A major locus for ivermectin resistance in a parasitic nematode

Doyle, S. R.; Illingworth, C. J. R.; Laing, R.; Bartley, D. J.; Redman, E.; Martinelli, A.; Holroyd, N.; Morrison, A. A.; Rezansoff, A.; Tracey, A.; Devaney, E.; Berriman, M.; Sargison, N.; Cotton, J. A.; Gilleard, J. S.

doi:10.1101/298901

bioRxiv · 10.1101/298901

A major locus for ivermectin resistance in a parasitic nematode

Doyle, S. R.·Illingworth, C. J. R.·Laing, R.·Bartley, D. J.·Redman, E.·Martinelli, A.·Holroyd, N.·Morrison, A. A.·Rezansoff, A.·Tracey, A.·Devaney, E.·Berriman, M.·Sargison, N.·Cotton, J. A.·Gilleard, J. S.

View original source ↗Export metadata ↓

Abstract

BackgroundInfections with helminths cause an enormous disease burden in billions of animals and plants worldwide. Large scale use of anthelmintics has driven the evolution of resistance in a number of species that infect livestock and companion animals, and there are growing concerns regarding the reduced efficacy in some human-infective helminths. Understanding the mechanisms by which resistance evolves is the focus of increasing interest; robust genetic analysis of helminths is challenging, and although many candidate genes have been proposed, the genetic basis of resistance remains poorly resolved. ResultsHere, we present a genome-wide analysis of two genetic crosses between ivermectin resistant and sensitive isolates of the parasitic nematode Haemonchus contortus, an economically important gastrointestinal parasite of small ruminants and a model for anthelmintic research. Whole genome sequencing of parental populations, and key stages throughout the crosses, identified extensive genomic diversity that differentiates populations, but after backcrossing and selection, a single genomic quantitative trait locus (QTL) localised on chromosome V was revealed to be associated with ivermectin resistance. This QTL was common between the two geographically and genetically divergent resistant populations and did not include any leading candidate genes, suggestive of a previously uncharacterised mechanism and/or driver of resistance. Despite limited resolution due to low recombination in this region, population genetic analyses and novel evolutionary models supported strong selection at this Q.TL, driven by at least partial dominance of the resistant allele, and that large resistance-associated haplotype blocks were enriched in response to selection. ConclusionsWe have described the genetic architecture and mode of ivermectin selection, revealing a major genomic locus associated with ivermectin resistance, the most conclusive evidence to date in any parasitic nematode. This study highlights a novel genome-wide approach to the analysis of a genetic cross in non-model organisms with extreme genetic diversity, and the importance of a high quality reference genome in interpreting the signals of selection so identified.

Source connections

Published article ↗

Explore related subjects

genomics Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Doyle, S. R., Illingworth, C. J. R., Laing, R., Bartley, D. J., Redman, E., Martinelli, A., Holroyd, N., Morrison, A. A., Rezansoff, A., Tracey, A., Devaney, E., Berriman, M., Sargison, N., Cotton, J. A., Gilleard, J. S.. 2018-04-23. A major locus for ivermectin resistance in a parasitic nematode. https://doi.org/10.1101/298901

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Recurrent mitotic error and purifying selection shape chromosomal mosaicism across human tissues

Mosaic chromosomal alterations (mCAs) have been extensively studied in cancer and clonal hematopoiesis but less so in healthy solid tissues. Here, we characterized mCAs in 19 tissues across 25 donors (aged 42-89+ years) by analyzing >200x whole-genome sequencing data generated by the Somatic Mosaicism across Human Tissues (SMaHT) Network. Across 722 tissue samples, we identified 1,008 autosomal mCAs >1 Mb in length and ubiquitous losses of sex chromosomes. Surprisingly, the highest levels of Y chromosome loss in males (5-10% cell fraction in elderly donors) were observed in the lung, adrenal gland, and heart. These tissues also tended to experience more X loss in females, revealing a gradient of mitotic error burden across human tissues. Autosomal aneuploidies displayed distinct tissue-specific patterns indicative of negative selection against most events, except in the adrenal gland, in which low-level aneuploidy was pervasive. In contrast to the adrenal gland, testis rarely harbored aneuploidies but frequently experienced low-level copy-neutral loss of heterozygosity (CN-LOH), suggesting increased mitotic recombination in spermatogonial stem cells. Recurrent X chromosome losses within tissues of female donors exhibited allelic skews explained by a combination of genetic and epigenetic effects. Together, these results show that the chromosomal landscape of aging human tissues is shaped by genetics and recurrent mutations, most but not all of which are held in check by purifying selection.

