WormBase: an evolving resource for nematode biology

Lead Research Organisation: The Wellcome Trust Sanger Institute
Department Name: Pathogen Variation

Abstract

Many developments in modern medicine are based on the enormous progress made over the last 50 years in our understanding of how our genes work. For example, drugs interact with genes to change how biological systems function. Much of the research that has led to this progress is hard or impossible to do in humans. Because all animals share evolutionary origins, study of simple animals helps to understand human biology. Certain key model organisms have been the focus of intensive study, and some of the most important progress has been made with extremely simple animals. One of these is the tiny roundworm, or nematode, Caenorhabditis elegans. C. elegans research has been strategically supported by the MRC for over 40 years, leading to two Nobel prizes in the last five years, and is a key contributor to our understanding of basic processes such as cell death and aging.

In addition to its relevance for understanding animal biology, research on C. elegans is particularly important to our understanding of the biology of other nematodes. Globally, more than one billion people are infected with nematode parasites, including blood-borne filarial parasites, such as Onchocerca that causes river blindness, and Wuchereria that cause elephantiasis; as well as intestinal nematodes such as hookworms, whipworms and giant round worms. Typically infections are associated with and promote poverty. For most parasitic nematodes, maintaining full life cycles in the laboratory is either difficult or impossible and few molecular tools exist. Thus researchers are highly reliant on functional studies in C. elegans and their extrapolation (via sequence homology) into the parasites of sister taxa.

Genetic research has been revolutionized by obtaining the complete DNA sequence (the genome) of the organism being studied, which contains all the gene sequences. C. elegans was the first animal to have its genome sequenced and now major programmes are collecting genome sequences for parasitic species. To use genome sequences and all the new information about genes requires information resources that tie together DNA information with experimental data, and relate corresponding genes across animals. This application will enable the support and development of WormBase, the reference information resource for all genomic and biological data for C. elegans, and its expansion to enable the curation of genomic and experimental information for increasing numbers of nematode parasites. WormBase is essential both for fundamental research that uses C. elegans as a model, and for research into nematodes that cause disease. By relating these two branches of nematode research, WormBase will be uniquely placed to enable community-wide exploitation of data emerging for parasites by applying information, experience, and technological infrastructure developed for C. elegans.

Technical Summary

This application will support two of six UK posts working on WormBase, the established community database for the genome and biology of the Caenorhabditis elegans - a key model organism, established through long term strategic support of the MRC - and other medically relevant nematode species. The genomes of several species of parasitic nematodes are already accessible via WormBase and hundreds more are expected over the coming few years. The funding of this proposal will enable the evolution of the resource to maximise the value of these data.

Through this proposal we will (a) curate the genome sequence and core annotation for C.elegans and key parasitic nematodes, actively incorporating new data from the literature, and developing new models for rapid, community-driven curation of newly sequenced genomes; (b) provide computational annotation and comparative genomic analysis for hundreds of nematode genomes; (c) revise the core data management infrastructure, to support the necessary increases in scale that will be required ; and (d) integrate and deliver for public access every two months the entire database, built from data collected and curated at all three WormBase groups. To do this efficiently, we will combine in-house tools with the use of sequence analysis, curation and data management software developed with the joint WTSI/EBI Ensembl project for genome annotation, as well as software and standards developed for the GMOD consortium of model organism databases, of which we are a member. WormBase is freely available for browsing and download from www.wormbase.org, and also contributes the genome sequence and gene sequences to the primary DNA and protein databases, and participates in other core biological information collaborations including the GO consortium. WormBase is co-funded by NIH, who support the two US groups and the remainder of the UK group.

Planned Impact

Basic molecular insights in C. elegans have driven major fundamental advances in modern medicine, illustrated by 2 Nobel Prizes in the last decade: the 2002 prize to Brenner, Sulston and Horvitz for identifying genes that regulate organ development and apoptosis in C. elegans, along with the equivalent genes in man; and the 2006 prize to Fire & Mello for the discovery of RNA interference.

