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It has been argued that cerebral asymmetry (the "torque") is the characteristic that defines the human brain and that morphological findings in psychosis are consistent with a deviation in this sex-dependent dimension of brain growth. Evidence from sex chromosome aneuploidies and an association within families between sex and handedness is consistent with the presence of a determinant of cerebral asymmetry (a possible correlate of language) on the X and the Y chromosomes. During hominid evolution a 3.5 Mb translocation occurred from the ancestral X chromosome to the Y chromosome, resulting in duplication of the Protocadherin11X gene, such that it is represented on the X and Y chromosomes in man, whereas there is a single X-linked gene in other mammals. We re-date the duplicative translocation to 6 million years ago, that is, close to the chimpanzee-hominid bifurcation. Sequence comparisons with the chimpanzee, bonobo, gorilla, and orangutan indicate that in contrast to earlier purifying selection there has been accelerated change in the Protocadherin11X ectodomain as well as the Protocadherin11Y sequence in the hominid lineage since the duplication. The evolutionary sequence of events together with the prior case for an X-Y homologous gene suggests that this gene-pair is a candidate for the evolution of hominid-specific characteristics including the sexual dimorphism of cerebral asymmetry, a putative correlate of language.

An increased incidence of psychiatric and structural brain abnormalities in individuals with Klinefelter syndrome (KS, 47 XXY) could be due to the presence of extra copies of X-Y homologous genes that escape X inactivation. Of particular interest are the two brain-expressed genes Protocadherin11XY (PCDH11XY) and the Synaptobrevin-like gene (SYBL1) which have been duplicated from the X chromosome to the Y chromosome to give X-Y homologous gene pairs that are specific to modern humans. We examined the DNA of KS individuals reported recently by DeLisi et al. 2005 and determined the parental origin of the X alleles, the degree of skewed X inactivation and investigated the CpG island methylation status of PCDH11XY and SYBL1 by bisulphite sequencing and quantification of methylated HpaII sites. We used a novel method for quantification of unmethylated CpGs with the restriction enzyme McrBC which cuts methylated but not unmethylated CpGs. The results showed that KS individuals have two methylated and one unmethylated SYBL1 allele whereas PCDH11XY is unmethylated and escapes X inactivation on the extra X chromosome. Overexpression of PCDH11XY in KS is probable and variable escape from inactivation of this Homo sapiens-specific gene could account for some abnormalities in KS. The origin of the parental alleles or their preferential X inactivation was not associated with psychotic symptoms., ((c) 2006 Wiley-Liss, Inc.)

Genes escaping X-inactivation are predicted to contribute to differences in gene dosage between the sexes and are the prime candidates for being involved in the phenotype observed in individuals with X chromosome aneuploidies. Of particular interest is ProtocadherinX (PCDH11X or PCDHX), a recently described gene expressed in brain. In humans, PCDH11X has a homologue on the Y chromosome and is predicted to escape from X-inactivation. Employing bisulphite sequencing analysis we found absence of CpG island methylation on both the active and the inactive X chromosomes, providing a strong indication that PCDH11X escapes inactivation in humans. Furthermore, a sexual dimorphism in levels of expression in brain tissue was observed by quantitative real-time PCR, with females presenting an up to 2-fold excess in the abundance of PCDH11X transcripts. We relate these findings to sexually dimorphic traits in the human brain. Interestingly, PCDH11X/Y gene pair is unique to Homo sapiens, since the X-linked gene was transposed to the Y chromosome after the human-chimpanzee lineages split. Although no differences in promoter methylation were found between humans and chimpanzees, evidence of an upregulation of PCDH11X in humans deserves further investigation.