Exploiting nematode genomes to illuminate parasite biology

The spread of resistance to anthelminthic drugs represents a threat to our ability to control parasitic worms in livestock and could ultimately affect treatment of human helminth infections. Understanding the genetic basis of anthelminthic drug resistance would allow us to track the spread of resistance and adapt management strategies to slow this spread, but for some classes of anthelminthics this understanding has remained elusive. With many collaborators, we have been working with parasitic nematodes of small ruminants as a model for anthelminthic resistance in nematodes. Armed with chromosome-level reference genomes for the parasite Haemonchus contortus, and more recently for many other species, we have attempted to go beyond genetic approaches based on assumptions about gene function to use unbiased, genome-wide approaches to identify the genetic basis of resistance and study its evolution. This work has identified a single major locus for ivermectin resistance, which globally distributed population genomic data confirms may underpin ivermectin resistance in other populations. It has been challenging to identify a causal variant in this large QTL. An apparently completely different locus is under selection in the related worm Teladorsagia circumcincta in both farm populations and in experimental settings. I’ll discuss some possible reasons why we have so far failed to pinpoint the genetic basis of ivermectin resistance and some ideas about how we might be able to do so.

Professor James Cotton

University of Glasgow, UK

Professor James Cotton

University of Glasgow, UK

James Cotton completed a PhD on gene family evolution at the University of Glasgow, followed by post-doctoral positions on phylogenetics and molecular evolution in London and Ireland. Following a position at Queen Mary, University of London he moved to the Wellcome Sanger Institute, where he was a member of the parasite genomics group for over ten years before returning to Glasgow in 2022. Since then he has worked on the genetics of eukaryotic parasites, focusing on building genomic resources for key species of medical or veterinary importance, and then using those tools to understand parasite biology. This has often involved generating large-scale data on parasite genetic variation to study parasite population genetics, evolution and epidemiology. One particular interest has been in the evolution of anthelminthic drug resistance, using the gastro-intestinal nematode Haemonchus contortus and other nematode parasites of livestock as a model for the genetics and evolution of resistance.

Genomic epidemiology is emerging as a valuable tool for informing helminth control strategies. Recent advances in population genomics applied to Fasciola hepatica, Onchocerca volvulus, Wuchereria bancrofti, and Brugia malayi have demonstrated utility in characterising drug resistance loci, estimating reproductive worm burden, assessing treatment response, and elucidating transmission dynamics. In F hepatica, comparative analyses have identified region specific triclabendazole resistance loci, underscoring the need for geographically tailored surveillance. In filarial parasites, genome-wide data from individual microfilariae have enabled the estimation of reproductive worm burden and the differentiation between recrudescence and reinfection, two critical parameters for evaluating treatment efficacy and mass drug administration (MDA) programs that were previously difficult to obtain. Genetic relatedness and population structure analyses have provided further insight into transmission dynamics, revealing parasite movement within and between host populations, across geographic regions, and among host species. These approaches offer a framework for tracking transmission pathways and the spread of epidemiologically important traits such as drug resistance. However, broader implementation and effective integration of genomic tools into control programs will require continued development and coordinated efforts. Although technical advances such as exome capture and whole-genome amplification have significantly improved the recovery of parasite DNA from clinical and field samples, further refinement of methods to obtain parasite genetic data from diverse sample types, such as stool biobanks, blood smears, and vector samples for xenomonitoring, should remain a high priority. In parallel, it is essential to establish curated population genomic databases and standardised, modular analytical pipelines adaptable to varied epidemiological scenarios to support the design of gene panels with informative markers suitable for field-deployable genotyping platforms. Genomic methods when used as a complement to parasitological techniques have the capacity to significantly enhance the precision and effectiveness of helminth control efforts.

Professor Makedonka Mitreva

Washington University School of Medicine, USA

Professor Makedonka Mitreva

Washington University School of Medicine, USA

Makedonka Mitreva is the Gordon R. Miller Professor of Medicine at Washington University School of Medicine. Her research focuses on neglected tropical diseases affecting low-resource communities and the human microbiome. She is committed to advancing omics-driven discoveries and translating them into clinical applications through interdisciplinary collaboration, with the goal of improving global health. Dr Mitreva has authored over 250 peer-reviewed publications. In recognition of her global impact, she received the Bailey K. Ashford Medal from the American Society of Tropical Medicine and Hygiene in 2021, was inducted as a Fellow of ASTMH in 2022, and was elected to the American Academy of Microbiology in 2023.