Parasitic nematodes are studied with the aim of killing or controlling them. WormBase will significantly facilitate the direct exploitation and application of large-scale data from sequence based experiments towards this aim. Furthermore, the proposed resource will leverage the in-depth and highly organised knowledge-base of C. elegans into the poorer resourced areas of parasitic nematode research.

The application of genomic science towards medical improvements is still in its infancy, but for pathogens with smaller and simpler genomes such as viruses and bacteria, genomic insights are already being translated into tangible benefits e.g. tracking pathogen transmission and the monitoring of drug resistance. For parasitic nematodes, genomic research is expected to deliver significant benefits in the medium term, for which ready access to the data is a clear requirement. The primary beneficiaries will be the people directly suffering from nematode infections, which includes about 2 billion people infected with soil-transmitted helminths alone (WHO 2012). Advances in drug treatment, transmission reduction or vaccination could improve the lives of many people who may otherwise suffer from serious gastrointestinal disease, stunted growth and mental development, malnutrition and fatigue, disfigurement, blindness, or liver and bladder pathologies. Although some effective anthelmintics exist, the available arsenal of drugs is limited and the spread of drug resistance a real danger. Furthermore, large-scale improvements in the treatment and control of helminthiases are likely to bring huge socio-economic benefits to some of the least developed countries.

In addition to the direct health improvements from a reduction in helminth infections, people in endemic areas could also benefit indirectly e.g. by an improved response to vaccinations, by reduced transmission or by an improved disease outcome for other diseases such as tuberculosis, malaria, and HIV/AIDS, as co-infections with helminths have been shown to have potentially adverse effects (see Elliott and Yazdanbakhsh, 2012, and other articles in the same issue of this journal for recent reviews).

Looking further into the future, a thorough understanding of nematodes and their interactions with the human immune system may lead to fundamental new insights that will allow a much more sophisticated manipulation of the human immune system for medical purposes. Such knowledge may ultimately be exploited for and benefit the effective treatment of allergies and other (autoimmune) diseases.

Publications

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Alliance Of Genome Resources Consortium (2020) Alliance of Genome Resources Portal: unified model organism research platform. in Nucleic acids research

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Alliance Of Genome Resources Consortium (2022) Harmonizing model organism data in the Alliance of Genome Resources. in Genetics

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Foster JM (2020) Sex chromosome evolution in parasitic nematodes of humans. in Nature communications

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Harris TW (2014) WormBase 2014: new views of curated biology. in Nucleic acids research

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Howe K (2017) WormBase ParaSite - a comprehensive resource for helminth genomics in Molecular and Biochemical Parasitology

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Howe KL (2016) WormBase 2016: expanding to enable helminth genomic research. in Nucleic acids research

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International Helminth Genomes Consortium (2019) Comparative genomics of the major parasitic worms. in Nature genetics

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Lee RYN (2018) WormBase 2017: molting into a new stage. in Nucleic acids research

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Tracey A (2020) Nearly Complete Genome Sequence of Brugia malayi Strain FR3. in Microbiology resource announcements

 
Title Integration of quantitative gene expression data for parasitic worms into WormBase 
Description All life-stage specific RNASeq gene expression data sets for key parasitic worm genomes (B. mayai, O. volvulus and S. ratti) are extracted from the archives, annotated with the appropriate terms from the WormBase development ontology. The reads are aligned to the genome and quantitative estimates of gene expression are made per-gene, per-life-stage. These data are displayed in the "Expression" section of the gene report pages. The data is also made available from our FTP site. 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact No notable impact for this specific data in isolation. It enriches the information presented on the gene report pages, which are the main entry point for WormBase. 
 
