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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - May 14 2017
Externally publishedYes

Keywords

  • Dosage compensation
  • Sex chromosomes
  • Sex differences
  • Turner syndrome: Klinefelter syndrome: ZFX
  • X-chromosome
  • X-inactivation
  • Y-chromosome

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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