Commentary on Annett, Yeo et al., Klar, Saugstad and Orr: cerebral asymmetry, language and psychosis--the case for a Homo sapiens-specific sex-linked gene for brain growth.

Annett, Yeo et al. and Klar have each proposed theories that relate the genetics of cerebral lateralization to predisposition to psychosis. These theories are considered in relation to the central paradox that psychosis is associated with a substantial biological disadvantage. Annett's heterozygote advantage hypothesis critically identified lateralization as a major determinant of ability, but it appears that what is inherited is degrees (as suggested by Yeo et al.) rather than (or as well as) direction of lateralization. Relative hand skill has been shown (Crow, T.J., Crow, L.R., Done, D.J., Leask, S.J., 1998. Relative hand skill predicts academic ability: global deficits at the point of hemispheric indecision. Neuropsychologia 36, 1275-1282.) to be a powerful predictor (interacting with sex) of academic ability but the greatest region of vulnerability (that includes reading disability and predisposition to psychosis) is close to the point of equal hand skill ('hemispheric indecision'). In contrast with Annett's single locus, Yeo's polygenic and Klar's strand-segregation hypotheses, each of which postulates an autosomal locus or loci, the hypothesis of a single gene for asymmetry located in a sex-specific region of homology on both X and Y chromosomes can account for sex differences, as observed in age of onset, and premorbid precursors of psychosis, as well as differences in the general population in relation to degrees of hand skill, verbal ability and cerebral asymmetry. The evolutionarily recent transposition to, and subsequent paracentric inversion in, the Y chromosome short arm of a 4-Mb block from Xq21.3 (the proximal long arm of the X) are candidates for speciation events in the lineage that led to Homo sapiens. A gene associated with a range of variation (that may be due to a high mutation site, or perhaps to epigenetic modification) on the Y that overlaps with, but differs quantitatively from, that on the X may explain the sex differences associated with psychosis, and may be relevant to its persistence. Such a gene could be the principal determinant in Man of the rate of brain growth, as suggested by Saugstad and by the findings of a recent study of adolescent onset psychosis (James, A., Crow, T.J., Renowden, S., Wardell, M., Smith, D.M., Anslow, P., in press. Is the course of brain development in schizophrenia delayed? Evidence from onsets in adolescence. Schizophr. Res.).