title: Evolutionary genomics of epidemic visceral leishmaniasis in the Indian subcontinent.
abstract: Leishmania donovani causes visceral leishmaniasis (VL), the second most deadly vector-borne parasitic disease. A recent epidemic in the Indian subcontinent (ISC) caused up to 80% of global VL and over 30,000 deaths per year. Resistance against antimonial drugs has probably been a contributing factor in the persistence of this epidemic. Here we use whole genome sequences from 204 clinical isolates to track the evolution and epidemiology of L. donovani from the ISC. We identify independent radiations that have emerged since a bottleneck coincident with 1960s DDT spraying campaigns. A genetically distinct population frequently resistant to antimonials has a two base-pair insertion in the aquaglyceroporin gene LdAQP1 that prevents the transport of trivalent antimonials. We find evidence of genetic exchange between ISC populations, and show that the mutation in LdAQP1 has spread by recombination. Our results reveal the complexity of L. donovani evolution in the ISC in response to drug treatment.
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Hideo
authors.initials: H
authors.lastname: Imamura
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, United Kingdom.|School of Maths, Applied Maths and Statistics, National University of Ireland Galway, Galway, Ireland.
authors.forename: Tim
authors.identifier: http://orcid.org/0000-0002-8385-6730
authors.initials: T
authors.lastname: Downing
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Frederik
authors.identifier: http://orcid.org/0000-0003-2542-5585
authors.initials: F
authors.lastname: Van den Broeck
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Mandy J
authors.initials: MJ
authors.lastname: Sanders
authors.affiliation: BP Koirala Institute of Health Sciences, Dharan, Nepal.
authors.forename: Suman
authors.initials: S
authors.lastname: Rijal
authors.affiliation: Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.
authors.forename: Shyam
authors.initials: S
authors.lastname: Sundar
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Mannaert
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Manu
authors.initials: M
authors.lastname: Vanaerschot
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Maya
authors.initials: M
authors.lastname: Berg
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Géraldine
authors.initials: G
authors.lastname: De Muylder
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Franck
authors.initials: F
authors.lastname: Dumetz
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Cuypers
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Maes
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Domagalska
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.|Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: Saskia
authors.initials: S
authors.lastname: Decuypere
authors.affiliation: BP Koirala Institute of Health Sciences, Dharan, Nepal.
authors.forename: Keshav
authors.identifier: http://orcid.org/0000-0002-9747-3431
authors.initials: K
authors.lastname: Rai
authors.affiliation: BP Koirala Institute of Health Sciences, Dharan, Nepal.
authors.forename: Surendra
authors.initials: S
authors.lastname: Uranw
authors.affiliation: BP Koirala Institute of Health Sciences, Dharan, Nepal.
authors.forename: Narayan Raj
authors.initials: NR
authors.lastname: Bhattarai
authors.affiliation: BP Koirala Institute of Health Sciences, Dharan, Nepal.
authors.forename: Basudha
authors.initials: B
authors.lastname: Khanal
authors.affiliation: Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Prajapati
authors.affiliation: Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.
authors.forename: Smriti
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Institut für Mikrobiologie und Hygiene, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Olivia
authors.initials: O
authors.lastname: Stark
authors.affiliation: Institut für Mikrobiologie und Hygiene, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schönian
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Harry P
authors.identifier: http://orcid.org/0000-0002-9963-1827
authors.initials: HP
authors.lastname: De Koning
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.|Department of Chemistry and Chemical Biology, Northeastern University, Boston, United States.
authors.forename: Luca
authors.initials: L
authors.lastname: Settimo
authors.affiliation: Laboratory of Molecular Parasitology, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Benoit
authors.identifier: http://orcid.org/0000-0002-0353-365X
authors.initials: B
authors.lastname: Vanhollebeke
authors.affiliation: Department of Infectious Diseases and Immunology, Council of Scientific and Industrial Research, Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Syamal
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Ostyn
authors.affiliation: Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Marleen
authors.identifier: http://orcid.org/0000-0001-8051-6776
authors.initials: M
authors.lastname: Boelaert
authors.affiliation: Department of Biomedical Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Matthew
authors.identifier: http://orcid.org/0000-0002-9581-0377
authors.initials: M
authors.lastname: Berriman
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.|Department of Biomedical Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Dujardin
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: James A
authors.identifier: http://orcid.org/0000-0001-5475-3583
authors.initials: JA
authors.lastname: Cotton
mesh_terms: D000965:Antimony / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000494:pharmacology; D051398:Aquaporin 1 / Q000235:genetics; D004351:Drug Resistance; D058872:Epidemics; D019143:Evolution, Molecular; D014644:Genetic Variation; D018503:Genome, Protozoan; D006801:Humans; D007194:India / Q000453:epidemiology; D007893:Leishmania donovani / Q000145:classification* / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D007898:Leishmaniasis, Visceral / Q000453:epidemiology* / Q000469:parasitology*; D017720:Molecular Epidemiology; D009390:Nepal / Q000453:epidemiology; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA
chemical_list: D000981:Antiprotozoal Agents; D051398:Aquaporin 1; D000965:Antimony
keywords: epidemiology; evolution; genomics; global health; infectious disease; leishmania donovani; microbiology