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At least 19 recordsLinked to original sources
PubMed2025

RNAi screening of uncharacterized genes identifies promising druggable targets in Schistosoma japonicum.

Schistosomiasis affects more than 250 million people worldwide and is one of the neglected tropical diseases. Currently, the treatment of schistosomiasis relies on a single drug-praziquantel-which has led to increasing pressure from drug resistance. Therefore, there is an urgent need to find new treatments. The development of genome sequencing has provided valuable information for understanding the biology of schistosomes. In the genome of Schistosoma japonicum, approximately 11% of the protein-coding sequences are uncharacterized genes (UGs) annotated as "hypothetical protein" or "protein of unknown function." These poorly understood genes have been unjustifiably neglected, although some may be essential for the survival of the parasites and serve as potential drug targets. In this study, we systematically mined the highly expressed UGs in both genders of this parasite throughout key developmental stages in their mammalian host, using our previously published S. japonicum genome and RNA-seq data. By employing in vitro RNA interference (RNAi), we screened 126 UGs that lack homologs in Homo sapiens and identified 8 that are essential for the parasite vitality. We further investigated two UGs, Sjc_0002003 and Sjc_0009272, which resulted in the most severe phenotypes. Fluorescence in situ hybridization demonstrated that both genes were expressed throughout the body without sex bias. Silencing either Sjc_0002003 or Sjc_0009272 reduced the cell proliferation in the body. Furthermore, in vivo RNAi indicated both genes are required for the growth and survival of the parasites in the mammalian host. For Sjc_0002003, we further characterize the underlying molecular cause of the observed phenotype. Through RNA-seq analysis and functional studies, we revealed that silencing Sjc_0002003 reduces the expression of a series of intestinal genes, including Sjc_0007312 (hypothetical protein), Sjc_0008276 (vha-17), Sjc_0002942 (PLA2G15), and Sjc_0003646 (SJCHGC09134 protein), leading to gut dilation. Our work highlights the importance of UGs in schistosomes as promising targets for drug development in the treatment of the schistosomiasis.

Schistosoma japonicum↗
PubMed2026

Scalable assembly of Ascaris mitogenomes from whole-genome data reveals a novel clade.

The genus Ascaris is an important group of giant parasitic roundworms, infecting over 700 million people globally and causing substantial economic losses in domestic pigs. Whilst species of Ascaris are morphologically indistinguishable, analysis of mitochondrial loci has revealed three clades (A, B, C) broadly associated with host species and geographic distribution. The diversity within these lineages may expand with the addition of further genomic data. Here, we present a bioinformatic framework for de novo assembly of complete mitochondrial genomes (mitogenomes) from low-coverage whole-genome data through host-read depletion or mtDNA read enrichment, followed by mtDNA-specific assembly. Our approach yielded 149 high-quality Ascaris mitogenome assemblies, enabling the study of population-level diversity, including the identification of a novel clade (Clade D, designated here) associated with human samples from Ethiopia. Our analysis further revealed Clade C to comprise of pig-derived samples from Europe based on characterisation of worms isolated in Germany. The methods described here provide a scalable framework for mitogenome reconstruction with insights into roundworm population-genomic and phylogenetic studies.

Animals↗
PubMed2024

Identifying transgene insertions in Caenorhabditis elegans genomes with Oxford Nanopore sequencing.

Genetically modified organisms are commonly used in disease research and agriculture but the precise genomic alterations underlying transgenic mutations are often unknown. The position and characteristics of transgenes, including the number of independent insertions, influences the expression of both transgenic and wild-type sequences. We used long-read, Oxford Nanopore Technologies (ONT) to sequence and assemble two transgenic strains of Caenorhabditis elegans commonly used in the research of neurodegenerative diseases: BY250 (pPdat-1::GFP) and UA44 (GFP and human α-synuclein), a model for Parkinson's research. After scaffolding to the reference, the final assembled sequences were ∼102 Mb with N50s of 17.9 Mb and 18.0 Mb, respectively, and L90s of six contiguous sequences, representing chromosome-level assemblies. Each of the assembled sequences contained more than 99.2% of the Nematoda BUSCO genes found in the C. elegans reference and 99.5% of the annotated C. elegans reference protein-coding genes. We identified the locations of the transgene insertions and confirmed that all transgene sequences were inserted in intergenic regions, leaving the organismal gene content intact. The transgenic C. elegans genomes presented here will be a valuable resource for Parkinson's research as well as other neurodegenerative diseases. Our work demonstrates that long-read sequencing is a fast, cost-effective way to assemble genome sequences and characterize mutant lines and strains.