Parasitic nematode control has been largely dependent on blanket administration of anthelmintic drugs in both humans and animals for many decades. However, this approach is increasingly unsustainable due to the emergence of anthelmintic drug resistance and concerns regarding environmental impacts. Consequently, more targeted evidence-based approaches are needed which in turn require better diagnostics and surveillance. High-throughput sequencing technologies now offer unprecedented opportunities to transform how parasitic nematode infections are detected, monitored, and managed and high-quality reference genomes are foundational for the development of the tools needed. In this talk I will discuss our work using metabarcoding and targeted sequencing to characterize complex parasitic nematode communities with an emphasis on anthelmintic drug resistance diagnostics, surveillance and management and the opportunities to leverage genomic data to enhance these approaches. I will discuss our continued development of nemabiome metabarcoding and deep sequencing tools and how we are using them to direct evidence-based parasite control as well as support the development of better molecular diagnostic tests. Examples will draw from projects on gastrointestinal nematodes of ruminant livestock, the canine hookworm Ancylostoma caninum and Human Soil Transmitted Helminths (STH).

Professor John Gilleard

University of Calgary, Canada

Professor John Gilleard

University of Calgary, Canada

Dr John Gilleard is a veterinarian and a Professor of Parasitology at the University of Calgary Faculty of Veterinary Medicine. His research program integrates parasitology, genomics, molecular diagnostics and molecular epidemiology to study anti-parasitic drug resistance and improve sustainable parasite control. He has active projects in livestock, companion animals and humans. He is a former president of the American Association of Veterinary Parasitology (2018), a Fellow of the Canadian Academy of Health Sciences (CAHS) and a Fellow of the Royal College of Veterinary Surgeons (RCVS).

The genome of the free-living rhabditid nematode Caenorhabditis elegans was the first to be sequenced for any animal, and has been fundamental to advances in not only nematode biology but in general understanding of the mechanics of life. This pioneering work on C. elegans ushered in a rich period of sequencing of other free-living and many parasitic species. These genomes were hard won products of application of new sequencing technologies and assembly approaches. With the invention of long-read sequencing platforms a new level of quality–measured as high completeness and contiguity–was achievable, and several high-quality genomes were published. However, these methods required significant starting material, meaning that good genomes were only achievable for inbred lines or from single specimens of the largest nematodes. Most nematode diversity was still inaccessible to genomics.

We have been working to effect the next step change in nematode genomics by developing technologies that can generate high-quality, chromosomally-complete genomes from single specimens of even the smallest free-living taxa. By generating data from single specimens we release nematode genome analysis from the joint strictures of collection of sufficient identified specimens of rare species and of assembling contiguous genomes from genetically diverse populations. I will present our methods–picogramme input multi-modal sequencing coupled with ultra-low input Hi-C–and over 100 new genomes we have generated for a wide diversity of parasitic and freeliving nematodes. I will present the rejuvenated “959 Nematodes Genomes Project” and invite all to contribute and benefit from the expanding possibilities of nematode genomics.

Professor Mark Blaxter

Wellcome Sanger Institute, UK

Professor Mark Blaxter

Wellcome Sanger Institute, UK

Mark Blaxter leads the Sanger Institute’s Tree of Life programme, generating and analysing genome sequences from thousands of species across the tree of life, especially Britain and Ireland (the Darwin Tree of Life project). His own research portfolio focuses on the genomics of neglected, non-model organisms - especially using the chromosomally-complete genome sequences generated by Tree of Life work - and the interpretation of those genomes in ecological and evolutionary contexts (including, inter alia, parasitic and free living nematodes, tardigrades, gastropod and bivalve molluscs, butterflies, bees, flies, birds, algae, fungi and bacteria). He has played a key role in defining pattern and process in chromosome evolution in lepidoptera (comprising 10% of all described species) and nematodes. Before joining Sanger, he was Professor of Evolutionary Genomics in the University of Edinburgh. He was elected a Fellow of the Royal Society of Edinburgh in 2014.

