Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.06.19.660630

Large-Scale Restructuring of the Caspase-1 Gene Cluster Region in Mammals

Stevens, D.·Daish, T.·Grutzner, F.
View original source ↗Export metadata ↓

Abstract

The inflammatory response is an important component of the host immune defence mechanism against pathogens. Activation of the NLRP3 inflammasome has been shown to have a wide range of triggers including fungal, bacterial and viral components, cellular stress and environmental irritants. The NLRP3 inflammasome has been well characterised in mouse and humans but limited information is available from other mammalian species. In order to gain a better understanding of the evolution of genes involved in the NLRP3 inflammasome pathway, we examined them in mammalian species representing the three major groups (eutheria, metatheria and prototheria) and in chicken as an outgroup. Our results show that the inflammasome pathway machinery is generally well conserved though chicken appears to lack several key components and monotremes have a duplication of Syk. Analysis of the proinflammatory caspase cluster and neighboring genes revealed massive reorganisation as well as the previously described multiple duplications that occurred during mammalian evolution. Our data suggest that Caspase-1 moved to a new chromosomal region in early mammalian evolution. This was followed by expansion of the cluster and accumulation of additional genes regulating inflammatory responses such as Card16, Card17, Card18 and the Birc genes. The expansion of key gene families flanking Caspase-1 may have led to an expansion of inflammasome pathways and a more regulated immune system in humans through the CARD genes.

Explore related subjects

geneticsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Stevens, D., Daish, T., Grutzner, F.. 2025-06-21. Large-Scale Restructuring of the Caspase-1 Gene Cluster Region in Mammals. https://doi.org/10.1101/2025.06.19.660630

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

KEEP EXPLORING

Related preprints

bioRxiv2026

Large language model-based bibliometric evaluation of population descriptors in human genetics

As the use of population descriptors such as race, ethnicity, and ancestry have become increasingly common in modern genetics research, there have been growing calls to critically examine their use. Most notably, in 2023, the National Academies of Science, Engineering, and Medicine (NASEM) published a report titled Using Population Descriptors in Genetics and Genomics Research: A New Framework for an Evolving Field, which included eight specific and actionable recommendations for researchers to implement the ethical and accurate use of population descriptors in genetic research. Here, we use the 2023 NASEM report as a benchmark to analyze the use of population descriptors in genome-wide association studies (GWAS). We develop a general toolkit for large language model-based bibliometrics, operationalize the report's recommendations into an evaluation framework, and apply this framework to evaluate all 4,007 papers from the GWAS Catalog published between 2007 and 2025 with full text available on PubMedCentral. We find significant improvements in adherence to NASEM report recommendations over time. However, most improvements predate the publication of the NASEM report itself, suggesting the report functioned primarily as a synthesis of existing best practices rather than a catalyst for change. We conclude by highlighting opportunities for growth in the field of human genetics.

genetics↗
bioRxiv2026

Mitigating biases of rescaling in forward-in-time population genetic simulations

Forward-in-time population genetic simulations are widely used in evolutionary analyses, but simulating large populations and long genomic regions remains computationally demanding. To reduce this cost, parameter rescaling is widely employed, in which the original evolutionary process is approximated by one with a smaller population size and fewer generations. Recently, several studies using the SLiM simulator have raised concerns about the accuracy of this rescaling approach. In this study, we show that many of the biases reported in these studies can be mitigated by using a different simulation algorithm. These results reveal that the accuracy of parameter rescaling depends on how well the simulation algorithm preserves diffusion-limit properties under rescaling.

genetics↗
bioRxiv2026

OPA1 controls mitochondrial dysfunction-driven liver fibrosis in MASLD

Progressive hepatic fibrosis is the principal determinant of morbidity and mortality in metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/MASH). Mitochondrial dysfunction is a hallmark of MASH, and the release of mitochondrial damage-associated molecular patterns (mito-DAMPs) from injured hepatocytes can promote fibrosis. However, how mitochondrial dynamics and quality control shape the fibrotic response in MASLD/MASH remains unclear. Here, through large-scale genomic analyses of mitochondrial genes governing mitophagy, fusion and fission in human MASLD, with a power-equivalent sample size of approximately 700,000 individuals, we identify a strong association between hepatic fibrosis and the mitochondrial fusion factor dynamin-like GTPase optic atrophy 1 (OPA1). OPA1 transcripts and protein abundance in the liver epithelium were progressively dysregulated with advancing fibrosis. In mice, hepatocyte-specific OPA1 loss alone was sufficient to induce hepatic stellate cell activation and fibrosis in zone 3, promoted the release of mito-DAMPs into the circulation and exacerbated fibrosis in experimental MASH. These findings identify OPA1 as a central regulator of the hepatic fibrotic response and connect defective mitochondrial homeostasis to mito-DAMP release, hepatic stellate cell activation and fibrosis in MASLD.

genetics↗