. 65, 201–216 (1979).

    Article  CAS  PubMed  Google Scholar 

  37. Rao, V., Fujiwara, N., Porcelli, S.A. & Glickman, M.S. Mycobacterium tuberculosis controls host innate immune activation through cyclopropane modification of a glycolipid effector molecule. J. Exp. Med. 201, 535–543 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bachrach, U. et al. Inhibitory activity of sinefungin and SIBA (5′-deoxy-5′-S-isobutylthio-adenosine) on the growth of promastigotes and amastigotes of different species of Leishmania. FEBS Lett. 121, 287–291 (1980).

    Article  CAS  PubMed  Google Scholar 

  39. Knuepfer, E., Stierhof, Y.D., McKean, P.G. & Smith, D.F. Characterization of a differentially expressed protein that shows an unusual localization to intracellular membranes in Leishmania major. Biochem. J. 356, 335–344 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. McKean, P.G., Denny, P.W., Knuepfer, E., Keen, J.K. & Smith, D.F. Phenotypic changes associated with deletion and overexpression of a stage-regulated gene family in Leishmania. Cell. Microbiol. 3, 511–523 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Yan, S. et al. A low-background inducible promoter system in Leishmania donovani. Mol. Biochem. Parasitol. 119, 217–223 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Cruz, A., Coburn, C.M. & Beverley, S.M. Double targeted gene replacement for creating null mutants. Proc. Natl. Acad. Sci. USA 88, 7170–7174 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Denise, H. et al. Studies on the CPA cysteine peptidase in the Leishmania infantum genome strain JPCM5. BMC Mol. Biol. 7, 42 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Laurentino, E.C. et al. A survey of Leishmania braziliensis genome by shotgun sequencing. Mol. Biochem. Parasitol. 137, 81–86 (2004).

    Article  PubMed  Google Scholar 

  45. Bonfield, J.K., Smith, K. & Staden, R. A new DNA sequence assembly program. Nucleic Acids Res. 23, 4992–4999 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Rutherford, K. et al. Artemis: sequence visualization and annotation. Bioinformatics 16, 944–945 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Staden, R. & McLachlan, A.D. Codon preference and its use in identifying protein coding regions in long DNA sequences. Nucleic Acids Res. 10, 141–156 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Claverie, J.M., Sauvaget, I. & Bougueleret, L. K-tuple frequency analysis: from intron/exon discrimination to T-cell epitope mapping. Methods Enzymol. 183, 237–252 (1990).

    Article  CAS  PubMed  Google Scholar 

  49. Yang, Z. PAML: a program package for phylogenetic analysis by maximum likelihood. Comput. Appl. Biosci. 13, 555–556 (1997).

    CAS  PubMed  Google Scholar 

  50. Price, A.L., Jones, N.C. & Pevzner, P.A. De novo identification of repeat families in large genomes. Bioinformatics 21, i351–i358 (2005).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We acknowledge the support of the Wellcome Trust Sanger Institute core sequencing and informatics groups. We thank N. Goldman (European Bioinformatics Institute) for advice on the evolutionary analysis, C. Hertz-Fowler for help in constructing the figures, J. Shaw for his help in selecting the strain for the L. braziliensis genome sequencing project and D. Harper for quality scores on the sequencing projects. This study was funded by the Wellcome Trust through its support of the Pathogen Sequencing Unit at the Wellcome Trust Sanger Institute. L.O.B. and J.C.R. were recipients of Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) fellowships. D.P.D. was supported by a postgraduate studentship from the Biotechnology and Biological Sciences Research Council. J.C.R. received financial support from the UNICEF/UNDP/WORLD BANK/WHO Special Programme for Research and Training in Tropical Diseases (TDR).

