Methylation of two Homo sapiens-specific X-Y homologous genes in Klinefelter's syndrome (XXY).

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.