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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↗
PubMed2003

Coexpression of neighboring genes in Caenorhabditis elegans is mostly due to operons and duplicate genes.

In many eukaryotic species, gene order is not random. In humans, flies, and yeast, there is clustering of coexpressed genes that cannot be explained as a trivial consequence of tandem duplication. In the worm genome this is taken a step further with many genes being organized into operons. Here we analyze the relationship between gene location and expression in Caenorhabditis elegans and find evidence for at least three different processes resulting in local expression similarity. Not surprisingly, the strongest effect comes from genes organized in operons. However, coexpression within operons is not perfect, and is influenced by some distance-dependent regulation. Beyond operons, there is a relationship between physical distance, expression similarity, and sequence similarity, acting over several megabases. This is consistent with a model of tandem duplicate genes diverging over time in sequence and expression pattern, while moving apart owing to chromosomal rearrangements. However, at a very local level, nonduplicate genes on opposite strands (hence not in operons) show similar expression patterns. This suggests that such genes may share regulatory elements or be regulated at the level of chromatin structure. The central importance of tandem duplicate genes in these patterns renders the worm genome different from both yeast and human.

Animals↗
PubMed2025

Multi-omics analyses reveal DjTcf4 critical for proper timing of differentiation in planarian regeneration.

The blastema is key to forming complete tissues in regenerating Dugesia japonica (D. japonica). However, the dynamic changes in cellular compositions and transcription landscapes in blastema during regeneration are understudied. Here, through genome reannotation, 3D spatial transcriptome construction, single-cell RNA sequencing (scRNA-seq), and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) analyses of changes in gene expression and chromatin structures, we delineate key transcription factors regulating the developmental trajectories of major cell clusters in the regenerating head. Importantly, we find that the T cell factor 4 (DjTcf4)-positive cells highly accumulate at wound areas, and its gene network is critical for the proper timing of development during regeneration in multiple progenitor cells. Depletion of DjTcf4 and its target genes leads to singular eye and/or dull tail phenotypes and delays regeneration. Taken together, we build multi-omics atlases in D. japonica and reveal the noncanonical function of the DjTcf4 network in developmental pattern formation, laying a foundation for studies of regeneration in D. japonica.

Animals↗
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

Characterisation of Trichuris incognita n sp in Côte 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 Côte 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 Côte 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 μg/kg) then with oxantel pamoate (20 mg/kg). We constructed a species tree of the Trichuris genus using 12 434 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 β-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↗
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 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↗
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

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↗
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

Diversity at the HYP1 locus in potato cyst nematodes does not result from developmentally-programmed somatic mutations.

Most genetic diversity stems from spontaneous mutations, that is, errors in DNA repair or replication. But for dozens of organisms across the tree of life, mutations at specific loci are not spontaneous but developmentally programmed: effectively, some organisms edit their own DNA sequences. This is perhaps most common among pathogens and parasites, many of which use editing to diversify genes that produce important antigens. Plant-parasitic potato cyst nematodes are damaging agricultural pests that establish a lifelong feeding site inside the root of their host plant. We previously observed extensive diversity of rare alleles at HYP1, the most highly expressed gene that encodes a protein secreted by potato cyst nematodes during parasitism. Importantly, HYP1 alleles differ from each other by complex, in-frame rearrangements of short repeated sequence motifs within a single exon. Combining several lines of evidence, we previously hypothesized that potato cyst nematodes use developmentally-programmed mutations, or editing, to diversify HYP1 alleles in the soma. In the current work, we now test this hypothesis. We employ highly accurate long-read DNA sequencing of a simplified genetic system to identify potential rare edited alleles, we use a transgenic yeast system to describe large de novo mutations at HYP1, and we interpret our findings in light of key population genetic parameters as well as the genetic diversity surrounding HYP1 and across the genome.

Animals↗