Parasitic nematodes such as Strongyloides have complex life cycles that involve both free-living and parasitic stages. As a result, identical genomes have to produce entirely different phenotypes, implicating whole-scale remodelling of gene networks. S. ratti is an excellent model to study this process because both parasitic and free-living adult worms can develop, enabling direct comparison of parasite-specific traits between individuals of the same life-cycle stage. Parasitic S. ratti adults switch on a number of parasitism genes, which are mostly located in a small number of genomic clusters. However, how these clusters are coordinatedly regulated is unknown. Here, we investigate the hypothesis that epigenetic regulation via post-translational modifications to histone proteins on chromatin is responsible for whole-scale activation of parasitism clusters. We investigate the distribution of a number of histone modifications genome-wide. We compare these to the model nematodes C. elegans and P. pacificus, shedding light on the conservation of chromatin landscapes across millions of years. Comparison of histone modification profiles between the X chromosome and the autosomes enables us to determine how sex chromosome dosage compensation is regulated in S. ratti. Surprisingly, we demonstrate that histone post-translational modifications remain remarkably stable at parasitism genes between free-living and parasitic stages, indicating that other processes rather than remodelling of the chromatin landscape control parasite-specific gene expression programs. Overall, our work presents the first genome-wide view of the epigenetic landscape of a parasitic nematode, and hint at a potentially unprecedented example of chromatin-independent transcriptional regulation.

Dr Peter Sarkies

University of Oxford, UK

Dr Peter Sarkies

University of Oxford, UK

Peter studied for his first degree in Oxford before doing a PhD at the LMB in Cambridge under the supervision of Julian Sale, working on DNA repair and epigenetic inheritance. For his postdoc he switched to C. elegans to study small non-coding RNA biogenesis and function. In 2015 he established an independent group at Imperial in London to use nematodes as a model to study the evolution of epigenetic pathways. He moved his lab to Oxford in 2021, where he continues to work on epigenetic pathways across nematodes, including Strongyloides.

Strongyloidiasis is a neglected tropical disease with significant yet underreported public health impact. In Ghana, especially in the Volta and Oti regions, its prevalence and genetic diversity remain poorly defined due to limited surveillance and low-sensitivity diagnostics. This cross-sectional study analysed 1,392 archived human stool samples from seven communities across three districts (Adaklu, Hohoe and Nkwanta North). Samples were pooled (≤10 per pool) for DNA extraction and PCR targeting the 18S rRNA gene of Strongyloides spp., with positive pools subsequently unpooled for individual testing. Sanger sequencing was performed on PCR-positive individual samples, and phylogenetic and haplotype analyses were conducted in MEGA 12, IQ-TREE and PopART. The pooled prevalence was 7.2% (95% CI: 5.5–9.3), while individual prevalence was 18.5% (95% CI: 16.5–20.6). Community-level prevalence varied, highest in Lancha (27.9%) and Abledzie (22.2%). Logistic regression showed no significant association between infection and sex, age or district. Phylogenetic analysis of 18S rRNA sequences revealed Ghanaian Strongyloides isolates clustering with reference sequences from Europe, Australia and Asia, with only minor sequence variation. This study provides the first molecular evidence of Strongyloides burden and genetic relatedness in the Volta and Oti regions and highlights the need for more sensitive diagnostics and strengthened surveillance.

Ms Grace Opoku Gyamfi

Noguchi Memorial Institute for Medical Research, Ghana

Ms Grace Opoku Gyamfi

Noguchi Memorial Institute for Medical Research, Ghana

As a Ghanaian research assistant at the Noguchi Memorial Institute for Medical Research, I’m passionate about infectious diseases particularly neglected tropical diseases (NTDs), genomics, and burgeoning interest in bioinformatics. I recently completed an online course in data analytics to better my analytical skills. I hold a bachelor’s degree in Biological Sciences and a recently completed master’s degree in applied Parasitology, and I am committed to advancing both research excellence and personal development.

Outside the lab, I am passionate about humanitarian activities, participating in the Rotary Club, Vacation Initiative in Science Africa and supporting local community donation projects. I’ve recently discovered the joy of reading and joined a book club, proof that it’s never too late to pick up a good habit (thanks, Atomic Habits). I love good food, hangout with friends, and binge-watching series. I’m also hoping to learn swimming and return to cycling. I’m inspired daily by my mother’s resilience and determination who remains my greatest role model.

