A quantitative model of a phenotypically variable genetic defect

• 成果类型: Article
• 署名作者: Simpkins, Alison G.; Skinner, Dominic J.; Felix, Brox; Marmion, Robert A.; Schottenfeld-Roames, Jodi; Shvartsman, Stanislav Y.
• 署名单位: Princeton University; Simons Foundation; Flatiron Institute; Princeton University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2619147123
• 发表日期: 2026-08-18
• 页码: e2619147123
• 关键词: phenotypic variability; FGF signaling; Drosophila trachea; drosophila; TRACHEAL; mutations; homolog; activation; expression; migration; encodes; signal; DISCORDANT

摘要

Phenotypic variability is a hallmark of human disease. It results from a combination of genetic modifiers, environment, and stochastic effects, but their contributions are hard to disentangle. Here, we establish the specification of terminal cells in the Drosophila tracheal system as a model for phenotypic variability and phenotypic emergence in Mendelian disorders. By perturbing Fibroblast growth factor (FGF) ligand dosage, which leads to a loss of terminal cells, we find that both microenvironmental and stochastic effects contribute to variability in terminal cell specification. We demonstrate that the phenotype results from reduced Ras-ERK signaling and use live imaging to identify molecular and morphological features of successful and failed terminal cell specification. Finally, using liability-threshold modeling, we quantify the relative magnitudes of genetic perturbations, microenvironmental effects, and stochasticity, establishing a strategy for dissecting the origins of phenotypic variability.