TY - JOUR
T1 - Sex-chromosome dosage effects on gene expression in humans
AU - Raznahan, Armin
AU - Parikshak, Neelroop N.
AU - Chandran, Vijay
AU - Blumenthal, Jonathan D.
AU - Clasen, Liv S.
AU - Alexander-Bloch, Aaron F.
AU - Zinn, Andrew R.
AU - Wangsa, Danny
AU - Wise, Jasen
AU - Murphy, Declan G.M.
AU - Bolton, Patrick F.
AU - Ried, Thomas
AU - Ross, Judith
AU - Giedd, Jay N.
AU - Geschwind, Daniel H.
PY - 2018/7/10
Y1 - 2018/7/10
N2 - 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.
AB - 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.
KW - Klinefelter syndrome
KW - Sex chromosomes
KW - Sex differences
KW - Turner syndrome
KW - X-inactivation
UR - http://www.scopus.com/inward/record.url?scp=85049635443&partnerID=8YFLogxK
U2 - 10.1073/pnas.1802889115
DO - 10.1073/pnas.1802889115
M3 - Article
AN - SCOPUS:85049635443
SN - 0027-8424
VL - 115
SP - 7398
EP - 7403
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 28
ER -