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Authors and Affiliations

  1. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK

    Christopher S Peacock, Kathy Seeger, David Harris, Lee Murphy, Michael A Quail, Nick Peters, Ellen Adlem, Adrian Tivey, Martin Aslett, Arnaud Kerhornou, Alasdair Ivens, Audrey Fraser, Marie-Adele Rajandream, Tim Carver, Halina Norbertczak, Tracey Chillingworth, Zahra Hance, Kay Jagels, Sharon Moule, Doug Ormond, Simon Rutter, Rob Squares, Sally Whitehead, Ester Rabbinowitsch, Claire Arrowsmith, Brian White, Scott Thurston, Daniel Jeffares, Barclay Barrell & Matthew Berriman

  2. Departmento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina, de Ribeirão Preto, Universidade de São Paulo, Avenida Bandeirantes 3900, Ribeirão Preto, CEP 14049-900, São Paulo, Brazil

    Jeronimo C Ruiz, Loislene O Brito, Luiz R O Tosi & Angela K Cruz

  3. Laboratoire de Génomique Fonctionnelle des Trypanosomatides, Universitité Victoir Segalen Bordeaux II, UMR-5162 CNRS, Bordeaux Cedex, 33076, France

    Frédéric Bringaud

  4. Department of Biology, Immunology and Infection Unit, University of York, York, YO10 5YW, UK

    Sandra L Baldauf, Adam Faulconbridge, Daniel P Depledge, Samuel O Oyola & Deborah F Smith

  5. Wellcome Centre for Molecular Parasitology and Division of Infection & Immunity, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, Glasgow, G12 8TN, UK

    James D Hilley & Jeremy C Mottram

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  1. Christopher S Peacock
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Contributions

C.S.P., M.B., D.F.S., A.K.C., J.C.M. and B.B. worked on all aspects of work, contributed to the design of the project and wrote the article. C.S.P. and J.C.R. annotated the genomes; K.S., D.H. and L.M. carried out the assembly and finishing of the genomes; A.F., T.C., Z.H., K.J., S.M., D.O., S.R., R.S., S.W., C.A. and B.W. sequenced the genomes and M.A.Q., H.N., E.R. and S.T. made the clone libraries. N.P., E.A., A.T., M.A., A.K., A.I., M.-A.R. and T.C. wrote and developed software for annotation and comparative analysis of the three genome sequences. F.B. worked on identifying the transposable elements, and S.L.B. and A.F. worked on the phylogenetic analysis of CFA synthase. A.K.C., L.O.B. and L.R.O.T. elucidated the RNAi pathway. D.J. performed the evolutionary analysis, and D.P.D. analyzed the amino acid repeats. D.F.S., J.C.M., S.O.O. and J.D.H. worked on some of the species-specific genes.

Corresponding authors

Correspondence to Christopher S Peacock or Matthew Berriman.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

The predicted structure of the telomere-associated transposable elements (TATEs) found in L. braziliensis. (PDF 41 kb)

Supplementary Fig. 2

RNAi machinery in Leishmania species. (PDF 49 kb)

Supplementary Fig. 3

The phylogenetic tree for cyclopropane fatty acyl phosholipid synthase (CFAS). (PDF 71 kb)

Supplementary Table 1

Summary of motifs reported in RNAi proteins. (PDF 15 kb)

Supplementary Table 2

Leishmania loci with species-specific differences and conserved pseudogenes. (PDF 169 kb)

Supplementary Table 3

dN/dS analysis of Leishmania genes annotated with Gene Ontology Biological Process terms. (PDF 70 kb)

Supplementary Table 4

Genes predicted to have evolved at different rates between the three species of Leishmania. (PDF 230 kb)

Supplementary Table 5

Gene Ontology groups that are overrepresented in the 924 genes that show significant divergence within orthologous groups. (PDF 56 kb)

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Peacock, C., Seeger, K., Harris, D. et al. Comparative genomic analysis of three Leishmania species that cause diverse human disease. Nat Genet 39, 839–847 (2007). https://doi.org/10.1038/ng2053

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