🎙️ Episode 24: The Role of the X Chromosome in Complex Trait Genetics — Unraveling Dosage-Compensation Mechanisms
🧬 In this installment of Base por Base, we delve into groundbreaking work by Fu et al. (2025) in The American Journal of Human Genetics, which systematically interrogates how the X chromosome shapes human quantitative traits. Leveraging data from over 350,000 UK Biobank participants with replication in more than 400,000 FinnGen individuals, the study quantifies the X chromosome’s contribution to trait heritability, examines sex-specific genetic variance, and elucidates the interplay between X-inactivation and upregulation processes in balancing dosage between sexes and with the autosomes .

🔍 Key Highlights: In a comprehensive analysis of 48 traits, the authors report that the X chromosome accounts for roughly 3% of the heritability explained by autosomes, demonstrating a proportional yet distinct contribution to complex trait variation; they confirm near-complete X chromosome inactivation in females and hemizygosity in males, leading to approximately double the genetic variance on X in men versus women; compelling evidence emerges for partial escape from inactivation impacting traits such as height; moreover, the study reveals that single active copies of X-linked loci exert allele effects about 1.6-fold greater than those on autosomes, supporting a model of partial transcriptional upregulation on X relative to autosomes .

🧠 Conclusion: By integrating large-scale biobank data with advanced heritability and effect-size modeling, this work inaugurates a new era in understanding X-linked genetic architecture. It highlights how near-complete inactivation, nuanced escape, and dosage compensation via allele-level upregulation collectively maintain balanced contributions of the X chromosome to human phenotypic diversity, offering vital insights for future locus discovery and sex-specific analyses in genomics .

📖 Reference:
Fu, Y., Kenttämies, A., Ruotsalainen, S., Pirinen, M., & Tukiainen, T. (2025). Role of X chromosome and dosage-compensation mechanisms in complex trait genetics. The American Journal of Human Genetics, 112, 1–14. https://doi.org/10.1016/j.ajhg.2025.04.004

📜 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International (CC BY 4.0) license – https://creativecommons.org/licenses/by/4.0/