X-linked Genes and Mental Functioning

David Skuse
Behavioural and Brain Sciences Unit; Institute of Child Health

The X-chromosome has played a crucial role in the development of sexually selected characteristics for over 300 Myr, and during that time it has accumulated a disproportionate number of genes concerned with mental functions. Evidence is emerging, from studies of both humans and mice, for a relatively specific influence of X-linked genes on social cognition and emotional regulation as well as upon general intelligence. Mechanisms of sexual dimorphism due to X-linked genes can be distinct from - although possibly complementary to — the influence of sex steroids [1]. First, a small number of X-linked genes are expressed differently in male and female brains in mouse models [2]. Second, many human X-linked genes, outside the X-Y pairing pseudoautosomal regions, escape X-inactivation [3]. To date, little is known about the influence of that process on neural development and function but clues can be gleaned from the study of X-monosomic females who are haploinsufficient for expression of all non-inactivated genes relative to 46,XX females [4]. Finally, from studies of both X-monosomic humans (45,X) and mice (39,X) evidence is emerging of X-linked imprinted genes upon brain structure and function [5]. There have been several recent publications supporting these hypotheses, with provisional identification of candidate genes.


  1. Skuse D.H. X-linked genes and mental functioning. Hum. Mol. Genet., 2005 14: R27-R32.

  2. Arnold,A.P., and Burgoyne,P.S. Are XX and XY brain cells intrinsically different? Trends Endocrinol. Metab., 2004 15: 6-11.

  3. Carrel L., Willard H.F. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature, 2005 434:400-404.

  4. Skuse D.H., Morris J.S, and Dolan R.J. Functional dissociation of amygdala-modulated arousal and cognitive appraisal in Turner syndrome. Brain, 2005 28:2084-2096.

  5. Davies W., Isles A., Smith R., Karunadasa D., Burrmann D., Humby T., Ojarikre O., Biggin C., Skuse D., Burgoyne P., and Wilkinson L. Xlr3b is a new imprinted candidate for X-linked parent-of-origin effects on cognitive function in mice. Nat. Genet., 2005 37:625-629.