bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2023.12.07.570117

Improving the suppressive power of homing gene drive by co-targeting a distant-site female fertility gene

Faber, N. R.·Xu, X.·Chen, J.·Hou, S.·Du, J.·Pannebakker, B. A.·Zwaan, B. J.·van den Heuvel, J.·Champer, J.
View original source ↗Export metadata ↓

Abstract

Gene drive technology has the potential to address major biological challenges, including the management of disease vectors, invasive species, and agricultural pests. After releasing individuals carrying the gene drive in the target population, suppression gene drives are designed to spread at a rapid rate and carry a recessive fitness cost, thus bringing about a decline in population size or even complete suppression. Well-studied homing suppression drives have been shown to be highly efficient in Anopheles mosquitoes and were successful in eliminating large cage populations. However, for other organisms, including Aedes mosquitoes, homing gene drives are so far too inefficient to achieve complete population suppression, mainly due to lower rates of drive conversion, which is the rate at which wild type alleles are converted into drive alleles. Low drive conversion is also a major issue in vertebrates, as indicated by experiments in mice. To tackle this issue, we propose a novel gene drive design that has two targets: a homing site where the drive is located and drive conversion takes place (with rescue for an essential gene), and a distant site for providing the fitness cost for population suppression (preferably a female fertility gene, for which no rescue is provided). We modeled this design and found that the two-target system allows suppression to occur over a much wider range of drive conversion efficiency. Specifically, in the new design, the suppressive power depends mostly on total gRNA cutting efficiency instead of just drive conversion efficiency, which is advantageous because cut rates are often substantially higher than drive conversion rates. We constructed a proof of concept in Drosophila melanogaster and show that both components of the gene drive function successfully. However, embryo drive activity from maternally deposited Cas9 as well as fitness costs for female drive heterozygotes both remain significant challenges for two-target and standard suppression drives. Overall, our improved gene drive design eases the development of strong homing suppression gene drives for many species where drive conversion is less efficient.

Source connections

Explore related subjects

geneticsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Faber, N. R., Xu, X., Chen, J., Hou, S., Du, J., Pannebakker, B. A., Zwaan, B. J., van den Heuvel, J., Champer, J.. 2023-12-08. Improving the suppressive power of homing gene drive by co-targeting a distant-site female fertility gene. https://doi.org/10.1101/2023.12.07.570117

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↗