Volume 231, Issue 1, September 2025

This invited review by Roy examines the use of Caenorhabditis elegans as a model organism in drug discovery and chemical genetics. Highlighting its advantages as a cost-effective, whole-animal drug-screening platform, it surveys over 9,600 published studies to identify key research trends. The article revisits Sydney Brenner’s seminal 1974 drug screen, reviews large-scale efforts that uncovered novel candidate drugs, anthelmintics, and nematicides, and shows how genetics can reveal drug targets. By integrating historical context with recent advances, the review underscores the enduring value of C. elegans as a small animal model for early-stage drug research.

The extent to which different species adapt to shared environmental variation is poorly understood. Here Fan, Cridland, and Begun use transcriptome variation in the accessory gland and testis from low vs. high latitude populations of D. melanogaster and D. simulans to investigate this question. The authors found that the two species show parallel patterns of gene expression differences between two populations in the accessory gland. This suggests that natural selection plays a major role in shaping even small magnitude gene expression differences across many genes, and that the two species transcriptomes are adapting in a similar manner in response to latitudinally varying selection pressures.

MECP2 is commonly mutated in Rett syndrome, however MECP2 variants have also been identified in individuals with autism spectrum disorder (ASD). Chen et al. establish functional assays for MECP2 variants using Drosophila and Saccharomyces cerevisiae and calibrate these assays according to ACMG guidelines for clinical interpretation of variant function. The authors classify four of the nine identified ASD variants as loss of function variants, thus providing the first experimental evidence for MECP2 variants conferring ASD risk.

Identifying rare variants of uncertain significance (VUS) that may confer disease risk is an important challenge to overcome. Cyrus et al. developed an in vivo Drosophila assays that accurately distinguishes between pathogenic and benign variants in the Embryonic Ectoderm Development (EED) gene. EED is a member of the Polycomb Repressive Complex 2 (PRC2). Germline pathogenic variants cause Cohen-Gibson syndrome, while somatic variants are associated with blood cancers. The authors found mimicking pathogenic variants in Drosophila cause known PRC2 loss-of-function phenotypes while common, likely benign variants functioned normally. This shows that their efficient approach can be useful in reclassifying human EED variants of uncertain significance.

Candida glabrata, the second-most common Candida species, is a high-priority pathogen due to its increasing clinical relevance and resistance to antifungal drugs. It shows strong adaptation to oxidative stress and amino acid starvation. This study highlights the critical roles of Gcn2 kinase and Gcn4 transcription factor in enabling stress adaptation, ensuring survival in nutrient-depleted and oxidative environments. Gcn4 is particularly crucial for host survival and virulence. Targeting the Gcn2-Gcn4 may offer promising therapeutic strategies against C. glabrata infections.