Imprinting, the X Chromosome, and the Male Brain

David Skuse
Behavioural Sciences Unit; Institute of Child Health

Genomic imprinting is the differential marking of maternally and paternally inherited alleles of specific genes or chromosome regions during gametogenesis. The imprint silences the allele from one parent. A number of imprinted genes that are expressed in the brain have been identified in humans. They control the actions of other genes, or regulate their products. Sexual dimorphism in the vertebrate brain is conventionally thought to be due to the epigenetic action of gonadal hormones. Sex differences could also reflect the actions of an imprinted X-linked locus. Until very recently no imprinted gene had been described on the X chromosome in humans.

We have found evidence for the existence of such a genetic locus in a study of Turner syndrome, a sporadic disorder of females, in which all or part of one X chromosome is deleted. We have now studied 119 females with Turner syndrome and a single X chromosome; in 86 the X was maternally derived (45,Xm) and in 33 it was of paternal origin (45,Xp). The 45,Xp group were significantly better adjusted, with superior verbal skills. Preliminary findings indicate the relatively better social adjustment in the 45,Xp than the 45,Xm females could be mediated by skills in processing socially salient perceptual cues, such as emotional expression in face and voice. These skills are relatively superior in normal 46,XmXp females than 46,XmY males.

Our observations imply the existence of a genetic locus for certain social skills, which is imprinted and is not expressed from the maternally derived X chromosome. Neuropsychological and molecular investigations of 15 females with partial deletions of the short arm of the paternally derived X chromosome indicate the putative imprinted locus escapes X-inactivation and probably lies on Xq or close to the centromere on Xp.

If the imprinted locus is expressed only from the X chromosome of paternal origin its existence could explain why 46,XY males (whose single X chromosome is maternal) are more vulnerable to developmental disorders of language and social cognition, such as autism, than 46,XX females. It is arguable males gained some evolutionary advantage from the imprinting of the maternally derived locus, at the expense of such vulnerability. The reasons why it should have evolved must remain speculative but males may, by virtue of being less socially responsive, achieve greater social dominance. It is thus plausible that the mechanism conferred both an advantage to males, which is passed by mothers to their sons, and an advantage to females (that of relatively greater social sensitivity) which is passed to daughters by their fathers.