Globally Divergent but Locally Convergent X- and Y-Chromosome Influences on Cortical Development

Cereb Cortex. 2016 Jan;26(1):70-9. doi: 10.1093/cercor/bhu174. Epub 2014 Aug 21.


Owing to their unique evolutionary history, modern mammalian X- and Y-chromosomes have highly divergent gene contents counterbalanced by regulatory features, which preferentially restrict expression of X- and Y-specific genes. These 2 characteristics make opposing predictions regarding the expected dissimilarity of X- vs. Y-chromosome influences on biological structure and function. Here, we quantify this dissimilarity using in vivo neuroimaging within a rare cohort of humans with diverse sex chromosome aneuploidies (SCAs). We show that X- and Y-chromosomes have opposing effects on overall brain size but exert highly convergent influences on local brain anatomy, which manifest across biologically distinct dimensions of the cerebral cortex. Large-scale online meta-analysis of functional neuroimaging data indicates that convergent sex chromosome dosage effects preferentially impact centers for social perception, communication, and decision-making. Thus, despite an almost complete lack of sequence homology, and opposing effects on overall brain size, X- and Y-chromosomes exert congruent effects on the proportional size of cortical systems involved in adaptive social functioning. These convergent X-Y effects (i) track the dosage of those few genes that are still shared by X- and Y-chromosomes, and (ii) may provide a biological substrate for the link between SCA and increased rates of psychopathology.

Keywords: aneuploidy; cortical thickness; pseudoautosomal; surface area.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Adult
  • Aneuploidy
  • Brain / anatomy & histology*
  • Child
  • Chromosomes, Human, X*
  • Chromosomes, Human, Y*
  • Evolution, Molecular
  • Female
  • Humans
  • Male
  • Young Adult