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Sex-chromosome dosage effects on gene expression in humans

Proceedings of the National Academy of Sciences - PNAS, 2018-07, Vol.115 (28), p.7398-7403 [Peer Reviewed Journal]

Volumes 1–89 and 106–115, copyright as a collective work only; author(s) retains copyright to individual articles ;Copyright National Academy of Sciences Jul 10, 2018 ;2018 ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.1802889115 ;PMID: 29946024

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Title:
Sex-chromosome dosage effects on gene expression in humans
Author: Raznahan, Armin ; Parikshak, Neelroop N. ; Chandran, Vijay ; Blumenthal, Jonathan D. ; Clasen, Liv S. ; Alexander-Bloch, Aaron F. ; Zinn, Andrew R. ; Wangsa, Danny ; Wise, Jasen ; Murphy, Declan G. M. ; Bolton, Patrick F. ; Ried, Thomas ; Ross, Judith ; Giedd, Jay N. ; Geschwind, Daniel H.
Subjects: Aneuploidy ; Animal models ; Animals ; Binding sites ; Biological Sciences ; Cellular communication ; Chromosomes ; Chromosomes, Human, X - genetics ; Chromosomes, Human, X - metabolism ; Chromosomes, Human, Y - genetics ; Chromosomes, Human, Y - metabolism ; Data processing ; Dosage ; Female ; Gender aspects ; Gender differences ; Gene Dosage ; Gene expression ; Gene Expression Regulation ; Genes ; Genome-Wide Association Study ; Genomes ; Genotype & phenotype ; Homology ; Humans ; Kruppel-Like Transcription Factors - genetics ; Kruppel-Like Transcription Factors - metabolism ; Male ; Mice ; Mice, Knockout ; Models, Genetic ; Phenotypic variations ; Sex ; Sex chromosomes ; Sex differences ; Transcription factors ; Y chromosomes
Is Part Of: Proceedings of the National Academy of Sciences - PNAS, 2018-07, Vol.115 (28), p.7398-7403
Description: 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 geneswith 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.
Publisher: United States: National Academy of Sciences
Language: English
Identifier: ISSN: 0027-8424
EISSN: 1091-6490
DOI: 10.1073/pnas.1802889115
PMID: 29946024
Source: Geneva Foundation Free Medical Journals at publisher websites
MEDLINE
PubMed Central

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Sex-chromosome dosage effects on gene expression in humans

Volumes 1–89 and 106–115, copyright as a collective work only; author(s) retains copyright to individual articles ;Copyright National Academy of Sciences Jul 10, 2018 ;2018 ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.1802889115 ;PMID: 29946024

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