Caenorhabditis elegans↗
PubMed2004

WormBase as an integrated platform for the C. elegans ORFeome.

The ORFeome project has validated and corrected a large number of predicted gene models in the nematode C. elegans, and has provided an enormous resource for proteome-scale studies. To make the resource useful to the research and teaching community, it needs to be integrated with other large-scale data sets, including the C. elegans genome, cell lineage, neurological wiring diagram, transcriptome, and gene expression map. This integration is also critical because the ORFeome data sets, like other 'omics' data sets, have significant false-positive and false-negative rates, and comparison to related data is necessary to make confidence judgments in any given data point. WormBase, the central data repository for information about C. elegans and related nematodes, provides such a platform for integration. In this report, we will describe how C. elegans ORFeome data are deposited in the database, how they are used to correct gene models, how they are integrated and displayed in the context of other data sets at the WormBase Web site, and how WormBase establishes connection with the reagent-based resources at the ORFeome project Web site.

Animals↗
PubMed1992

C. elegans unc-4 gene encodes a homeodomain protein that determines the pattern of synaptic input to specific motor neurons.

The creation of neural circuits depends on the formation of synapses between specific sets of neurons. Little is known, however, of the molecular mechanisms governing synaptic choice. A mutation in the unc-4 gene alters the pattern of synaptic input to one class of motor neurons in the Caenorhabditis elegans ventral nerve cord. In unc-4(e120), the presynaptic partners of VA motor neurons are replaced with interneurons appropriate to motor neurons of the VB class. This change in neural specificity is not accompanied by any detectable effects on neuronal morphology or process extension. We show that the absence of a functional unc-4 gene product accounts for the mutant phenotype. The unc-4 gene encodes a homeodomain protein and thus is likely to function as a transcription factor. The limited effect of the unc-4 null mutation on cell fate may mean that unc-4 regulates the expression of a small number of target genes and that the products of these genes are directly involved in the choice of synaptic partners.

Alleles↗
PubMed2025

Genetic structuring and estimation of reproductive adults in Onchocerca volvulus: A genome-wide analysis across hosts and regions.

Genomic analysis of parasites can deepen our understanding of their transmission, population structure, and important biological characteristics. Onchocerciasis (river blindness), caused by the parasitic nematode Onchocerca volvulus, involves adult worms residing in subcutaneous nodules that produce larval-stage microfilariae (mf), which are routinely detected in the skin for diagnosis. Whole-genome studies of mf are limited; most analyses have focused on the mitochondrial genome. We conducted a genome-wide analysis with 94% median nuclear genome coverage, analyzing 171, 37, and 98 mf from 16, 3, and 5 individuals from Ghana, Liberia, and the Democratic Republic of Congo, respectively. These data were used to investigate population differentiation, estimate the number of reproductive adult worms, and analyze genetic variation across chromosomes. Population genetic analyses across hosts and countries showed that nuclear genome diversity can reveal fine-scale genetic structure, even between geographically close countries, providing more resolution than mitochondrial haplotype data. By reconstructing maternal and paternal sibships, we estimated the number of reproductively active adult filariae. Comparisons between adult worm estimates from genetic data and nodule observations showed that genetics-based estimates were higher or equal to observed worm counts in 8 out of 9 hosts for female worms and 7 out of 9 hosts for male worms. Our analysis also revealed lower-than-expected X chromosome diversity, consistent with neo-X chromosome fusions in filarial species. This study represents an important step in using nuclear genome data from mf to support onchocerciasis elimination efforts and in developing genetic tools that could inform mass drug administration programs.

Onchocerca volvulus↗
PubMed2025

Chromosomal genome assembly resolves drug resistance loci in the parasitic nematode Teladorsagia circumcincta.

The parasitic nematode Teladorsagia circumcincta is one of the most important pathogens of sheep and goats in temperate climates worldwide and can rapidly evolve resistance to drugs used to control it. To understand the genetics of drug resistance, we have generated a highly contiguous genome assembly for the UK T. circumcincta isolate, MTci2. Assembly using PacBio long-reads and Hi-C long-molecule scaffolding together with manual curation resulted in a 573 Mb assembly (N50 = 84 Mb, total scaffolds = 1,286) with five autosomal and one sex-linked chromosomal-scale scaffolds consistent with its karyotype. The genome resource was further improved via annotation of 22,948 genes, with manual curation of over 3,200 of these, resulting in a robust and near complete resource (96.3% complete protein BUSCOs) to support basic and applied research on this important veterinary pathogen. Genome-wide analyses of drug resistance, combining evidence from three distinct experiments, identified selection around known candidate genes for benzimidazole, levamisole and ivermectin resistance, as well as novel regions associated with ivermectin and moxidectin resistance. These insights into contemporary and historic genetic selection further emphasise the importance of contiguous genome assemblies in interpreting genome-wide genetic variation associated with drug resistance and identifying key loci to prioritise in developing diagnostic markers of anthelmintic resistance to support parasite control.

