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Sex Chromosome Dosage Effects On Gene Expression In Humans

Armin Raznahan, Neelroop Parikshak, Vijayendran Chandran, Jonathan Blumenthal, Liv Clasen, Aaron Alexander-Bloch, Andrew Zinn, Danny Wangsa, Jasen Wise, Declan Murphy, Patrick Bolton, Thomas Ried, Judith Ross, Jay Giedd, Daniel Geschwind
doi: https://doi.org/10.1101/137752
Armin Raznahan
Developmental Neurogenomics Unit, National Institute of Mental Health, NIH, Bethesda, MD, USA
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  • For correspondence: raznahana@mail.nih.gov
Neelroop Parikshak
Neurogenetics Program, Department of Neurology and Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
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Vijayendran Chandran
Department of Pediatrics, School of Medicine, University of Florida, Gainesville, FL 32610-0296, USA
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Jonathan Blumenthal
Developmental Neurogenomics Unit, National Institute of Mental Health, NIH, Bethesda, MD, USA
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Liv Clasen
Developmental Neurogenomics Unit, National Institute of Mental Health, NIH, Bethesda, MD, USA
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Aaron Alexander-Bloch
Developmental Neurogenomics Unit, National Institute of Mental Health, NIH, Bethesda, MD, USA
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Andrew Zinn
McDermott Center for Human Growth and Development and Department of Internal Medicine, University of Texas Southwestern Medical School, TX, USA
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Danny Wangsa
Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
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Jasen Wise
Qiagen, Frederick, MD, USA
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Declan Murphy
Institute of Psychiatry, Psychology and Neuroscience, King’s College London, University of London, UK
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Patrick Bolton
Institute of Psychiatry, Psychology and Neuroscience, King’s College London, University of London, UK
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Thomas Ried
Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
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Judith Ross
Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA
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Jay Giedd
Department of Psychiatry, UC San Diego, La Jolla, CA, USA
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Daniel Geschwind
Neurogenetics Program, Department of Neurology and Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
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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, XXYY). For sex chromosomes, we demonstrate a pattern of obligate dosage sensitivity amongst evolutionarily preserved X-Y homologs, and update prevailing theoretical models for SCD compensation by detecting X-linked genes whose expression increases with decreasing X- and/or Y-chromosome dosage. We further show that SCD-sensitive sex chromosome genes regulate specific co-expression networks of SCD-sensitive autosomal genes with critical cellular functions and a demonstrable potential to mediate previously documented SCD effects on disease. Our findings detail wide-ranging effects of SCD on genome function with implications for human phenotypic variation.

SIGNIFICANCE STATEMENT Sex chromosome dosage (SCD) effects on human gene expression are central to the biology of sex differences and sex chromosome aneuploidy syndromes, but challenging to study given the co-segregation of SCD and gonadal status. We address this obstacle by systematically modelling SCD effects on genome wide expression data from a large and rare cohort of individuals with diverse SCDs (XO, XX, XXX, XXXX, XY, XXY, XYY, XXYY, XXXXY). Our findings update current models of sex chromosome biology by (i) pinpointing a core set of X- and Y-linked genes with “obligate” SCD sensitivity, (ii) discovering several non-canonical modes of X-chromosome dosage compensation, and (iii) dissecting complex regulatory effects of X-chromosome dosage on large autosomal gene networks with key roles in cellular functioning.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Posted November 16, 2017.
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Sex Chromosome Dosage Effects On Gene Expression In Humans
Armin Raznahan, Neelroop Parikshak, Vijayendran Chandran, Jonathan Blumenthal, Liv Clasen, Aaron Alexander-Bloch, Andrew Zinn, Danny Wangsa, Jasen Wise, Declan Murphy, Patrick Bolton, Thomas Ried, Judith Ross, Jay Giedd, Daniel Geschwind
bioRxiv 137752; doi: https://doi.org/10.1101/137752
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Sex Chromosome Dosage Effects On Gene Expression In Humans
Armin Raznahan, Neelroop Parikshak, Vijayendran Chandran, Jonathan Blumenthal, Liv Clasen, Aaron Alexander-Bloch, Andrew Zinn, Danny Wangsa, Jasen Wise, Declan Murphy, Patrick Bolton, Thomas Ried, Judith Ross, Jay Giedd, Daniel Geschwind
bioRxiv 137752; doi: https://doi.org/10.1101/137752

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