@article{cff2c4888ebd4fed876014d4552a1a93,
title = "Sex-chromosome dosage effects on gene expression in humans",
abstract = "A fundamental question in the biology of sex differences has eluded direct study in humans: How does sex-chromosome dosage (SCD) shape genome function? To address this, we developed a systematic map of SCD effects on gene function by analyzing genome-wide expression data in humans with diverse sex-chromosome aneuploidies (XO, XXX, XXY, XYY, and XXYY). For sex chromosomes, we demonstrate a pattern of obligate dosage sensitivity among evolutionarily preserved X-Y homologs and update prevailing theoretical models for SCD compensation by detecting X-linked genes that increase expression with decreasing X- and/or Y-chromosome dosage. We further show that SCD-sensitive sex-chromosome genes regulate specific coexpression networks of SCD-sensitive autosomal genes with critical cellular functions and a demonstrable potential to mediate previously documented SCD effects on disease. These gene coexpression results converge with analysis of transcription factor binding site enrichment and measures of gene expression in murine knockout models to spotlight the dosage-sensitive X-linked transcription factor ZFX as a key mediator of SCD effects on wider genome expression. Our findings characterize the effects of SCD broadly across the genome, with potential implications for human phenotypic variation.",
keywords = "Klinefelter syndrome, Sex chromosomes, Sex differences, Turner syndrome, X-inactivation",
author = "Armin Raznahan and Parikshak, {Neelroop N.} and Vijay Chandran and Blumenthal, {Jonathan D.} and Clasen, {Liv S.} and Alexander-Bloch, {Aaron F.} and Zinn, {Andrew R.} and Danny Wangsa and Jasen Wise and Murphy, {Declan G.M.} and Bolton, {Patrick F.} and Thomas Ried and Judith Ross and Giedd, {Jay N.} and Geschwind, {Daniel H.}",
note = "Funding Information: aDevelopmental Neurogenomics Unit, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892; bNeurogenetics Program, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; cCenter for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; dDepartment of Pediatrics, School of Medicine, University of Florida, Gainesville, FL 32610; eMcDermott Center for Human Growth and Development, University of Texas Southwestern Medical School, Dallas, TX 75390; fDepartment of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX 75390; gGenetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; hQiagen, Frederick, MD 21703; iInstitute of Psychiatry, Psychology and Neuroscience, King{\textquoteright}s College London, University of London, London WC1B 5DN, United Kingdom; jDepartment of Pediatrics, Thomas Jefferson University, Philadelphia, PA 19107; and kDepartment of Psychiatry, University of California, San Diego, La Jolla, CA 92093 Publisher Copyright: {\textcopyright} 2018 National Academy of Sciences. All rights reserved.",
year = "2018",
month = jul,
day = "10",
doi = "10.1073/pnas.1802889115",
language = "English (US)",
volume = "115",
pages = "7398--7403",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "28",
}