️ 24: The Role of the X Chromosome in Complex Trait Genetics — Unraveling Dosage-Compensation Mechanisms

️ 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/

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