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Genetic and geographic structure of Schistosoma japonicum miracidia sampled in Sichuan, China. (a) Map showing locations of the 12 villages sampled, indicated by colored dots. Yellow lines represent major roads and blue lines indicate rivers and major streams. The map was created with ArcGIS ArcMap⁵² (version 10.6; https://desktop.arcgis.com/en/arcmap/). (b) Proportion of rare alleles shared among villages with mean, interquartile ranges, and outliers beyond the 2.5th percentile shown. Inter-village distances are Euclidean. All comparisons were significantly different (all p < 2.2 × 10–16; Mann–Whitney U test). (c) Principal component analysis (PCA) of genetic variation from 200 miracidia across all 12 villages. The first two principal components (PC1 and PC2) respectively account for 4.2% and 2.5% of the genetic variation among individuals. (d) Neighbor-joining tree of miracidia colored by village (top) and sampling timepoint (bottom). (e) ADMIXTURE plot showing optimal k = 4 genetic clusters grouped by village and sampling timepoint. Timepoints are labeled with year of collection (e.g., 2008 in d or 08 in e); Summer and late Fall 2016 collections are labeled with small s or f, respectively.
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Schistosomiasis persists in Asian regions despite aggressive elimination measures. To identify factors enabling continued parasite transmission, we performed reduced representation genome sequencing on Schistosoma japonicum miracidia collected across multiple years from transmission hotspots in Sichuan, China. We discovered strong geographic struct...
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Citations
... It remains unknown if these unique genetic traits are related to differences in transmission and disease epidemiology, however, it is certainly clear that Zanzibari S. haematobium populations are not comparable to those from the African mainland. Increased sample sets and population genomic level analyses (Shortt et al., 2021) would provide further insights into these genetic traits and if they impact control interventions. ...
Zanzibar is among the few places in sub-Saharan Africa where interruption of Schistosoma transmission seems an achievable goal. Our systematic review identifies and discusses milestones in schistosomiasis research, control and elimination efforts in Zanzibar over the past 100 years. The search in online databases, libraries, and the World Health Organization Archives revealed 153 records published between May 1928 and August 2022. The content of records was summarised to highlight the pivotal work leading towards urogenital schistosomiasis elimination and remaining research gaps. The greatest achievement following 100 years of schistosomiasis interventions and research is undoubtedly the improved health of Zanzibaris, exemplified by the reduction in Schistosoma haematobium prevalence from>50% historically down to<5% in 2020, and the absence of severe morbidities. Experiences from Zanzibar have contributed to global schistosomiasis guidelines, whilst also revealing challenges that impede progression towards elimination. Challenges include: transmission heterogeneity requiring micro-targeting of interventions, post-treatment recrudescence of infections in transmission hotspots, biological complexity of intermediate host snails, emergence of livestock Schistosoma species complicating surveillance whilst creating the risk for interspecies hybridisation, insufficient diagnostics performance for light intensity infections and female genital schistosomiasis, and a lack of acceptable sanitary alternatives to freshwater bodies. Our analysis of the past revealed that much can be achieved in the future with practical implementation of integrated interventions, alongside operational research. With continuing national and international commitments, interruption of S. haematobium transmission across both islands is within reach by 2030, signposting the future demise of urogenital schistosomiasis across other parts of sub-Saharan Africa.
... Various local scale applications of helminth population genomics have included studying the potential for transmission foci, the potential impacts of chemotherapeutic control measures and assessment of reservoir hosts (table 2). An example addressing transmission dynamics is provided by Shortt et al. (2021) where miracidia of Schistosoma japonicum were collected from 12 villages (maximum distance ∼25 km) in Sichuan, China, in 2007China, in , 2008China, in , 2010 and 2016. Using model-based and non-model-based clustering analyses, individuals from the same village largely belonged to the same cluster, regardless of the timeperiod sampled. ...
... Sibling miracidia were also found in pre-praziquantel and post-praziquantel treatment of the same host, indicating that individuals likely retained infections of adult flukes. Collectively, the results of Shortt et al. (2021) parallel findings from a microsatellite-based landscape genetics study on the roundworm A. lumbricoides in that there are local parasite transmission foci and that these foci are stable over time and after drug treatment. ...
... At the individual host level, Berger et al. (2021) did not find evidence of highly related S. mansoni miracidia from individuals in shoreline villages of Lake Victoria. Vianney et al. (2022), however, did find some related S. mansoni miracidia from island villages of Lake Victoria using the relatedness measure of Shortt et al. (2021). The relatedness measure of Shortt et al. (2021) is a withinstudy relative measure as the proportion of shared alleles cut-off to determine relatedness differs in Vianney et al. (2022); thus, a direct comparison between the S. japonicum and S. mansoni studies is not possible. ...