Title Onchocerca volvulus genome in WormBase 
Description The genome of Onchocerca volvulus has been sequenced at the Sanger Institute and incorporated into WormBase as a reference (curated) organism. The first phase of curation involved manually checking and fixing 2000 gene models that were supported by conflicting evidence. 
Type Of Material Database/Collection of data 
Year Produced 2014 
Provided To Others? Yes  
Impact No notable impact yet 
URL http://www.wormbase.org/species/o_volvulus#4--10
 
Title Strongyloides ratti genome in WormBase 
Description The Wellcome Trust Sanger Institute has produced a high-quality reference genome for S. ratti, and this has been incorporated into WormBase as a "core" genome, with curation of protein-coding and non-coding gene structure and integration of large-scale gene expression data. 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact None yet 
URL http://www.wormbase.org/species/s_ratti
 
Title Trichuris muris genome in WormBase 
Description The Wellcome Trust Sanger Institute has produced a high-quality reference genome for Trichuris muris, and this has been incorporated into WormBase as a "core" genome. This provides a infrastructure and platform for the curation of protein-coding and non-coding gene structure and integration of large-scale gene expression data. 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact None yet. 
URL http://ftp://ftp.ebi.ac.uk/pub/databases/wormbase/releases/WS264/species/t_muris/
 
Title WormBase 
Description Genomic and research database for the model organism C. elegans and selected other nematodes. WormBase is released 6 times per year, and each release includes additional data sets curated from the literature and submitted directly, improvements to the genome annotation for C. elegans and other species, and new features on the website. 
Type Of Material Database/Collection of data 
Provided To Others? Yes  
Impact Ubiquitous use by nematode research communities; increasingly used by human geneticists; development of community standards and tools for genomics (e.g. GMOD, GFF3, Gbrowse). 
URL http://www.wormbase.org
 
Title WormBase- ongoing releases 
Description WormBase is primarily a model organism resource which provides deeply curated genomic and functional genomic data to enable C elegans research. Six WormBase data releases are produced per year, reflecting ongoing curation and data integration. 
Type Of Material Database/Collection of data 
Provided To Others? Yes  
Impact Four helminth species (Brugia malayi, Onchocerca volvulus, Trichuris muris and Strongyloides ratti) are now also integrated into WormBase. These genomes can benefit from the deeper level of curation that the WormBase infrastructure supports, including gene model curation (with full history tracking) and literature curation. 
URL https://wormbase.org/
 
Description The WormBase Consortium 
Organisation California Institute of Technology
Country United States 
Sector Academic/University 
PI Contribution The consortium is responsible for the production, maintenance and development of WormBase and associated tools and resources. One of the two MRC-funded posts is the project leader for the genomics and database production components of the project. These activities include curation of the C. elegans reference genome and annotation (including gene structures), incorporation of new genomes and data sets, maintenance and developmenr of the core database schema, and the deployment large-scale data analysis and integration pipelines for each release. The other MRC-funded post works specifically on enriching the data for a small set of parasitic worms in WormBase
Collaborator Contribution They curate and integrate data on gene function in C. elegans from the research literature, and develop ontologies and novel text-mining methods to assist with this; they produce and manage the website and associated tools for the project; they perform the majority of the training on how to use the resource to C. elegans geneticists; they provide input into project goals, operations and activities.
Impact All data and services provided by the consortium are made available via a central web hub, www.wormbase.org. The consortium is multi-disciplinary, ranging from computer scientists / software engineers, through bioinformaticians (whose duties cover both curation biological data and computer programming), to biologists (whose principle role is the curation of biological data)
 
Description The WormBase Consortium 
Organisation Ontario Institute for Cancer Research (OICR)
Country Canada 
Sector Academic/University 
PI Contribution The consortium is responsible for the production, maintenance and development of WormBase and associated tools and resources. One of the two MRC-funded posts is the project leader for the genomics and database production components of the project. These activities include curation of the C. elegans reference genome and annotation (including gene structures), incorporation of new genomes and data sets, maintenance and developmenr of the core database schema, and the deployment large-scale data analysis and integration pipelines for each release. The other MRC-funded post works specifically on enriching the data for a small set of parasitic worms in WormBase
Collaborator Contribution They curate and integrate data on gene function in C. elegans from the research literature, and develop ontologies and novel text-mining methods to assist with this; they produce and manage the website and associated tools for the project; they perform the majority of the training on how to use the resource to C. elegans geneticists; they provide input into project goals, operations and activities.
Impact All data and services provided by the consortium are made available via a central web hub, www.wormbase.org. The consortium is multi-disciplinary, ranging from computer scientists / software engineers, through bioinformaticians (whose duties cover both curation biological data and computer programming), to biologists (whose principle role is the curation of biological data)
 
