Whole genome sequencing of multiple Leishmania donovani clinical isolates provides insights into population structure and mechanisms of drug resistance

Tim Downing, Hideo Imamura, Saskia Decuypere, Taane G Clark, Graham H Coombs, James A Cotton, James D Hilley, Simonne de Doncker, Ilse Maes, Jeremy C Mottram, Mike A Quail, Suman Rijal, Mandy Sanders, Gabriele Schönian, Olivia Stark, Shyam Sundar, Manu Vanaerschot, Christiane Hertz-Fowler, Jean-Claude Dujardin, Matthew Berriman

Research output: Contribution to journalArticle

245 Citations (Scopus)

Abstract

Visceral leishmaniasis is a potentially fatal disease endemic to large parts of Asia and Africa, primarily caused by the protozoan parasite Leishmania donovani. Here, we report a high-quality reference genome sequence for a strain of L. donovani from Nepal, and use this sequence to study variation in a set of 16 related clinical lines, isolated from visceral leishmaniasis patients from the same region, which also differ in their response to in vitro drug susceptibility. We show that whole-genome sequence data reveals genetic structure within these lines not shown by multilocus typing, and suggests that drug resistance has emerged multiple times in this closely related set of lines. Sequence comparisons with other Leishmania species and analysis of single-nucleotide diversity within our sample showed evidence of selection acting in a range of surface- and transport-related genes, including genes associated with drug resistance. Against a background of relative genetic homogeneity, we found extensive variation in chromosome copy number between our lines. Other forms of structural variation were significantly associated with drug resistance, notably including gene dosage and the copy number of an experimentally verified circular episome present in all lines and described here for the first time. This study provides a basis for more powerful molecular profiling of visceral leishmaniasis, providing additional power to track the drug resistance and epidemiology of an important human pathogen.
Original languageEnglish
Pages (from-to)2143-2156
Number of pages14
JournalGenome Research
Volume21
Issue number12
Early online date28 Oct 2011
DOIs
Publication statusPublished - Dec 2011

Fingerprint

Leishmania donovani
Drug Resistance
Visceral Leishmaniasis
Genome
Gene Dosage
Population
Endemic Diseases
Nepal
Genetic Structures
Leishmania
Genes
Parasites
Epidemiology
Plasmids
Nucleotides
Chromosomes
Pharmaceutical Preparations

Keywords

  • Leishmania donovani
  • reference genome
  • population genetics
  • structural variation
  • aneuploidy

Cite this

Downing, Tim ; Imamura, Hideo ; Decuypere, Saskia ; Clark, Taane G ; Coombs, Graham H ; Cotton, James A ; Hilley, James D ; de Doncker, Simonne ; Maes, Ilse ; Mottram, Jeremy C ; Quail, Mike A ; Rijal, Suman ; Sanders, Mandy ; Schönian, Gabriele ; Stark, Olivia ; Sundar, Shyam ; Vanaerschot, Manu ; Hertz-Fowler, Christiane ; Dujardin, Jean-Claude ; Berriman, Matthew. / Whole genome sequencing of multiple Leishmania donovani clinical isolates provides insights into population structure and mechanisms of drug resistance. In: Genome Research. 2011 ; Vol. 21, No. 12. pp. 2143-2156.
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Downing, T, Imamura, H, Decuypere, S, Clark, TG, Coombs, GH, Cotton, JA, Hilley, JD, de Doncker, S, Maes, I, Mottram, JC, Quail, MA, Rijal, S, Sanders, M, Schönian, G, Stark, O, Sundar, S, Vanaerschot, M, Hertz-Fowler, C, Dujardin, J-C & Berriman, M 2011, 'Whole genome sequencing of multiple Leishmania donovani clinical isolates provides insights into population structure and mechanisms of drug resistance', Genome Research, vol. 21, no. 12, pp. 2143-2156. https://doi.org/10.1101/gr.123430.111

Whole genome sequencing of multiple Leishmania donovani clinical isolates provides insights into population structure and mechanisms of drug resistance. / Downing, Tim; Imamura, Hideo; Decuypere, Saskia; Clark, Taane G; Coombs, Graham H; Cotton, James A; Hilley, James D; de Doncker, Simonne; Maes, Ilse; Mottram, Jeremy C; Quail, Mike A; Rijal, Suman; Sanders, Mandy; Schönian, Gabriele; Stark, Olivia; Sundar, Shyam; Vanaerschot, Manu; Hertz-Fowler, Christiane; Dujardin, Jean-Claude; Berriman, Matthew.

In: Genome Research, Vol. 21, No. 12, 12.2011, p. 2143-2156.

Research output: Contribution to journalArticle

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AU - Imamura, Hideo

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AU - Coombs, Graham H

AU - Cotton, James A

AU - Hilley, James D

AU - de Doncker, Simonne

AU - Maes, Ilse

AU - Mottram, Jeremy C

AU - Quail, Mike A

AU - Rijal, Suman

AU - Sanders, Mandy

AU - Schönian, Gabriele

AU - Stark, Olivia

AU - Sundar, Shyam

AU - Vanaerschot, Manu

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AU - Dujardin, Jean-Claude

AU - Berriman, Matthew

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N2 - Visceral leishmaniasis is a potentially fatal disease endemic to large parts of Asia and Africa, primarily caused by the protozoan parasite Leishmania donovani. Here, we report a high-quality reference genome sequence for a strain of L. donovani from Nepal, and use this sequence to study variation in a set of 16 related clinical lines, isolated from visceral leishmaniasis patients from the same region, which also differ in their response to in vitro drug susceptibility. We show that whole-genome sequence data reveals genetic structure within these lines not shown by multilocus typing, and suggests that drug resistance has emerged multiple times in this closely related set of lines. Sequence comparisons with other Leishmania species and analysis of single-nucleotide diversity within our sample showed evidence of selection acting in a range of surface- and transport-related genes, including genes associated with drug resistance. Against a background of relative genetic homogeneity, we found extensive variation in chromosome copy number between our lines. Other forms of structural variation were significantly associated with drug resistance, notably including gene dosage and the copy number of an experimentally verified circular episome present in all lines and described here for the first time. This study provides a basis for more powerful molecular profiling of visceral leishmaniasis, providing additional power to track the drug resistance and epidemiology of an important human pathogen.

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KW - population genetics

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