Next generation sequencing technologies have facilitated a shift from a few targeted loci in population genetic studies to whole genome approaches. Here, we review the types of questions and inferences regarding the population biology and evolution of parasitic helminths being addressed within the field of population genomics. Topics include parabiome, hybridization, population structure, loci under selection and linkage mapping. We highlight various advances, and note the current trends in the field, particularly a focus on human-related parasites despite the inherent biodiversity of helminth species. We conclude by advocating for a broader application of population genomics to reflect the taxonomic and life history breadth displayed by helminth parasites. As such, our basic knowledge about helminth population biology and evolution would be enhanced while the diversity of helminths in itself would facilitate population genomic comparative studies to address broader ecological and evolutionary concepts.
... WGS from individual miracidia and cercaria, the readily available schistosome life stages, is challenging due to the low quantity of DNA available from these physically small samples [(15, 26); see also discussion in Rey et al. (6)]. Recent advances that use whole genome amplification (WGA) ameliorate this challenge, and thus substantially increase the feasibility of genomic surveillance by enabling WGS of individual parasites (12,27,28). Low-input DNA genomic library preparation approaches that accomplish amplification through PCR have also shown promising results using schistosome eggs or larval stage samples (29). ...
... A number of studies that have used WGS to sequence DNA from miracidia seem to have little host contamination (12,27,28), suggesting minimal off-target sequencing of host DNA using filtration and washing protocols to separate miracidia from host stool, as is used for the miracidial hatching test in China (30). However, other studies (13) have reported higher rates of contamination (based on higher fractions of genome sequencing reads that do not map to schistosome reference genomes), suggesting contamination may be more of an issue in some cases. ...
... The biology of schistosomes requires particular attention when considering experimental design for genomic scan approaches to detect and interpret patterns of selection. Schistosomes are overall genetically diverse, but they can be far more closely related in small geographic areas such as in areas of re-emergence or hotspots (6,12,27,90). This makes sense biologically because of the large number of eggs a single worm pair can produce, combined with the clonal nature and large numbers of cercaria produced from a single snail intermediate host. ...
Schistosomiasis is a neglected tropical disease caused by multiple parasitic Schistosoma species, and which impacts over 200 million people globally, mainly in low- and middle-income countries. Genomic surveillance to detect evidence for natural selection in schistosome populations represents an emerging and promising approach to identify and interpret schistosome responses to ongoing control efforts or other environmental factors. Here we review how genomic variation is used to detect selection, how these approaches have been applied to schistosomes, and how future studies to detect selection may be improved. We discuss the theory of genomic analyses to detect selection, identify experimental designs for such analyses, and review studies that have applied these approaches to schistosomes. We then consider the biological characteristics of schistosomes that are expected to respond to selection, particularly those that may be impacted by control programs. Examples include drug resistance, host specificity, and life history traits, and we review our current understanding of specific genes that underlie them in schistosomes. We also discuss how inherent features of schistosome reproduction and demography pose substantial challenges for effective identification of these traits and their genomic bases. We conclude by discussing how genomic surveillance for selection should be designed to improve understanding of schistosome biology, and how the parasite changes in response to selection.
... www.nature.com/scientificreports/ Population genetic analyses can provide insight into transmission patterns and responses by schistosome populations to control programs [7][8][9] . Schistosoma mansoni has a multitiered population structure. ...
... Schistosomiasis persists throughout the world and is now spreading from rural to urban areas despite control efforts, including successful treatment using the drug praziquantel 6,19 . Methods to detect the sources of recurring infections and the spread of new infections are of paramount importance, and genetic analysis has become prominent in the epidemiological toolbox 9 . In this study, we analyze allele frequency profiles calculated from fourteen microsatellite loci in Schistosoma mansoni infrapopulations existing in three communities in the state of Bahia, Brazil. ...
... Gene identity varies substantially among infrapopulations in the same community, although the average gene identity in the three communities is roughly the same, 0.348-0.357. Worm burden is a principal determinant of gene identity in infrapopulations, although there are contributing factors such as inbreeding and genetic kinship among the worms within an infrapopulation 8,9,13 . The high variability of gene identity among infrapopulations within a community is important because migration of S. mansoni to new locations involves human feces which transfer fertilized eggs from an entire infrapopulation. ...
