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Sex-chromosome dosage effects on gene expression in humans
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Abstract
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.
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“There is also evidence that sex chromosome dosage sensitive genes on the X chromosome regulate specific networks of autosomal genes, indicating an organized regulatory gene network of genes on the X chromosome and autosomes.107,110”
From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [107]
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“There is evidence of a unique and tissue-specific genome-wide methylation and transcription landscape in TS extending to both the X chromosome and the autosomes.103-109”
From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [107]
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Metadata
- Authors
- Raznahan, A., Parikshak, N. N., Chandran, V., Blumenthal, J. D., Clasen, L. S., Alexander-Bloch, A. F., Zinn, A. R., Wangsa, D., Wise, J., Murphy, D. G. M., Bolton, P. F., Ried, T., Ross, J., Giedd, J. N., & Geschwind, D. H.
- Affiliations
- National Institutes of Health (US)
- University of California, Los Angeles (US)
- University of Florida (US)
- Developmental Neurogenomics Unit, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892;
- The University of Texas Southwestern Medical Center (US)
- Qiagen, Frederick, MD 21703;
- University of London (GB)
- Thomas Jefferson University (US)
- University of California San Diego (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-06-26
- Volume
- 115
- Issue
- 28
- Pages
- 7398-7403
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6048519
- OpenAlex
- W2949507537
- Cited by
- 179
- References
- 44
- Citations by year
- 2026: 7 · 2025: 22 · 2024: 22 · 2023: 30 · 2022: 27 · 2021: 23 · 2020: 25 · 2019: 17 · 2018: 6
- FWCI
- 10.86
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Research Portal (King's College London) (submittedVersion, cc-by-nc-nd)
- Funders
- HHS | NIH | National Institute of Mental Health (1ZIAMH002949-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Sexual Differentiation and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- sex chromosome dosage, sex chromosome aneuploidy, gene expression, dosage compensation, X-linked genes, gene co-expression network, ZFX, transcription factor binding sites, sex differences, XXY
- MeSH terms
- Aneuploidy, Animals, Female, Gene Expression Regulation, Humans, Male, Models, Genetic, Mice, Knockout, Gene Dosage, Chromosomes, Human, X, Chromosomes, Human, Y, Mice, Kruppel-Like Transcription Factors, Genome-Wide Association Study
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