Animals↗
PubMed2026

Ambient temperature storage of individual parasitic nematode larvae for whole genome sequencing.

Soil-transmitted helminth (STH) infections are a major public health burden, and there are programmes of mass drug administration that attempt to ameliorate the harm that they cause. There has been increasing use of genomics to study STH infections and other parasitic nematodes, with particular interest in whole genome sequencing (WGS). For such studies, samples are commonly stored frozen, but in settings where these infections are endemic this can be difficult, and so there would be advantages to having ambient temperature storage methods. We investigated two ambient temperature storage methods - FTA cards and DESS buffer - for infective larvae of the rat parasites Nippostrongylus brasiliensis and Strongyloides ratti, prior to DNA extraction and then WGS. Our results showed that for individual larvae stored on FTA cards or in DESS buffer, this resulted in a lower proportion of sequence reads that mapped to the reference genomes, compared to the frozen control samples. Generally, for individual larvae, DESS-storage resulted in better sequencing results than FTA-storage. However, for pools of 10 or 50 larvae, then these ambient temperature storage methods generally resulted in comparable sequence read mapping to the frozen control samples.

Animals↗
PubMed2024

Investigating Environmental Determinants of Hookworm Transmission using GPS Tracking and Metagenomics Technologies.

To identify potential sources of hookworm infections in a Ghanaian community of endemicity that could be targeted to interrupt transmission, we tracked the movements of infected and noninfected persons to their most frequented locations. Fifty-nine participants (29 hookworm positives and 30 negatives) wore GPS trackers for 10 consecutive days. Their movement data were captured in real time and overlaid on a community grid map. Soil samples were collected and divided into two parts: one for determining the physical and chemical properties and the other for culture of helminth larvae. Soil parameters were determined using standard methods, and the number of larvae recovered from Baermann cultures (expressed as larvae per gram of soil) was recorded. We found no significant difference in the larval counts between sites of infected and noninfected participants (P = 0.59). Sandy-loam soil, pH, and effective cation exchange capacity were associated with high larval recovery counts (P <0.001), whereas nitrogen and clay content were associated with low counts (P <0.001). Genomic DNA was extracted from helminth larvae, and species were identified using metagenomic analysis of DNA sequences. The dominant helminth species identified were Panagrolaimus superbus, Parastrongyloides trichosuri, Trichuris trichiura (human whipworm), and Ancylostoma caninum (dog hookworm). Despite Necator americanus being the predominant species in the community, no larvae of this species were identified. This study, however, demonstrates the feasibility of applying molecular tools for identifying environmental factors and places associated with exposure to human and zoonotic helminths, including areas that may be targeted to break transmission in communities where infection is endemic.

Humans↗
PubMedDate not supplied

Molecular cloning and expression of an immunodominant 53-kDa excretory-secretory antigen from Trichinella spiralis muscle larvae.

A Trichinella spiralis cDNA expression library was constructed in lambda gt11 from muscle larvae mRNA and immunologically screened to identify genes encoding previously described immunodiagnostic excretory-secretory (ES) antigens. Screening the library with T. spiralis infection serum from swine or rabbit antiserum to T. spiralis ES antigen identified one clone, designated TsA-12, that contains a cDNA transcript 539 bp in length and codes for an apparent 123-kDa beta-galactosidase fusion protein that does not cross-react with Trichuris suis or Ascaris suum infection serum. Western blots of T. spiralis extracts and immunoperoxidase staining of tissue sections from muscle larvae using antibodies to purified TsA-12 demonstrate homology between TsA-12 and the 53 kDa diagnostic antigen from ES products (designated Ts.53) and localize the homologous native antigen to the stichocyte cells of the parasite. ELISA tests using TsA-12 as antigen, detected antibodies to T. spiralis in experimentally-infected mice as early as 14 days post-inoculation with maximum antibody titers being reached at 28 days post-inoculation. The TsA-12 dscDNA hybridizes to mRNA sequences expressed in both the muscle larvae and adult stages; however, concomitant expression of the native antigen is not observed within adult ES products. Southern blots of homologous and heterologous genomic DNAs probed with 32P-labeled TsA-12 dscDNA fragments verify TsA-12 as a T. spiralis specific sequence that is present in multiple copies within the parasite genome.