Patterns of diversity in pathogen genomes provide a window into the spatiotemporal spread of disease. In this study, we tested the hypothesis that Schistosoma mansoni parasites form genetic clusters that coincide with the communities of their human hosts. We also looked for genetic clustering of parasites at the sub-community level. Our data consists of 14 microsatellite DNA markers, typed from pooled DNA samples from N=254 N = 254 infected individuals living in three Brazilian communities. We found a one-to-one correspondence between genetic clusters found by K-means cluster analysis and communities when K = 3 . These clusters are also easily identified in a neighbor-joining tree and principal coordinates plots. K-means analysis with K > 3 also reveals genetic clusters of parasites at the sub-community level. These sub-clusters also appear on the neighbor-joining tree and principal coordinates plots. A surprising finding is a genetic relationship between subgroups in widely separated human communities. This connection suggests the existence of common transmission sites that have wide influence. In summary, the genetic structure of S. mansoni in Brazil juxtaposes local isolation that is occasionally broken by long-range migration. Permanent eradication of schistosomes will require both local efforts and the identification of regional infection reservoirs.
... There are several countries and areas that have made great progress in the fight against schistosomiasis in the past and may aim to achieve full interruption of transmission in the next few years [6][7][8][9][10]. These countries will need clear guidance on which intervention strategies to apply, which population groups to target, which diagnostics to use, and at what thresholds to change and adapt their strategies [11][12][13]. ...
Background
Global elimination of schistosomiasis as a public health problem is set as target in the new World Health Organization’s Neglected Tropical Diseases Roadmap for 2030. Due to a long history of interventions, the Zanzibar islands of Tanzania have reached this goal since 2017. However, challenges occur on the last mile towards interruption of transmission. Our study will investigate new tools and strategies for breaking schistosomiasis transmission.
Methods
The study is designed as an intervention study, documented through repeated cross-sectional surveys (2020–2024). The primary endpoint will be the sensitivity of a surveillance-response approach to detect and react to outbreaks of urogenital schistosomiasis over three years of implementation. The surveys and multi-disciplinary interventions will be implemented in 20 communities in the north of Pemba island. In low-prevalence areas, surveillance-response will consist of active, passive and reactive case detection, treatment of positive individuals, and focal snail control. In hotspot areas, mass drug administration, snail control and behaviour change interventions will be implemented. Parasitological cross-sectional surveys in 20 communities and their main primary schools will serve to adapt the intervention approach annually and to monitor the performance of the surveillance-response approach and impact of interventions. Schistosoma haematobium infections will be diagnosed using reagent strips and urine filtration microscopy, and by exploring novel point-of-care diagnostic tests.
Discussion
Our study will shed light on the field applicability and performance of novel adaptive intervention strategies, and standard and new diagnostic tools for schistosomiasis elimination. The evidence and experiences generated by micro-mapping of S. haematobium infections at community level, micro-targeting of new adaptive intervention approaches, and application of novel diagnostic tools can guide future strategic plans for schistosomiasis elimination in Zanzibar and inform other countries aiming for interruption of transmission.
Trial registration ISRCTN, ISCRCTN91431493. Registered 11 February 2020, https://www.isrctn.com/ISRCTN91431493
... populations have changed following MDA [22][23][24] , these have been restricted to a limited number of molecular markers. By contrast, few studies have analysed whole-genome or exome sequence data from populations of S. mansoni 17,25 or other schistosomes 17,[25][26][27] . ...
... As expected, our results show that MDA targeting school-age children has had a limited impact on the parasite population size or diversity at the community level. Our finding that the population of S. mansoni in Mayuge remains essentially panmictic is in contrast to Schistosoma japonicum populations in China, where one sign that elimination efforts have drastically reduced parasite circulation is the high level of population structure and relatedness between parasites from different hosts 27,103 . Together, these results suggest we are a long way from dramatically reducing schistosome transmission in this area of high infection prevalence and intensity. ...
Control and elimination of the parasitic disease schistosomiasis relies on mass administration of praziquantel. Whilst these programmes reduce infection prevalence and intensity, their impact on parasite transmission and evolution is poorly understood. Here we examine the genomic impact of repeated mass drug administration on Schistosoma mansoni populations with documented reduced praziquantel efficacy. We sequenced whole-genomes of 198 S. mansoni larvae from 34 Ugandan children from regions with contrasting praziquantel exposure. Parasites infecting children from Lake Victoria, a transmission hotspot, form a diverse panmictic population. A single round of treatment did not reduce this diversity with no apparent population contraction caused by long-term praziquantel use. We find evidence of positive selection acting on members of gene families previously implicated in praziquantel action, but detect no high frequency functionally impactful variants. As efforts to eliminate schistosomiasis intensify, our study provides a foundation for genomic surveillance of this major human parasite.
... At the infrapopulation level, parentage analyses using genome-scale polymorphism data (e.g. (Shortt et al., 2020)) of large miracidial samples per child may become a powerful tool to assess the strength of the genetic bottleneck and dissect re-infection from persistent infections following treatment. At the component population level, genomic data of a few miracidial samples from a large number of hosts will provide major insights into the long-term regional effects of treatment programs, ultimately allowing the identification of the main factors/interventions that could help schistosomiasis elimination. ...
