Genome-wide association studies identify new candidate genes and tissues underlying resistance to a natural toxin in drosophilids.

Michele Marconcini  ¹ , Caroline Fragnière  ¹ , Ambra Masuzzo  ¹ , Richard Benton  ¹

• PMID: 41692494
• DOI: 10.1093/g3journal/jkag032

Abstract

Many insects can rapidly evolve resistance to artificial insecticides through changes in toxin target proteins. Over longer timescales, insects also evolve resistance to naturally occurring toxins to exploit new ecological niches, but the underlying mechanisms often remain poorly understood. A classic example is Drosophila sechellia, an extreme specialist for the ripe noni fruit of Morinda citrifolia. Noni is toxic for other insects – including D. sechellia’s close relatives D. simulans and D. melanogaster – due to this fruit’s high content of octanoic acid (OA). However, the mechanistic bases of OA susceptibility and resistance across species remain unclear. Here, we first show that the species-specific tolerance of OA is independent of these drosophilids’ distinct microbiomes. Screening large, genetically-diverse panels of D. melanogaster and D. simulans strains revealed broad variation in OA resistance, with some lines surviving as well as D. sechellia. Resistance to OA does not correlate with resistance of these lines to other insecticides, implying a distinct toxicity mode-of-action. Genome-wide association and transcriptome-to-phenotype analyses identified multiple genes linked to OA resistance, with diverse expression patterns and functions, including epithelial septate junction formation, and lipid transport. Loss-of-function analysis in D. melanogaster confirmed that at least two of these – Bez, a CD36-family fatty acid transporter, and CG13003, a putative extracellular matrix component – positively contribute to OA resistance. Integration of our findings with those from previous complementary genetic approaches supports a model in which OA has no singular target, and that resistance is defined by multigenic and multi-tissue defense mechanisms.

Ancient co-option of LTR retrotransposons as yeast centromeres.

Max A B Haase  ^{1   2} , Luciana Lazar-Stefanita  ³ , Lyam Baudry  ⁴ , Aleksandra Wudzinska  ³ , Xiaofan Zhou  ⁵ , Antonis Rokas  ⁶ , Chris Todd Hittinger  ⁷ , Boris Pfander  ⁸ , Andrea Musacchio  ^{9   10} , Jef D Boeke  ^{11   12   13}

• PMID: 41708848
• DOI: 10.1038/s41586-025-10092-0

Abstract

Centromeres ensure accurate chromosome segregation, yet their DNA evolves rapidly across eukaryotes leaving the origins of new centromere architectures unclear^1-4. The brewer’s yeast Saccharomyces cerevisiae exemplifies this long-standing puzzle. Its centromeres shifted ancestrally from large, repeat-rich, epigenetically specified forms to the compact, genetically defined ‘point’ centromeres^1,5. How this transition occurred has remained unresolved⁶. Here we identify evolutionarily related ‘proto-point’ centromeres that provide a resolution to the evolutionary origins of point centromeres. Proto-point centromeres contain a single centromeric nucleosome positioned over an AT-rich core, accompanied by relaxed organization and sequence variability of flanking cis-elements. In two species, these proto-point centromeres lie within retrotransposon-derived repeat clusters, linking ancestral repeat-rich centromeres to genetically encoded ones. Comparative and phylogenetic analyses indicate that proto-point and point centromeres evolved in an ancestor with retrotransposon-rich centromeres. These results identify long-terminal-repeat retrotransposons, specifically Ty5 sequences, as the genetic substrate for point-centromere evolution and provide a mechanistic route by which an epigenetic centromere can become genetically specified. More broadly, they show how selfish elements can be co-opted to perform essential chromosomal functions.

• Feeding-regulated glycogen metabolism drives rhythmic liver protein secretion
• Meltem Weger  ¹ , Daniel Mauvoisin  ^{2   3} , Dominic Hoyle  ¹ , Jingkui Wang  ^{4   5} , Eva Martin  ^{2   4} , James Rae  ¹ , Charles Ferguson  ¹ , Glynis Klinke  ⁶ , Michelle Cielesh  ⁷ , Kyle L Macauslane  ⁸ , Mark Larance  ⁷ , Manfredo Quadroni  ⁹ , Iain Templeman  ¹⁰ , Jean-Philippe Walhin  ¹⁰ , Leonidas G Karagounis  ^{2   11   12} , James A Betts  ¹⁰ , Jonathan D Johnston  ¹³ , Fanny Durussel  ¹⁴ , Dmitri Firsov  ¹⁴ , Stephane Fournier  ^{15   16} , Olivier Müller  ^{15   16} , Benjamin L Schulz  ⁸ , Robert G Parton  ^{1   17} , Benjamin D Weger  ^{18   19} , Frédéric Gachon  ^{20   21   22   23}
• Affiliations
• PMID: 41644694
• DOI: 10.1038/s42255-026-01453-8
• Abstract
• The liver has a key role in inter-organ communication by secreting most circulating plasma proteins. However, the mechanisms governing hepatic protein secretion remain unclear. Here we show that hepatic protein secretion follows a diurnal rhythm regulated by food intake in humans and mice. Using liver microsomal proteomics, we find that proteins implicated in the early secretory pathway, such as protein glycosylation and folding in the endoplasmic reticulum (ER) and Golgi apparatus, exhibit a rhythmic expression profile, which is abolished in Bmal1-knockout mice. Mechanistically, we show that hepatic glycogenolysis provides substrates for protein N-glycosylation. In mice, perturbing hepatic glycogenolysis with pharmacological or nutritional interventions leads to ER stress and attenuates diurnal protein secretion. We confirm these results in humans, as genetic variants associated with glycogen storage disease and congenital disorders of glycosylation also alter hepatic protein secretion. Overall, our work uncovers hepatic glycogen metabolism as a circadian regulator of protein secretion.