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      Genetic Structure and Evolution of the Leishmania Genus in Africa and Eurasia: What Does MLSA Tell Us

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          Abstract

          Leishmaniasis is a complex parasitic disease from a taxonomic, clinical and epidemiological point of view. The role of genetic exchanges has been questioned for over twenty years and their recent experimental demonstration along with the identification of interspecific hybrids in natura has revived this debate. After arguing that genetic exchanges were exceptional and did not contribute to Leishmania evolution, it is currently proposed that interspecific exchanges could be a major driving force for rapid adaptation to new reservoirs and vectors, expansion into new parasitic cycles and adaptation to new life conditions.

          To assess the existence of gene flows between species during evolution we used MLSA-based (MultiLocus Sequence Analysis) approach to analyze 222 Leishmania strains from Africa and Eurasia to accurately represent the genetic diversity of this genus. We observed a remarkable congruence of the phylogenetic signal and identified seven genetic clusters that include mainly independent lineages which are accumulating divergences without any sign of recent interspecific recombination. From a taxonomic point of view, the strong genetic structuration of the different species does not question the current classification, except for species that cause visceral forms of leishmaniasis ( L. donovani, L. infantum and L. archibaldi). Although these taxa cause specific clinical forms of the disease and are maintained through different parasitic cycles, they are not clearly distinct and form a continuum, in line with the concept of species complex already suggested for this group thirty years ago. These results should have practical consequences concerning the molecular identification of parasites and the subsequent therapeutic management of the disease.

          Author Summary

          The mechanisms of genomic and genetic evolution in the Leishmania order, a protozoan group that contains about twenty pathogenic species, are the focus of much debate. Although these parasites have been considered for years to reproduce clonally, recent works have demonstrated both experimental and in natura intra- and inter-specific hybrids. Interspecific exchanges should be sources of plasticity and adaptation to new parasitic cycles. In this work we used a MultiLocus Sequence Analysis approach to analyze 222 Leishmania strains that belong to different species and were isolated in African and Eurasian foci. This analysis classified the different strains in seven robust genetic clusters that showed remarkable congruence of the phylogenetic message between them. From a taxonomic point of view, the seven clusters overlapped with most of the biochemical taxonomic groups currently in use except for species causing visceral forms of leishmaniasis. Contrary to what expected, we did not detect traces of interspecific recombination and genetic exchanges between the different species. Finally, these results should have consequences on the taxonomy, on our understanding of the epidemiology and on the therapeutic management of these infections.

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          Most cited references54

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          Analyzing the mosaic structure of genes.

          Some genes in prokaryotes consist of a mosaic of regions derived from different ancestors by horizontal gene transfer. A method is described for demonstrating the statistical significance of such mosaic structure and for locating the crossover points separating different regions.
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            An exact nonparametric method for inferring mosaic structure in sequence triplets.

            Statistical tests for detecting mosaic structure or recombination among nucleotide sequences usually rely on identifying a pattern or a signal that would be unlikely to appear under clonal reproduction. Dozens of such tests have been described, but many are hampered by long running times, confounding of selection and recombination, and/or inability to isolate the mosaic-producing event. We introduce a test that is exact, nonparametric, rapidly computable, free of the infinite-sites assumption, able to distinguish between recombination and variation in mutation/fixation rates, and able to identify the breakpoints and sequences involved in the mosaic-producing event. Our test considers three sequences at a time: two parent sequences that may have recombined, with one or two breakpoints, to form the third sequence (the child sequence). Excess similarity of the child sequence to a candidate recombinant of the parents is a sign of recombination; we take the maximum value of this excess similarity as our test statistic Delta(m,n,b). We present a method for rapidly calculating the distribution of Delta(m,n,b) and demonstrate that it has comparable power to and a much improved running time over previous methods, especially in detecting recombination in large data sets.
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              Chromosome and gene copy number variation allow major structural change between species and strains of Leishmania.

              Leishmania parasites cause a spectrum of clinical pathology in humans ranging from disfiguring cutaneous lesions to fatal visceral leishmaniasis. We have generated a reference genome for Leishmania mexicana and refined the reference genomes for Leishmania major, Leishmania infantum, and Leishmania braziliensis. This has allowed the identification of a remarkably low number of genes or paralog groups (2, 14, 19, and 67, respectively) unique to one species. These were found to be conserved in additional isolates of the same species. We have predicted allelic variation and find that in these isolates, L. major and L. infantum have a surprisingly low number of predicted heterozygous SNPs compared with L. braziliensis and L. mexicana. We used short read coverage to infer ploidy and gene copy numbers, identifying large copy number variations between species, with 200 tandem gene arrays in L. major and 132 in L. mexicana. Chromosome copy number also varied significantly between species, with nine supernumerary chromosomes in L. infantum, four in L. mexicana, two in L. braziliensis, and one in L. major. A significant bias against gene arrays on supernumerary chromosomes was shown to exist, indicating that duplication events occur more frequently on disomic chromosomes. Taken together, our data demonstrate that there is little variation in unique gene content across Leishmania species, but large-scale genetic heterogeneity can result through gene amplification on disomic chromosomes and variation in chromosome number. Increased gene copy number due to chromosome amplification may contribute to alterations in gene expression in response to environmental conditions in the host, providing a genetic basis for disease tropism.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, USA )
                1935-2727
                1935-2735
                June 2013
                13 June 2013
                : 7
                : 6
                : e2255
                Affiliations
                [1 ]Department of Parasitology, Montpellier University Hospital, Montpellier, France
                [2 ]Pasteur Institute, Genotyping of Pathogens and Public Health, Paris, France
                [3 ]Méthodes et Algorithmes pour la Bioinformatique, LIRMM, UMR 5506 CNRS – Université Montpellier 2, Montpellier, France, Institut de Biologie Computationnelle, Montpellier, France
                [4 ]MIVEGEC, CNRS 5290, IRD 224, Universités Montpellier 1 et 2, Montpellier, France
                [5 ]Parasitologie-Mycologie, Centre Hospitalier Universitaire de Nice et Faculté de Médecine, Université de Nice-Sophia Antipolis, Inserm U 1065, Nice, France
                Charité University Medicine Berlin, Germany
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: CR LD VB FC. Performed the experiments: FEB LD CR. Analyzed the data: CR FEB LD VB FC PM. Contributed reagents/materials/analysis tools: FP VB FC. Wrote the paper: CR LD FEB. DNA sequencing: FEB LD.

                Article
                PNTD-D-12-01489
                10.1371/journal.pntd.0002255
                3681676
                23785530
                e7477755-3474-497d-8129-a99f48e626d1
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 19 November 2012
                : 25 April 2013
                Page count
                Pages: 14
                Funding
                FEB was a recipient of a PhD grant from the Fondation Infectiopole Sud ( http://www.infectiopolesud.com). This study was also supported by a French National Project, ANR 06-SEST-20 IAEL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Evolutionary Biology
                Genetics
                Genomics
                Microbiology
                Medicine
                Infectious Diseases

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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