Blood flukes within the genus Schistosoma (schistosomes) are responsible for the major disease, schistosomiasis, in tropical and sub-tropical areas. This disease is predominantly present on the African continent with more than 85% of the human cases. Schistosomes are also parasites of veterinary importance infecting livestock and wildlife. Schistosoma population genetic structure and diversity are important characteristics that may reflect variations in selection pressures such as those induced by host (mammalian and snail) environments, habitat change, migration and also treatment/control interventions, all of which also shape speciation and evolution of the whole Schistosoma genus. Investigations intoschistosome population genetic structure, diversity and evolution has been an area of important debate and research. Supported by advancesin molecular techniques with capabilitiesfor multi-locus genetic analyses for single larvae schistosome geneticinvestigations have greatly progressed in the last decade. This paper aims to review the genetic studies of both animal and human infecting schistosome. Population genetic structures are reviewed at different spatial scales: local, regional or continental (i.e. phylogeography). Within species genetic diversities are discussed compared and the compounding factors discussed, including the effect of mass drug administration. Finally, the ability for intra-species hybridisation questions species integrities and poses many questions in relation to the natural epidemiology of co-endemic species. Here we review molecularly confirmed hybridisation events (in relation to human disease) and discuss the possible impact for ongoing and future control and elimination.
... Recently, higher resolution reduced-representation genomic methods (i.e., doubledigest RAD-seq [10]) have been used to infer parasite population genetic structure and transmission patterns [11]. These studies showed that degrees of parasite diversity and relatedness vary within-and between-hosts, highlighting the utility of large genetic data sets to understand fine-scale transmission pathways [12]. However, even these higher-resolution data have limited utility for inferring variation among functional genomic regions (e.g., protein-coding diversity) that may be important for understanding responses of the parasite population to control-driven selection. ...
... To date, however, population genomic studies of schistosomiasis have been limited by the need to pool individual samples to obtain adequate DNA, resulting in estimates of broad regional patterns of parasite genetic structure [13][14][15]. Recently, several studies demonstrated that individual miracidia can be effectively used for large-scale genotyping through the use of whole genome amplification (WGA), thereby circumventing limitations imposed by low yield of single miracidium samples [11,12,16,17]. ...
... A total of 22 archived field-collected samples of S. japonicum miracidia were obtained from 11 infected humans in Sichuan Province, China in 2016 during village-wide infection surveys using methods described in [19,21] as part of an ongoing study of the reemergence and persistence of schistosomiasis in regions targeted for elimination. Individual miracidia were collected from two villages, denoted as village C and M, in which village C was sampled using RADseq data in a previous study [12]. Generally, we designed this sampling to test our approach for surveying multiple fine-scale levels of relatedness, including: within-host, between hosts from a single village, and between hosts from different nearby villages. ...
Genomic approaches hold great promise for resolving unanswered questions about transmission patterns and responses to control efforts for schistosomiasis and other neglected tropical diseases. However, the cost of generating genomic data and the challenges associated with obtaining sufficient DNA from individual schistosome larvae (miracidia) from mammalian hosts have limited the application of genomic data for studying schistosomes and other complex macroparasites. Here, we demonstrate the feasibility of utilizing whole genome amplification and sequencing (WGS) to analyze individual archival miracidia. As an example, we sequenced whole genomes of 22 miracidia from 11 human hosts representing two villages in rural Sichuan, China, and used these data to evaluate patterns of relatedness and genetic diversity. We also down-sampled our dataset to test how lower coverage sequencing could increase the cost effectiveness of WGS while maintaining power to accurately infer relatedness. Collectively, our results illustrate that population-level WGS datasets are attainable for individual miracidia and represent a powerful tool for ultimately providing insight into overall genetic diversity, parasite relatedness, and transmission patterns for better design and evaluation of disease control efforts.
Soil-transmitted helminths (STHs) are intestinal pathogens affecting over a billion people worldwide. STH control relies on microsopy-based diagnostics to monitor parasite prevalence and enable post-treatment surveillance, however, molecular diagnostics are rapidly being developed due to increased sensitivity, particularly in low-STH-prevalence settings. The genetic diversity of helminths and its potential impact on molecular diagnostics remains unclear. Using low-coverage genome sequencing, we assessed the presence of STHs in worm, faecal and purified egg samples from 27 countries, identifying differences in the genetic connectivity and diversity of STH-positive samples across regions and cryptic diversity between closely related human- and pig-infective species. We defined substancial copy number and sequence variants in current diagnostic targets and validated the impact of genetic variants on qPCR diagnostics using in vitro assays. Our study provides insights into the diversity and genomic epidemiology of STHs, highlighting challenges and opportunities for developing molecular diagnostics needed to support STH control efforts.
