The dynamics of mutational selection in cutaneous squamous carcinogenesis

Greta Skrupskelyte  ¹ , Joanna C Fowler  ² , Stefan Dentro  ^{2   3   4} , Carine Winkler  ⁵ , Irina Abnizova  ² , Niklaus Beumer  ^{3   6   7} , Roshan Sood  ² , Thomas Quarrell  ⁸ , Charlotte King  ² , Jivko Kamarashev  ⁹ , Emmanuella Guenova  ^{10   11} , Moritz Gerstung  ^{3   4} , Benjamin A Hall  ¹² , Liliane Michalik  ⁵ , Philip H Jones  ^{13   14}

• PMID: 41526710
• DOI: 10.1038/s42003-025-09406-9

Abstract

Identifying the mutant genes that are selected during carcinogenesis is key to identifying candidates for intervention and understanding the processes that promote transformation. Here we applied two selection metrics to study the dynamics of mutational selection in a mouse model of ultraviolet light driven skin carcinogenesis in which multiple synchronous tumors develop in each animal. Sequencing normal skin and tumors over a time course revealed two genetic routes to squamous carcinoma. Nonsynonymous Trp53 mutants were positively selected in both epidermis and tumors and present in 90% of tumors. The remaining tumors carried other oncogenic mutants, including activating Kras mutations. However, other positively selected mutant genes lost their competitive advantage in heavily mutated epidermis and in tumors. We found ten mutant genes under negative selection in normal skin, one of which was also negatively selected in tumors. In addition one gene was negatively selected in tumors but not normal skin. We conclude that analysing selection in normal tissue alongside tumors may resolve the dynamics of selection in carcinogenesis and refine the identification of cancer drivers.

Olfactory receptors: Making sense (and antisense) of monogenic expression

Richard Benton  ¹

• PMID: 41401789
• DOI: 10.1016/j.cub.2025.11.002

Abstract

Monogenic expression of odorant receptors (ORs) in individual sensory neurons is a hallmark of olfactory systems in insects and vertebrates. New studies highlight how transcriptional interference and antisense transcription might ensure such selectivity in large OR arrays of social insects.

Single nucleotide variants in UNC13C associated with neurodevelopmental disorders affect ethanol sensitivity in Drosophila

Franz Müller  ¹ , Sonja Neuser  ² , Gaurav Shrestha  ³ , Netra P Neupane  ⁴ , Katharina J Götze  ¹ , Nicola Brunetti-Pierri  ^{5   6   7} , Gaetano Terrone  ⁵ , Alexandre Reymond  ⁸ , Koen L van Gassen  ⁹ , Eva Brilstra  ⁹ , Katharina Steindl  ¹⁰ , Anais Begemann  ¹⁰ , Anita Rauch  ¹⁰ , Jonathan Rips  ¹¹ , Duha Fahham  ¹¹ , Tahsin Stefan Barakat  ¹² , Olivier Patat  ¹³ , Jérémie Mortreux  ¹⁴ , Matthew Hoi Kin Chau  ^{15   16   17} , Jill A Rosenfeld  ¹⁸ , Elizabeth Mizerik  ^{18   19} , Swati Srivastava  ^{18   20} , Xi Luo  ^{18   20} , Anne-Kristin Dahse  ¹ , Nicole Scholz  ¹ , Joydip Das  ⁴ , Gregg Roman  ²¹ , Tobias Langenhan  ^{1   22   23} , Rami Abou Jamra  ² , Achmed Mrestani  ^{1   24} , Dmitrij Ljaschenko  ¹

Affiliations

• PMID: 41399760
• PMCID: PMC12702192
• DOI: 10.1016/j.bbrep.2025.102375

Abstract

UNC13s are presynaptic proteins essential for neurotransmitter release at chemical synapses. In this study, we present eleven patients from nine families with severe neurodevelopmental impairments, who carry rare, biallelic UNC13C single-nucleotide variants (SNVs). Six missense variants, each identified in compound heterozygosity in one of three of these patients, were introduced into the Drosophila melanogaster ortholog unc13 using a previously established CRISPR/Cas9-based method for rapid and scarless genomic modifications, hypothesising that they underlie the observed clinical manifestations. However, none of the introduced mutations influenced Mendelian ratios, negative geotaxis, or lifespan of the fruit flies. Interestingly, two variants located outside the gene regions encoding known UNC13C domains caused a decreased ethanol sensitivity in Drosophila, while the Thr1729Met substitution within the C₁ domain resulted in increased ethanol sensitivity. Molecular dynamics simulations of the latter mutant gene product suggested that the altered protein conformation enhances exposure of the ethanol-binding site, thereby increasing sensitivity to ethanol. These findings reinforce previous evidence highlighting the critical role of the C₁ domain in ethanol sensitivity. Given the involvement of the C₁ domain in synaptic plasticity this result might implicate an influence of the Thr1729Met on synaptic function.

Keywords: Chemical synapse; Dunc13; Ethanol sensitivity; Molecular dynamics simulation; Neurodevelopmental disease; UNC13C; Unc13.

© 2025 The Authors.