A case (based upon an association with cerebral asymmetry) has been presented for a gene for psychosis within the Xq21.3/Yp region of homology that is specific to Homo sapiens. We tested this hypothesis using the pentanucleotide marker DXYS 156 that is located within this region. In 84 families affected by schizophrenia or schizo-affective disorder no tendency toward increased allele sharing amongst siblings was observed (χ2 = 0.002). We conclude either that this region does not include a gene predisposing to psychosis or that if it does, the relevant variation is epigenetic rather than sequence-based. With respect to the latter possibility we draw attention to the recent evolutionary history of the Xq21.3/Yp region. Genes within the region are in transition to protection from X inactivation and therefore may be epigenetically labile. © 2002 Wiley-Liss, Inc.