The dynamic genetic determinants of increased transcriptional divergence in spermatids

• Published in: Nature communications Vol. 15; no. 1; pp. 1272 - 13
• Main Authors: Panten, Jasper, Heinen, Tobias, Ernst, Christina, Eling, Nils, Wagner, Rebecca E., Satorius, Maja, Marioni, John C., Stegle, Oliver, Odom, Duncan T.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.02.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 38/39; 45/47; 45/91; 631/181/2474; 631/208/135; 631/208/514/1949; 631/208/728; 64/60; Animals; Cancer research; Cell differentiation; Cells; Differentiation (biology); Divergence; Dynamical systems; Gene expression; Gene Expression Regulation; Gene regulation; Genetic effects; Genomes; Genomics; Humanities and Social Sciences; Hybrid systems; Male; Medical research; Mice; Molecular biology; multidisciplinary; Science; Science (multidisciplinary); Sperm; Spermatids; Spermatogenesis; Transcription; Variability
• DOI: 10.1038/s41467-024-45133-1
• ISSN: 2041-1723

Cis- genetic effects are key determinants of transcriptional divergence in discrete tissues and cell types. However, how cis- and trans- effects act across continuous trajectories of cellular differentiation in vivo is poorly understood. Here, we quantify allele-specific expression during spermatogenic differentiation at single-cell resolution in an F1 hybrid mouse system, allowing for the comprehensive characterisation of cis- and trans -genetic effects, including their dynamics across cellular differentiation. Collectively, almost half of the genes subject to genetic regulation show evidence for dynamic cis -effects that vary during differentiation. Our system also allows us to robustly identify dynamic trans -effects, which are less pervasive than cis -effects. In aggregate, genetic effects were strongest in round spermatids, which parallels their increased transcriptional divergence we identified between species. Our approach provides a comprehensive quantification of the variability of genetic effects in vivo, and demonstrates a widely applicable strategy to dissect the impact of regulatory variants on gene regulation in dynamic systems. Here the authors show that genetic changes between species often alter gene expression in a cell type-specific manner. Most of this variability is driven by locally functioning cis-acting variation, and this contributes to the speed at which cell types accumulate expression changes.