Host–parasite interactions are powerful drivers of evolution, often generating extraordinary genetic diversity in both partners. Understanding how this diversity arises in parasites, and what role it plays in their biology, is essential both for basic science and for improving strategies to reduce their impact. We have developed new low-input sequencing approaches that generate high-quality genome assemblies from individual parasites and have applied these methods to numerous nematodes infecting humans, livestock, and wild animals. In doing so, we have discovered that hyper-divergent haplotypes – large tracks of sequence that differ markedly between individuals – are a common feature of parasitic nematode genomes. Many of these haplotypes encode genes involved in host interaction, including several previously trialled vaccine antigens, and in some cases encode different sets of genes, meaning that individuals of the same species can express distinct sets of host-interacting proteins. We hypothesise that this “hyperdiversity” plays a key role during infection by facilitating evasion of host immunity. In this talk, I will present our current data on the evolution, function, and real-world relevance of hyper-divergent haplotypes across multiple parasite species. I will also highlight the major open questions (What evolutionary processes generate and maintain hyper-divergent haplotypes? What roles does these haplotypes play during infection? And to what extent might they undermine vaccine efficacy?) and explain how single-parasite genomics can be used to address them.

Dr Lewis Stevens

Wellcome Sanger Institute, UK

Dr Lewis Stevens

Wellcome Sanger Institute, UK

Lewis is an evolutionary biologist working at the Wellcome Sanger Institute. He uses nematodes as a model system, and his current focus is in understanding the causes and consequences of regions of extreme genetic diversity in parasitic nematodes.

The HYP genes of plant-parasitic Globodera nematodes encode secreted effector proteins with staggering sequence diversity. Previous work on HYPs strongly suggests that this diversity is allelic and that it is produced by developmentally-programmed rearrangements: that is, the nematodes edit HYP genes in their somatic cells by shuffling a set of short DNA sequence motifs within a hypervariable domain. Although the germline diversity of HYP alleles is small, such editing is thought to create hundred or thousands of distinct somatic alleles across a population. Both the mechanism of HYP editing and its pathogenic function are unknown. In this talk, we discuss a DNA repair hypothesis for the editing mechanism that the nematode uses to rearrange HYP genes, and we evaluate this in light of the latest findings. We also present an immune evasion hypothesis for the pathogenic function of HYP editing, which we discuss in comparison with a range of analogous editing systems in distantly related organisms.

Dr Vincent Hanlon

University of Cambridge, UK

Dr Vincent Hanlon

University of Cambridge, UK

Vincent's work bridges the genetics of mutation and technology development for DNA sequencing. Previously, he worked on the accumulation of heritable somatic mutations in large old trees, before developing single-cell DNA sequencing protocols and associated bio-informatics for haplotyping and inversion-calling applications. Now his research focuses on the somatic diversification of HYP genes in Globodera plant-parasitic nematodes.

Strongyloides ratti is a common parasitic nematode of rats. It has c. 900 genes associated with parasitism. Among these are genes encoding astacin-like metalloproteases, acetylcholinesterases, CAP domain-containing proteins, and transthyretin-like proteins. Many of these genes are arranged adjacently in gene clusters referred to as "parasitism islands". In UK S. ratti populations these parasitism islands have higher levels of polymorphisms than other genomic regions. Most of these polymorphisms are non-synonymous, suggesting functional divergence among parasitism island gene products. To explore the functional impact of such variation in the island genes, we analysed genomes from twenty-five wild UK S. ratti genotypes using long-read sequencing and characterised their parasitism islands. We find that parasitism island structure is diverse among genotypes in terms of the number of islands, their genomic position, and gene composition. Focusing on astacin-like metalloproteases, structural protein modelling and alignment with experimentally-determine structures shows that over 85% of parasitism island encoded astacins lack the zinc-binding motif that is essential for protease activity. This loss contrasts with astacins encoded outside of parasitism islands, where most retain the motif and, presumably, protease activity. Because genes encoding these non-canonical, motif-deficient astacins are highly expressed, we suspect that they may have alternative, non-protease functions such as substrate binding, and phylogenetic analyses shows that their evolution is Strongyloides-specific.