Amino Acid Sequence↗
PubMed2022

Genomic landscape of drug response reveals mediators of anthelmintic resistance.

Like other pathogens, parasitic helminths can rapidly evolve resistance to drug treatment. Understanding the genetic basis of anthelmintic drug resistance in parasitic nematodes is key to tracking its spread and improving the efficacy and sustainability of parasite control. Here, we use an in&#xa0;vivo genetic cross between drug-susceptible and multi-drug-resistant strains of Haemonchus contortus in a natural host-parasite system to simultaneously map resistance loci for the three major classes of anthelmintics. This approach identifies new alleles for resistance to benzimidazoles and levamisole and implicates the transcription factor cky-1 in ivermectin resistance. This gene is within a locus under selection in ivermectin-resistant populations worldwide; expression analyses and functional validation using knockdown experiments support that cky-1 is associated with ivermectin survival. Our work demonstrates the feasibility of high-resolution forward genetics in a parasitic nematode and identifies variants for the development of molecular diagnostics to combat drug resistance in the field.

Ivermectin↗
PubMed1990

Echinococcus multilocularis: characterization of a DNA probe.

A 0.6 kb DNA fragment has been isolated from a genomic sublibrary of the cestode Echinococcus multilocularis. This DNA-fragment showed a strong hybridization signal to 32PdCTP labeled total DNA prepared from E. multilocularis metacestode material. The fragment was subcloned into the Escherichia coli vector Bluescript BS+ resulting in the recombinant plasmid pAL1. The recombinant parasite DNA probe was labeled by biotinylation and hybridized to Southern blots of resolved EcoRI/PstI digested genomic DNA originating from E. multilocularis, E. granulosus and other helminth species (Taenia hydatigena, T. crassiceps, T. saginata, Mesocestoides corti, Hymenolepis diminuta, Moniezia expansa). The Southern blot hybridization experiments revealed that the DNA probe pAL1 was specific for E. multilocularis and E. granulosus. By comparison of the hybridization banding patterns a clear discrimination between E. multilocularis and E. granulosus was possible at the genome level. Furthermore, pAL1 was used to detect genetic variation within a set of different E. multilocularis isolates which had been experimentally maintained in mice by parasite tissue transplantation.

Animals↗
PubMed1989

Parasite development and adaptive specialization.

The complex life-cycles of parasitic animals are a product of exploiting the process of development to generate organisms with different biological potentials within a species. Successive stages of the parasite adapt to functions such as host invasion and transmission, and to the colonization of a variety of niches, often involving different hosts, tissues or cells. Understanding the molecular basis of adaptive biology among parasites is a major challenge that lies at the heart of research in contemporary parasitology. Differences in scale at the levels of genomic complexity and cell biology exist between most parasitic protozoa and helminths, rendering a cautionary note to making generalized observations. The two principal approaches used to gain insights into adaptive specializations are to start with a biological activity and identify the molecule, or select molecules with particular properties and deduce function. Both have their part to play, with their inherent advantages and limitations, and both are illustrated with examples of studies on adaptive biology among parasitic nematodes.

Adaptation, Physiological↗
PubMed2026

Characterisation of Trichuris incognita n sp in C&#xf4;te d'Ivoire: a morphological, genomic, and genome-wide association with drug sensitivity study.

