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      Genome-Scale Multilocus Microsatellite Typing of Trypanosoma cruzi Discrete Typing Unit I Reveals Phylogeographic Structure and Specific Genotypes Linked to Human Infection

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          Abstract

          Trypanosoma cruzi is the most important parasitic infection in Latin America and is also genetically highly diverse, with at least six discrete typing units (DTUs) reported: Tc I, IIa, IIb, IIc, IId, and IIe. However, the current six-genotype classification is likely to be a poor reflection of the total genetic diversity present in this undeniably ancient parasite. To determine whether epidemiologically important information is “hidden” at the sub-DTU level, we developed a 48-marker panel of polymorphic microsatellite loci to investigate population structure among 135 samples from across the geographic distribution of TcI. This DTU is the major cause of resurgent human disease in northern South America but also occurs in silvatic triatomine vectors and mammalian reservoir hosts throughout the continent. Based on a total dataset of 12,329 alleles, we demonstrate that silvatic TcI populations are extraordinarily genetically diverse, show spatial structuring on a continental scale, and have undergone recent biogeographic expansion into the southern United States of America. Conversely, the majority of human strains sampled are restricted to two distinct groups characterised by a considerable reduction in genetic diversity with respect to isolates from silvatic sources. In Venezuela, most human isolates showed little identity with known local silvatic strains, despite frequent invasion of the domestic setting by infected adult vectors. Multilocus linkage indices indicate predominantly clonal parasite propagation among all populations. However, excess homozygosity among silvatic strains and raised heterozygosity among domestic populations suggest that some level of genetic recombination cannot be ruled out. The epidemiological significance of these findings is discussed.

          Author Summary

          The arrival of the Trypanosoma cruzi online genome now provides vital information for the study of Chagas disease. Using this resource, we identified and developed a genome-scale panel of rapidly evolving microsatellite markers that can be used to unravel the micro-epidemiology of this parasite. We then tested these against a panel of isolates belonging to the most widely occurring and ancient major lineage, T. cruzi I (TcI). Our study includes samples from across the geographical distribution of this lineage, including isolates from wild vectors, domestic vectors, as well as wild mammalian reservoirs and human hosts. This is the first time T. cruzi has been subjected to such high-resolution population genetic analysis. Our study shows that important epidemiological information lies at the intra-lineage level, especially when wild and domestic populations of parasite are compared. Crucially, in Venezuela, where Chagas disease may be resurgent despite decades of control effort, genotypes of parasites found in the wild are rarely represented in humans, despite evidence that infected wild vectors do invade houses. In this manuscript, we examine the epidemiological implications of this finding and others, and suggest how the approach we have developed can now be used to investigate the true nature of parasite transmission at Chagas disease foci throughout the Americas.

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          Most cited references58

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          Arlequin (version 3.0): An integrated software package for population genetics data analysis

          Arlequin ver 3.0 is a software package integrating several basic and advanced methods for population genetics data analysis, like the computation of standard genetic diversity indices, the estimation of allele and haplotype frequencies, tests of departure from linkage equilibrium, departure from selective neutrality and demographic equilibrium, estimation or parameters from past population expansions, and thorough analyses of population subdivision under the AMOVA framework. Arlequin 3 introduces a completely new graphical interface written in C++, a more robust semantic analysis of input files, and two new methods: a Bayesian estimation of gametic phase from multi-locus genotypes, and an estimation of the parameters of an instantaneous spatial expansion from DNA sequence polymorphism. Arlequin can handle several data types like DNA sequences, microsatellite data, or standard multi-locus genotypes. A Windows version of the software is freely available on http://cmpg.unibe.ch/software/arlequin3.
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            genalex 6: genetic analysis in Excel. Population genetic software for teaching and research

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              The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease.

              Whole-genome sequencing of the protozoan pathogen Trypanosoma cruzi revealed that the diploid genome contains a predicted 22,570 proteins encoded by genes, of which 12,570 represent allelic pairs. Over 50% of the genome consists of repeated sequences, such as retrotransposons and genes for large families of surface molecules, which include trans-sialidases, mucins, gp63s, and a large novel family (>1300 copies) of mucin-associated surface protein (MASP) genes. Analyses of the T. cruzi, T. brucei, and Leishmania major (Tritryp) genomes imply differences from other eukaryotes in DNA repair and initiation of replication and reflect their unusual mitochondrial DNA. Although the Tritryp lack several classes of signaling molecules, their kinomes contain a large and diverse set of protein kinases and phosphatases; their size and diversity imply previously unknown interactions and regulatory processes, which may be targets for intervention.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                May 2009
                May 2009
                1 May 2009
                : 5
                : 5
                : e1000410
                Affiliations
                [1 ]London School of Hygiene and Tropical Medicine, London, United Kingdom
                [2 ]Instituto de Medicina Tropical, Universidad Central de Venezuela, Los Chaguaramos, Caracas, Venezuela
                [3 ]Centro Nacional de Enfermedades Tropicales, Santa Cruz, Bolivia
                [4 ]Universidad Mayor de San Simon, Cochabamba, Bolivia
                [5 ]Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Patologia Experimental, Universidad Nacional de Salta, Salta, Argentina
                [6 ]Instituto Evandro Chagas, Rodovia, Belem, Para, Brazil
                The Pennsylvania State University, United States of America
                Author notes

                Conceived and designed the experiments: MSL MAM MWG. Performed the experiments: MSL HJC. Analyzed the data: MSL MDL. Contributed reagents/materials/analysis tools: HJC MDL MY JV FT PD VCV SAV. Wrote the paper: MSL MAM MDL MY.

                Article
                09-PLPA-RA-0142R2
                10.1371/journal.ppat.1000410
                2669174
                19412340
                480fdda8-07d2-4936-8587-b40dce5686e0
                Llewellyn et al. 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
                : 30 January 2009
                : 1 April 2009
                Page count
                Pages: 9
                Categories
                Research Article
                Evolutionary Biology/Microbial Evolution and Genomics
                Infectious Diseases/Epidemiology and Control of Infectious Diseases
                Infectious Diseases/Neglected Tropical Diseases
                Infectious Diseases/Protozoal Infections
                Microbiology/Parasitology
                Molecular Biology/Molecular Evolution
                Public Health and Epidemiology/Epidemiology
                Public Health and Epidemiology/Infectious Diseases

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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