genomics↗

bioRxiv2026

A Chromosome Scale Genome Assembly for the Australian blue mussel Mytilus planulatus

Mussels belonging to the genus Mytilus are among the world's most ecologically and economically important bivalve molluscs. Although the genus most likely originated in the Northern Hemisphere, the evolutionary history of Southern Hemisphere lineages, including the timing and number of colonisation events leading to the extant Australian populations, remains debated. Limited genomic resources have hindered the reconstruction of these evolutionary histories. In Australia, distinguishing native Mytilus planulatus from invasive Mytilus galloprovincialis is critical for biosecurity and conservation, but previous molecular approaches lacked sufficient resolution to resolve species boundaries and hybridisation patterns. Here, we present the first chromosome-scale reference genome for M. planulatus. The assembly consists of 14 chromosomes and over 51,000 annotated protein-coding genes per haplotype. Comparative analysis revealed extensive structural variation and widespread hemizygosity despite a largely conserved chromosomal organisation relative to M. galloprovincialis. Population analyses using SNPs and gene presence-absence variation in resequenced individuals confirmed previously inferred patterns of population structure and establish this reference genome as a valuable resource for future studies of genome evolution, adaptation and population genomics in Mytilus.

genomics↗

bioRxiv2026

An Isogenic iPSC Model of LMNA p.R482W Recapitulates Adipocyte Dysfunction in Familial Partial Lipodystrophy Type 2

Familial partial lipodystrophy type 2 (FPLD2) is a rare autosomal dominant disorder caused by pathogenic variants in LMNA, most commonly p.R482W, and is characterized by selective loss of subcutaneous adipose tissue, severe insulin resistance, and dyslipidemia. The cellular mechanisms underlying adipocyte dysfunction in FPLD2 remain incompletely understood, in part because existing in vitro models rely on patient-derived, non-isogenic cell lines or require non- physiologic transgene overexpression to achieve adipogenic differentiation. Here, we describe a CRISPR/Cas9-edited isogenic iPSC model of FPLD2 in which the heterozygous LMNA c.1444C>T (p.R482W) variant was introduced into a healthy donor-derived iPSC line. Using a transgene-free mesenchymal progenitor differentiation protocol, we generated LMNAp.R482W and isogenic control adipocytes and characterized their transcriptomic and functional phenotypes. Bulk RNA- sequencing demonstrated strong concordance in adipogenesis gene expression between genotypes during differentiation (Pearson {rho} = 0.968), yet LMNAp.R482W adipocytes exhibited significant downregulation of key adipogenic, lipid-handling, and extracellular matrix genes compared to isogenic controls. Functionally, LMNAp.R482W adipocytes showed markedly impaired glucose uptake under both basal and insulin-stimulated conditions, consistent with severe insulin resistance. Seahorse extracellular flux analysis revealed a globally quiescent metabolic state with significantly reduced oxygen consumption rate (126.5 vs. 261.5 pmol/min, p < 0.0001) and extracellular acidification rate (27.6 vs. 46.7 mpH/min, p < 0.0001). To validate these findings in human tissue, gene set enrichment analysis results from the iPSC model were compared to single-nucleus RNA-sequencing data from subcutaneous white adipose tissue biopsies of individuals with FPLD2 carrying the LMNA p.R482W variant. Across 37 mutually significant pathways, 59.5% were concordant between the iPSC model and human adipose tissue, including the pathways most central to FPLD2 pathophysiology: adipogenesis, fatty acid metabolism, oxidative phosphorylation, and inflammatory response. These findings establish this isogenic iPSC system as a faithful cellular model of FPLD2 adipocyte biology and a platform for functional characterization of LMNA variants of uncertain significance.

genomics↗