Description WormBase consortium 
Organisation WormBase (Biology and Genome of C.Elegans)
Country United States 
Sector Charity/Non Profit 
PI Contribution WormBase Consortium is led by Paul Sternberg of CalTech, Kevin Howe of the EBI, Matt Berriman of the Wellcome Sanger Institute, and Lincoln Stein of the Ontario Institute for Cancer Research. The consortium runs a model organism database containing data from research on C. elegans and other nematodes. WormBase Parasite provides searching and data access capabilities that are not available through the WormBase website
Collaborator Contribution WormBase curates reference genomes which are then imported into WormBase Parasite and provide important functional information for understanding the genomes of comparator species.
Impact Provision of annotated genomes for C. elegans and Brugia malayi
Start Year 2014
 
Description Advanced Course in Helminth Bioinformatics 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Three members of the WormBase ParaSite team acted as instructors in a 5 day workshop on Helminth Bioinformatics, hosted by the West African Centre for Cell Biology of Infectious Pathogens, Accra, Ghana. The workshop had approximately 20 participants, all postgraduate or post-doctoral researchers based in institutions across Africa. Material covered included use of the WormBase ParaSite database, an introduction to the Linux command line, transcriptomics, genome assembly, and population genetics. The main goal was to increase the genomics/bioinformatics capacity of helminth researchers in Africa. The course received excellent formal feedback, with WormBase Parasite being voted one of the most useful sections by many participants.
Year(s) Of Engagement Activity 2019
URL https://coursesandconferences.wellcomegenomecampus.org/our-events/helminth-bioinformatics-ghana-2019...
 
Description BSP drop in helpdesk 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact We ran a drop in desk at the annual British Society of Parasitology Spring meeting. We answered questions and demonstrated features from the user community.
Year(s) Of Engagement Activity 2019
 
Description Genome Decoders project 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact In 2017 we started a collaborative project with Institute for Research with Schools where we directly collaborate with school students (primarily A-level) to computationally analyse the genome of a parasitic worm. The 'event' is ongoing and currently involves 50 schools. A launch day was held in September attended by 200 students and teachers. It included seminars and workshop activities.
In 2018, the continuing project resulted in the "Engaged Team Prize" on the Wellcome Genome Campus.
Year(s) Of Engagement Activity 2017
URL http://publicengagement.wellcomegenomecampus.org/genome-decoders
 
Description Helminth genomics workshop, Shanghai 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact A WormBase ParaSite staff member acted as lead instructor on a 2 day course in Helminth Bioinformatics in Shanghai, China. The course had approximately 40 participants, largely postgraduate students, from across China. Material covered included basic concepts in bioinformatics and use of the WormBase ParaSite database. Formal feedback was very positive.
Year(s) Of Engagement Activity 2019
 
Description Poster presentation at the Parasitic Helminths: New Perspectives in Biology and Infection meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A WormBase ParaSite staff member presented a poster on the WormBase ParaSite resource at the Parasitic Helminths: New Perspectives in Biology and Infection conference (Hydra, Greece). Users were informed of new features and given the chance to ask questions on use of the resource.
Year(s) Of Engagement Activity 2019
 
Description Presentation and Workshop at annual "Molecular and Cellular Biology of Helminth Parasites" meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Workshop/tutorial resulted in increased awareness and understanding of how to use WormBase ParaSite, and ideas for further development
Year(s) Of Engagement Activity 2017,2018
 
Description Short talk in "Bridging the Divide" workshop, International C elegans meeting, UCLA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A WormBase ParaSite staff member gave a short talk on the resource in a parasitology session at the International C elegans Meeting. The audience included both parasitologists and C elegans researchers.
Year(s) Of Engagement Activity 2019
 
Description WormBase ParaSite webinar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Two WormBase ParaSite staff members ran a webinar on the use of the resource, aimed at all helminth researchers. The webinar received positive feedback, and remains available online as training material.
Year(s) Of Engagement Activity 2019
URL https://www.ebi.ac.uk/training/online/course/introduction-wormbase-parasite-resources