Dr Mohammed Ahmed

University of Liverpool, UK

Dr Mohammed Ahmed

University of Liverpool, UK

Mohammed Ahmed is a nematologist and evolutionary biologist whose research spans the systematics, genomics, and evolutionary history of nematodes and other parasitic organisms. Trained in nematode taxonomy and phylogeny, he employs integrative morphological and molecular approaches to uncover hidden diversity and evolutionary relationships across the nematode phylum, particularly those from poorly known groups. His earlier work addressed the taxonomy and phylogenomics of terrestrial and marine nematodes, demonstrating expertise in bioinformatics and high-throughput sequencing. Currently, Mohammed is a postdoc at the University of Liverpool focussing on the parasitic nematode Strongyloides ratti, exploring the genomic basis of parasitism. His work highlights large-scale gene-expansion events linked to parasitic lifestyle evolution, strain-level genomic diversity within S ratti populations and evolution of parasitism gene families. This research aims to offer new insights into how S ratti evolved novel genetic toolkits to invade, exploit and persist within its hosts.

Caenorhabditis elegans primarily reproduces by self-fertilization, which leads to reduced levels of genetic diversity and potentially limits the adaptive potential of the species. In previous studies, we amassed 1,952 wild C. elegans strains collected from around the globe, sequenced the genomes using short-read technologies, and found that these strains contain punctuated genomic regions of extreme genetic diversity (hyper-divergent regions, HDRs) when compared to the reference N2 strain. These HDRs are enriched for genes associated with environmental responses such as xenobiotic stress and olfaction and might play a role in adaptation. However, the gene content of these regions remains incomplete because the extreme divergence in HDRs between the wild and reference genomes complicates short-read DNA alignments. To address this limitation, we generated de novo assemblies of 144 wild strains using PacBio HiFi long-read sequencing. We predicted protein-coding genes in these wild strain genomes, identified single-nucleotide and structural variants, and created a gene-based pangenome. Our gene-based pangenome has elucidated gene copy-number variation among wild strains, and we have identified hundreds of novel genes. We quantified levels of enrichment for structural variants, copy-number variants of specific genes, and novel gene birth in HDRs. This gene-based pangenome will be used to create new genotype matrices and perform genome-wide association mappings to connect gene content differences to phenotypic variation across the species, further elucidating the molecular mechanisms of adaptation and the role HDRs have in the long-term survival of this androdioecious species.

Mr Lance O'Connor

John Hopkins University, USA

Mr Lance O'Connor

John Hopkins University, USA

Lance is a third year Cell, Molecular, Developmental Biology, and Biophysics PhD Candidate at John Hopkins University. He earned his BS in Cellular and Organismal Physiology from the University of Minnesota in 2023 and enrolled at John Hopkins University to study computational genomics in Erik Andersen's laboratory. Lance received an honourable mention for his NSF GFRP application in 2025 and a Victor Corces Excellence in Teaching Award from John Hopkins University. He is interested in how intraspecies genetic variation shapes adaptive potential of species and how genotypic variation influences phenotypic variation.

Hyper-divergent genomic regions have been discovered in diverse nematode species but the evolutionary processes responsible for these genomic patterns are not yet understood. Hypotheses for the generation and maintenance of hyper-divergent regions include balancing selection, introgression and recombination dynamics. Distinguishing between these mechanisms is difficult due to overlapping predictions for genomic signatures and the long divergence times separating many well-studied nematodes. Each of these evolutionary mechanisms interacts with the unique set of nematode mating systems, reproductive modes, host associations and modes of parasitism, creating a rich dataset for evolutionary analyses. Here, I take a comparative genomic approach to understanding hyper-divergent regions by studying high-quality assembled genome sequences at multiple phylogenetic scales across Rhabditina. Studying both parasitic and non-parasitic species across deep evolutionary time highlights patterns of convergence and divergence underlying both nematode genomes and hyper-divergent regions.

Dr Janna Fierst

Florida International University, USA

Dr Janna Fierst

Florida International University, USA

Dr Janna Fierst is an Associate Professor in Biological Sciences at the Florida International University in Miami, FL. She received her PhD in Biological Sciences from the Florida State University, studying evolutionary theory and concept-driven mathematical modelling in the labs of Dr David Houle and Dr Thomas F. Hansen. During her postdoctoral research in the laboratory of Dr Patrick C Phillips at the University of Oregon she focused on Caenorhabditis comparative genomics and bioinformatic analyses. She started her independent research lab at the University of Alabama in 2015 before moving to Miami in 2022. Work in her lab focuses broadly around using mathematical and computational approaches to study questions of genome evolution, both in nematodes and broadly across the tree of life.