BACKGROUND: Trichuriasis is a neglected tropical disease that affects up to 500 million individuals and can cause considerable morbidity. For decades, trichuriasis was thought to be caused by one species of whipworm, Trichuris trichiura. The aim of this study was to investigate the origin of differences in response rates to the best available anthelmintic treatment for trichuriasis-a combination of albendazole and ivermectin-in C&#xf4;te d'Ivoire by analysing the parasite population. METHODS: In this morphological, genomic, and genome-wide association study (GWAS) with drug sensitivity we used long-read and short-read sequencing approaches and assembled a high-quality reference genome of Trichuris incognita n sp isolated in a primary interventional study conducted in the Lagunes district of C&#xf4;te d'Ivoire. Children aged 6-12 years were screened between July 14, 2022, and July 31, 2022; children positive for T trichiura on duplicate Kato-Katz smears and with infection intensity of 200 eggs per gram or more were eligible and treated first with albendazole (400 mg) and ivermectin (200 &#x3bc;g/kg) then with oxantel pamoate (20 mg/kg). We constructed a species tree of the Trichuris genus using 12&#x2009;434 orthologous groups. We sequenced individual worms, which were used to confirm the phylogenetic placement and investigate patterns of adaptation through comparative genomic analyses. Finally, we conducted a GWAS to compare albendazole-ivermectin sensitive worms to drug non-sensitive worms. FINDINGS: 670 children were screened, of whom 243 were enrolled and from whom 271 worms were isolated after the first treatment and 827 worms after the second treatment. Sufficient DNA was recovered from 747 worms of which 721 were suitable for further bioinformatic analysis; of these, 179 were albendazole-ivermectin sensitive worms and 542 were drug non-sensitive worms. We present and characterise a new, human-infecting Trichuris species named T incognita n sp, which is morphologically indistinguishable from T trichiura, but forms a distinct phylogenetic clade, closer to Trichuris suis than to the canonical human-infective T trichiura. Comparative genomic analysis of genes suspected to confer resistance to either albendazole or ivermectin in helminths revealed a high number of &#x3b2;-tubulin orthologs, present in the whole population of T incognita n sp, compared with the canonical T trichiura species, but these genes were not associated with a resistant phenotype. The GWAS did not provide conclusive evidence of adaptation to drug pressure within the same species. INTERPRETATION: Our results demonstrate that trichuriasis can be caused by multiple whipworm species, and that differences in response rates might result from species responding differently to drug treatment, rather than from the intraspecies establishment of resistance. This discovery, coupled with the high tolerability of T incognita n sp to albendazole-ivermectin, marks a substantial shift in how we understand and approach whipworm infections. FUNDING: European Research Council.

Trichuris↗
PubMed2004

prot4EST: translating expressed sequence tags from neglected genomes.

BACKGROUND: The genomes of an increasing number of species are being investigated through generation of expressed sequence tags (ESTs). However, ESTs are prone to sequencing errors and typically define incomplete transcripts, making downstream annotation difficult. Annotation would be greatly improved with robust polypeptide translations. Many current solutions for EST translation require a large number of full-length gene sequences for training purposes, a resource that is not available for the majority of EST projects. RESULTS: As part of our ongoing EST programs investigating these "neglected" genomes, we have developed a polypeptide prediction pipeline, prot4EST. It incorporates freely available software to produce final translations that are more accurate than those derived from any single method. We show that this integrated approach goes a long way to overcoming the deficit in training data. CONCLUSIONS: prot4EST provides a portable EST translation solution and can be usefully applied to >95% of EST projects to improve downstream annotation. It is freely available from http://www.nematodes.org/PartiGene.

Animals↗
PubMed1991

Molecular cloning of Taenia taeniaeformis oncosphere antigen genes.

Infection of mice with the cestode Taenia taeniaeformis exhibits several important features common to other cestode infections, including the ability to vaccinate with crude antigen mixtures. Partial purification of the protective oncosphere antigens has been reported with a cutout from deoxycholate (DOC) acrylamide gels; this cutout was called fraction II (FII), and comprises approximately 10% of total DOC-soluble oncosphere antigen. Western blots of DOC gels probed with anti-FII antisera revealed a series of 3-5 discrete bands within the FII region. Further fractionation of the FII antigens on DOC gels was impractical due to limitations in supply of oncospheres, so a cDNA library was constructed from 150 ng of oncosphere mRNA and screened with alpha-FII antisera. Two distinct clone families were identified, oncA and oncB. Antibodies affinity-purified on either of two representative members, oncA1 and oncB1, recognised all the FII bands. Individual FII bands excised from a DOC gel resolved into an overlapping series of molecules when re-run on SDS-PAGE, indicating that each FII band consisted of several polypeptides of differing molecular weight. Immunoprecipitates resolved on SDS-PAGE revealed that alpha-FII recognised 3 major oncosphere antigens, of 62, 34 and 25 kDa; antisera against oncB precipitated both the 34- and 25-kDa antigens, whereas alpha-oncA antisera precipitated the 62-kDa antigen. We conclude that oncA and oncB encode the major antigens in the FII complex. The 62-kDa antigen encoded by oncA1 was the only common antigen precipitated by anti-FII and two other antisera raised against different protective extracts, suggesting that it may be a protective component in all three. Southern blot results indicate that oncA and oncB are distinct genes present at low copy number in the genome. Evidence is also presented suggesting that some cestode mRNAs, including oncA, may use variant polyadenylation signals.

Amino Acid Sequence↗